Cancer                         May 2003Dr Anshu P Gokarn
To understand oncology we shall discuss thefollowing …...I.     What is cancer ?II.    How cells continue dividing in an u...
PART I                    Basics of cancerDr Anshu P Gokarn
CANCER (Neoplasm) - What is it?         New Growth         Definition :       An abnormal mass of tissue, excessive    g...
Neoplasms – TheirCharacteristics      Enjoy a certain degree of autonomy      Parasitic in nature (regardless of       l...
Part IIDr Anshu P Gokarn
Dr Anshu P Gokarn
CELL DIVISION              Proliferating cells enter cell cycle which                           is :   G1 Phase           ...
Normal cell cycleInterphase – cell carries out it’s normal   activity but is resting from dividing   Also called growth p...
Dr Anshu P Gokarn
How cancer develops   Normal cell                       Transformation                             carcinogen   Step 1  ...
Progression of a normal         cell to cancer      Tumour      formation is a multi-step      process      Genes    mut...
Cell transformation from normal to cancer                                                                Dead cell        ...
Part III                       A. Molecular basis of cancer                       B. Carcinogens                       ...
Dr Anshu P Gokarn
How normal cell proliferation occurs :   Growth factor binds to specific receptor   Activates several signal transducing...
Some more factors…   Systems that regulate apoptosis    may be altered to cause cancer.   Cell adhesion proteins can als...
Carcinogenic genesGenes may be either : Effectors of transformation also known as   Oncogenes(eg. signal pathway molecule...
Some cell cycle regulators 1.   Integral membrane      tyrosine kinases ( erbB      and others ) 2.   growth factors ( sis...
Cellular genes controlling malignancyProtooncogenes –                            Tumor suppressorPositively influence     ...
Proto-oncogenes     Control cell proliferation and differentiation     Expressed in all subcellular compartments (nucleu...
Oncogenes   Mutated types of normal Wild Type Genes (proto-oncogenes)    promote cancer development   Act in a dominant ...
Oncogene mechanisms of activation    Changes to oncogenes confer advantage to affected cells    leading to transformation....
Oncogene mechanisms of action                                      Extracellular                                      grow...
Normal regulation of a gene that promotes cell                         division   Dr Anshu P Gokarn
Growth Factors   Mutations of genes encoding growth factors can render    them oncogenic (eg platelet derived growth fact...
Growth Factor Receptor    Mutations/Pathologic over-expression of growth     factor receptors have been detected in sever...
Cytoplasmic Oncogenes   Two important members          in     this    category are c-ras and c-abl   ras Gene Family inc...
Cytoplasmic Oncogenes   abl Gene altered in 90% of CML   Gene activated by chromosomal rearrangement with    another gen...
Nuclear Oncogenes   Bind to DNA elements in the promotors of specific    genes, enhancing (or occassionally inhibiting) g...
Tumor Suppressor Genes   Have normal, diverse functions to regulate cell growth    in a negative fashion (restrain neopla...
Tumor Suppressor Genes    Products of TSGs receive and process growth     inhibitory signals from their surroundings.   ...
Tumor Suppressor Genes   Mechanisms of inactivation     – Structural inactivation              Deletions              I...
The p53 gene…..  Tumor suppressor gene, present in most human   cancersFunction of p53 gene : To halt the cell in its cy...
The role of p53 in development of cancerIn normal cells, p53regulates cell growth bycontrolling cell proliferationand cell...
Growth Inhibitory Factors   Mutations in genes encoding soluble factors that bind    to cell membrane, transmit growth in...
DNA Repair Genes   “Humans literally swim in a sea    of environmental carcinogens.”   Cells can repair damage caused   ...
Apoptosis Regulating Genes   Apoptosis is programmed cell death   There are both proapoptotic genes (cell    death agoni...
Cancer: apoptosis    Apoptosis (programmed or     physiological cell death)     Process in which single cells are     rem...
bcl-2 family   Antiapoptosis         Proapoptosis (Death antagonists)   (Death agonists)          bcl-2              ba   ...
bcl-2 family  Antiapoptosis        Proapoptosis(Death antagonists)   (Death agonists)                           bax       ...
Telomerase Genes     With each cell division, shortening of specific tracts of      DNA at the ends of chromosomes occurs...
Telomerase Genes     In germ cells, telomere shortening is prevented by the      enzyme complex telomerase     Telomeras...
Molecular Basis of MultistepCarcinogenesis     No single gene can transform cells in                                     ...
Localization and function of cancer associated genesDr Anshu P Gokarn
How cancer develops (The Pathological changes)                       Stages of development of cancer   Dr Anshu P Gokarn
Cancer :Initiation to metastasis Dr Anshu P Gokarn
Dr Anshu P Gokarn
CarcinogenCarcinogen are chemicals that cause cancerCarcinogen may be:Environmental / Industrial   Benzene               ...
CarcinogensDrug induced      Alkylating agents       leukemia, bladder      DES                    liver,               ...
Dr Anshu P Gokarn
Risk Factors   Family history    Ex: breast cancer, colorectal cancer   Chromosomal abnormalities    ex : Down’s Syndrom...
Risk factors       DietEx : 1. Smoked / pickled food cancer stomach more          2. High fiber diet - less colorectal ca...
Risk Factors   Viral infection    Ex: cytomegalovirus : Kaposi’s sarcoma       Hepatitis B virus : liver cancer       HIV...
PART IVDr Anshu P Gokarn
Types of tumors      Benign tumor      Tumor is localized,cannot spread to other       sites,amenable to local surgical r...
Characteristics of benign and malignant tumors         Differentiation (lack of differentiation a hallmark of          ma...
Comparison  characteristics           Benign                 malignant                         Well differentiated.      L...
comparisoncharacteristics            benign              malignant4. Metastasis             Absent              Frequently...
Benign tumorDr Anshu P Gokarn
Malignant tumor (spreading)Dr Anshu P Gokarn
Structure of a tumor                                 Stroma                               (blood vessels,                 ...
Structure of a tumorDr Anshu P Gokarn
Dr Anshu P Gokarn
Nomenclature Benign    Fibrous       – fibroma    Cartilagenous – chondroma    Epithelial    -- microscopic / macroscop...
Nomenclature  Malignant     Arising from mesenchyme --- sarcomas                     Fibrous tissue --- fibrosarcoma     ...
Nomenclature                                           Melanoma in skin       Poorly differentiated carcinoma       Mixe...
Nomenclature  Malignant   Arising from white blood cells  Leukemias  Ex : Acute Lymphoblastic Leukemia   Arising from mo...
NomenclatureLung cancer-  Tumors arising from the  respiratory epithelium(bronchi,  bronchioles, alveoli)    Treatment De...
According to WHO classification……Four major cell types make 88% of all primary lungneoplasmsThey are:Squamous    / epider...
Differences between Small cell type and         Non- small cell type      Small cell type                    Non small cel...
Benign Neoplasms of the Lung          Represents less than 5 % of all primary tumors    Bronchial adenomas    Hamartomas...
Cancer of stomach    85% of stomach cancers are     adenocarcinomas    15% - lymphomas / leiomyosarcomas    Adenocarcin...
Tumors of the small intestine    Benign tumorsAdenomas – Islet cell adenoma (From the  pancreas)  Brunner’s gland adenoma...
Tumors of the small intestine Contd…..Malignant tumors Ampullary carcinomas – arise from biliary / pancreatic ducts Aden...
Tumors of the liver   Benign liver tumors Hepatocellular adenomas – In right lobe of the liver Focal nodular hyperplasi...
Breast cancer   Ductal adenocarcinoma - most common   Lobular carcinoma - the second malignant breast    tumour   Medul...
Solid tumors    Comprise a group of malignancies arising from the     various systems or organs with distinct behaviour  ...
Solid tumors Contd…..   Chemotherapy   systemic,   local or   regionalRegional chemotherapy - intra-tumoral,          ...
Dr Anshu P Gokarn
Various types of cancers       Haematological malignancies   Acute Lymphocytic Leukemia        Multiple    myeloma   A...
Various types of tumors                        Solid tumors   Adrenocortical carcinoma        Head and neck   Bronchoge...
Various types of cancers     Pediatric solid tumors     Wilm’s tumor     Ewing’s sarcoma     Embryonal      Rhabdomyos...
Dr Anshu P Gokarn
Metastases     Development of secondary implants discontinuous      with the primary tumor, possibly in remote areas.   ...
MetastasesOccurs by following routes1.      Hematogenous2.      Lymphatic3.      Seeding of cancer cells4.      Direct imp...
Metastases      Hematogenous   Favoured by sarcomas (carcinomas    are by no means shy about using it ! )   Liver and lu...
MetastasesLymphatic spread   More typical of carcinomas   Pattern of lymph node involvement depends on site    of involv...
MetastasesSeeding of cancers   Invasion of natural body cavities   Ex: carcinoma of colon can penetrate wall of the gut ...
   What happens to the patient ?Dr Anshu P Gokarn
Signs and symptoms   Pain   Loss of weight / muscle wasting   Loss of appetite/anaemia   Ulceration at the site   Ble...
Signs andsymptoms Dr Anshu P Gokarn
Diagnosis of cancer   History   Age   Sex   Family, personal history   Geographic location   Screening   Radiologic...
Diagnosis of cancerScreening   To detect possibility of cancer   Early detectionDisadvantage   Though not definitive re...
Diagnosis of cancerScreening tests widely usedIn women Pap staining --- cancer cervix Mammogram – breast cancerIn men P...
Diagnosis of cancer                   Molecular / Morphologic methodsTissue Biopsy Indicated almost all types of cancers...
Diagnosis of cancer Frozen section biopsy Advantages     determines nature of lesion     Helps evaluate the margins of e...
Diagnosis of cancerFine needle aspiration cytology Indicated  For readily palpable lesions of breast, thyroid,lymph   nod...
Diagnosis of cancer  Cytologic smears     Indicated in:      Carcinoma cervix, endometrial carcinoma,      bronchogenic c...
Diagnosis of cancer            Biochemical methods 1.    Biochemical assays Indications    To determine prognosis    To ...
Tumor Markers   Normal metabolic constituents / biochemical products    found in abnormal amount / at inappropriate time ...
Radioimmunoassay   Highly specific antibodies raised against tumor    antigens and labelled with flourescein stain /.   ...
Dr Anshu P Gokarn
Grading of cancer     Grading      Helps to estimate     The aggressiveness of the tumor     Level of malignancy     T...
Staging   Based on size of primary lesion   Extent of spread to regional lymph nodes   Presence/absence of lymph nodes...
Staging   Method    TNM classification    T = extent of primary tumor    N = regional lymph node involvement    M = Metas...
TNM classification    T0 ---- excised tumor    T1,T2,T3, – increase in size of     primary lesion    N0, N1,N2,N3—indic...
TNM Classification: ex: Breast cancer Primary Tumor    TX      primary tumor cannot be assessed    TO     No evidence of...
TNM Classification: ex: Breast cancer  Regional Lymph Nodes   NX       Regional lymph nodes cannot be assessed (ex:      ...
Investigations to define TNM classification    Tumor     Palpation     Inspection including endoscopy     Radiology    ...
Investigations to define TNM status  Metastases     Biochemical screening(ex : liver function tests)     Radionuclide sc...
PART - VDr Anshu P Gokarn
Cancer treatment      Types :         Radiotherapy         Chemotherapy         Immunotherapy         Endocrine Therap...
ChemotherapyThe treatment of cancer with drugs which killmalignant cells or modify their growth and leavehost cells unharm...
Purine            Pyrimidine        PALA-I nhibits pyrimidine                             synthesis             synthesis ...
Anti tumor drug action to the cycleDNA synthesis                     (G2) Premitotic         (S)                         i...
Anti tumor drug action to the cycle      Phase Non-Specific          Alkylating drugs          Nitrosoureas,          A...
Treatment Of CancerDRUG ACTION   Cycle Specific : only active cycling cells killed Toxicity is    generally expressed in ...
Alkylating agents          Nitrogen mustards           ex: Mechlorethanamine, cyclophosphamide,           Melphalan, Urac...
Alkylating agents Mechanism of action    Cells are destroyed by alkylation    Alkyl groups are added to constituents of ...
Alkylating agents - Cyclophosphamide    Mechanism of action similar but thrombocytopenia is less     severe while alopeci...
Alkylating agents (busulfan)     More effective on the myeloid series of cells     Causes depression of platelet and gra...
Nitrosureas   EX: carmustine, Lomustine, Streptozotocin   Alkylates the DNA and kills cells in all phases of cell    cyc...
AntimetabolitesII) Folic acid antagonistsEx: methotrexate    Purine analoguesEx : 6- mercaptopurine, Azathioprine    Pyr...
Antimetabolites Mechanism of action    Blocks the action of the metabolite by preventing the     combination of the metab...
Antimetabolites              Folic acid antagonists : Methotrexate         Folic acid                                     ...
Antimetabolites: (Purine antagonists)    Interferes with the synthesis and interconversion     of purines       6- Mercap...
Purine antagonists  Indications     Acute Leukemia mainly in children     Choriocarcinoma      Chronic Myelogenous leuk...
Pyrimidine antagonists(5- Fluorouracil)   Fluorinated analogue of pyrimidine   Binds to thymidylate synthetase to preven...
ProcarbazineMechanism of action   Undergoes metabolic activation to generate the cytotoxic    reactants which methylate D...
Hydroxyurea  Mechanism of action      Interferes with the activity of ribonucleoside       diphosphate reductase .      ...
Gemcitabine : newer antimetabolite.   Mechanism of action   Weak inhibitor of DNA polymerase   Potent inhibitor of ribo...
Radioactive isotopes   Radiations emitted by these isotopes produce    ionization in the cells thereby disrupting the cel...
AntibioticsMechanism of action   Blocking DNA dependent RNA synthesis                     (actinomycin D, Rubidomycin)  ...
Antibiotics (contd…..)   Bleomycin ---- epidermoid carcinoma of skin, respiratory                                 passage...
Antimitotic plant products (Vinca alkaloids)Act by:Inhibiting mitosisBinds to tubulin and prevents the formation of mito...
Antimitotic plant products     (Paclitaxel)Mechanism of actionBinds to microtubules and inhibits their depolymerization(mo...
DocetaxelMechanism of ActionLike paclitaxel, it prevents the breakdown of mitotic spindleClinical trials indicate its abou...
Natural Products (Camptothecins)Irinotecan, Topotecan   Combines with the Topo-isomerase I and inhibits its function   A...
Natural Products           (Epipodophyllotoxins)Etoposide   Form a ternary complex with Topoisomerase II and DNA   Resul...
Hormones and Hormone antagonistsMechanism of action   Act in a different manner from the cytotoxic drugs and can be    co...
Hormone and hormone antagonists   Selective lysis of leukemic lymphocytesEx : in ALL (Acute Lymphocytic Leukemia)   Inhi...
Hormones and hormone antagonistsTamoxifen   Nonsteroidal oestrogen it competes with the circulating    estrogen for bindi...
Hormone and hormone antagonistsSteroids  Direct lympholytic effect  Suppress mitosis in lymphocytes (due to this effect u...
L- Asparginase  Acts by depleting asparginase from the host  and denying the malignant cells the metabolite  Indications  ...
Newer agents : Carboplatin   Mechanism of action is similar to cisplatin.However:   Carboplatin is less reactive than ci...
Newer agents : Oxaliplatin   Unlike carboplatin and cisplatin it has a high volume of    distribution.   Unlike cisplati...
Newer agents : Nedaplatin    Nedaplatin – A recent addition to platinum compounds.    Along with 5FU effective in squamo...
Drugs commonly used to treat major types of         cancer: Hematological Malignancy    Leukemia: (ALL)Cancer Type/       ...
Drugs commonly used to treat major types of           cancer: Hematological MalignancyLeukemia: (Acute granulocytic Leukem...
Drugs commonly used to treat major types of        cancer: Hematological Malignancy      Leukemia: AMLCancer Type/        ...
Drugs commonly used to treat major types of             cancer: Leukemia and Multiplemyeloma               Leukemia : CLLC...
Drugs commonly used to treat major types   of                      cancer:   Hematological malignancy             Multiple...
Drugs commonly used to treat major types of           cancer: Hematological MalignancyCancer Type/                 Drugs u...
Drugs commonly used to treat major types of         cancer: Hematological MalignancyCancer Type/                Drugs used...
Drugs commonly used in Pediatric solid tumors, brain                   tumors, germ cell tumors and sarcomasCancer Type/ I...
Drugs commonly used to treat major types of                          cancerCancer Type/                Drugs used         ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/                  Drugs used ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/               Drugs used    ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/ Incidence      Drugs used   ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/               Drugs used    ...
Drugs commonly used to treat major types of cancers                        Solid tumorsCancer Type/ Incidence      Drugs u...
Nonmelanoma skin cancer:Incidence : 12.2% of all cancers  Cancer Type/ Incidence       Drugs used  1. Basal cell carcinoma...
Likely therapies in future for malignant melanoma     Melanomas often express cell-surface antigens which may      be rec...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/ Incidence     Drugs used    ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/               Drugs used    ...
Drugs commonly used to treat major types of                  cancer: solid tumorsCancer Type/        Drugs used           ...
Drugs commonly used to treat major types of                  cancer: solid tumors  Cancer Type/          Drugs used       ...
Drugs commonly used to treat major types of                  cancer: solid tumors     Cancer Type/         Drugs used     ...
 PART           - VIDr Anshu P Gokarn
Newer approaches to cancer Therapy     Measuring initial tumor growth factors or oncogenes helps      in: 1.   Selecting ...
Newer approaches to cancer therapy In Cytotoxic treatment    Most of the drugs interfere with DNA metabolism    Addition...
Advances in Cytotoxic Drug TreatmentDr Anshu P Gokarn
Newer approaches to cancer therapy    1. Topoisomerase inhibitors          What are Topoisomerases ?    Nuclear enzymes ...
Type II Topoisomerase inhibitors Act mainly by inhibiting Topoisomerase II     Drug in this class:    Epipodophyllotoxins...
Topoisomerase Type I inhibitors   Less widely available   Ex: Camptothecin   Unaceeptable gastroinrestinal toxicity obs...
Newer approaches to cancer therapy 2. New Antimetabolites: Gemcitabine    Anti-Folates like methotreaxte have been the mo...
Newer approaches to cancer therapy  3. Modulation of drug resistance     Normally mdr1 gene encodes a glycoprotein which ...
Dr Anshu P Gokarn
New Drug Targets   Inhibitors of Signal Transduction and second messenger    systems   Angiogenesis   Receptor targetin...
Molecular Therapy………   Drugs developed using past paradigms attack both    cancerous and healthy cells, often causing dev...
Research Avenues for Molecular Targeting                     Influence the cancer cell to                     re-regulate ...
Application of gene therapy to cancer   Strategy: to introduce novel genes into cancer cells to    convert them into "for...
Gene Therapy (contd……)   Novel non-viral gene delivery lipid vehicles to deliver genes to    cancer cells are also being ...
Gene Therapy (contd…..)Techniques that are possible   1. Immunomodulation by using tumor infiltrating    lymphocytes    T...
Oligonucleotides    Involves down regulation of expression of important     genes such as oncogenes which may be overexpr...
Antisense approach: Principle   Translation is inhibited by    degradation of mRNA by    RNAase H              OR   Inhi...
Antisense approach   Normal flow of genetic    information where a gene    is transcripted into an    mRNA and translated...
Inhibitors of signal transduction and second               messenger systems                          Mutation (ras)   Ove...
Inhibitors of signal transduction and    second messenger systems      Activation of Tyrosine kinases has a transforming ...
What is a telomere    The DNA molecule of a typical chromosome contains a linear array of genes     (encoding proteins an...
Telomerase Inhibitors   Telomerase is the enzyme that replenishes    shortened telomeres and allows cells to reproduce in...
Telomerase Inhibitors   B.-S. Herbert, A. E. Pitts, et al. at the    University of Texas Southwestern    Medical Center h...
Receptor Targeting     External domain of the receptor – the new target     Recombinant DNA technology used     Either ...
Angiogenesis inhibitorsTumor invasiveness and metastasisrequire neovascularization (formation ofnew blood vessels)Tumor  ...
Angiogenesis inhibitors…..   Like:  Suramin analogues  Antibodies to   proliferating   endothelium  Angioinhibins  Col...
Angiogenesis inhibitors in clinical                 trials   Thalidomide and TNP-470, a synthetic analogue of fumagillin ...
Common targets for angiogenesis inhibitorsAttack Points for angiogenesis inhibitors include specific cell              sur...
Newer developments in monoclonal Antibodies    Two step strategy used    Initially antibody allowed to     localize itse...
Dr Anshu P Gokarn
Monoclonal antibodies   Rituximab and Trastuzumab are monoclonal antibodies    approved by FDA   Rituxan – for treatment...
ADEPT MechanismADEPT – Antibody dependent enzyme prodrug therapyToxin is generated by1 enzyme attached to the antibody fro...
Immunotherapy   Antibodies designed specially to recognize    a specific cancer   When coupled with natural toxins, drug...
Immunotherapy against tumor antigens or                 mutant oncogenes   Endogenous antigens presented by HLA class I  ...
Dr Anshu P Gokarn
Vaccines in cancer   Dendritic cells are potent initiators    of anti-tumor responses.   They involve the activation of ...
Smart drugs searching out problem cells   Specially designed toxins are linked with agents           that bind    selecti...
Neopharm ,FDA and Nationalcancer institute have developedtwo highly selective tumor targetingagents1.Tumor targeted cytoto...
IL-13 targets receptors in thekidney , brain, berast, head andneck and Kaposi’s sarcomaSS1 seeks out and attaches tosites ...
Rasburicase – approved by the FDAAnticancer therapy leads to tumor lysisLeads to accumalation of uric acid in plasmaLeads ...
Biological Response Modifiers     They are antibodies, cytokines and other immune system      substances that can be prod...
Interferons    They are cytokines which occur naturally in the body.    Three major types:1.   Interferon alpha2.   Inte...
Biological Response Modifierslevamisole   Acts by modulating cell mediated immune response   Restores/ augments cutaneou...
Interleukins   Interleukins are also cytokines produced naturally in the    body   IL-2 (Aldesleukin) is the most widely...
Colony Stimulating Factors(CSF)   Also called as Haematopoeitic growth factors   They encourage the bone marrow stem cel...
Imatinib Mesylate   Inhibits specific protein tyrosinekinase which is targeted to plateletderived growth factor.   It sp...
What are protein Kinases?        Enzymes that transfer phosphate from adenosine         triphosphate to specific amino ac...
Disrupted regulation of oncogene : bcrabl gene              responsible for CML   Dr Anshu P Gokarn
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
Training on Cancer for Medical Representatives of Pharma Company
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  • Four simplified steps for normal cell growth and differentiation:)An extracellular growth factor binds to a specific receptor on the plasma membrane )The growth factor receptor is transiently activated, leading to a cascade of signaling cellular events, many of which involve signal-transducing proteins on the plasma membrane )The signal/message is transmitted from the plasma membrane via the cytosol to the nucleus via secondary messengers )Nuclear regulatory machinery is induced/activated to initiate cell replication and transcription.
  • s
  • Training on Cancer for Medical Representatives of Pharma Company

    1. 1. Cancer May 2003Dr Anshu P Gokarn
    2. 2. To understand oncology we shall discuss thefollowing …...I. What is cancer ?II. How cells continue dividing in an uncontrolled manner in cancer. Normal cell cycle Abnormalities associated with normal processIII. Factors that control cancer Natural factors Risk factors CarcinogensIV. Types of cancersV. Treatment available for cancerVI. Latest Treatment availableDr Anshu P Gokarn
    3. 3. PART I Basics of cancerDr Anshu P Gokarn
    4. 4. CANCER (Neoplasm) - What is it?  New Growth  Definition : An abnormal mass of tissue, excessive growth, uncoordinated with normal tissue and persistent growth even after the cessation of evoking stimuli.Fundamental to origin of all Cancers is :“Loss of responsiveness to normal growth control mechanisms” Dr Anshu P Gokarn
    5. 5. Neoplasms – TheirCharacteristics  Enjoy a certain degree of autonomy  Parasitic in nature (regardless of local environment or host nutritional status)  Require endocrine support of host  Dependent on host for blood supply and nutrition Dr Anshu P Gokarn
    6. 6. Part IIDr Anshu P Gokarn
    7. 7. Dr Anshu P Gokarn
    8. 8. CELL DIVISION Proliferating cells enter cell cycle which is : G1 Phase Pre nucleic acid synthesis interval S1 Phase Synthesis of DNA occurs G2 Phase Post synthetic interval M Phase Mitosis occurs, two G1 cells produced; which either directly enter next cycle or pass into non proliferating phase G0 G1 G2 Non-proliferating cells; a fraction of these are colonogenic – may remain quiet for G 0 Phase some time but can be recruited in cell cycle if stimulated later Dr Anshu P Gokarn
    9. 9. Normal cell cycleInterphase – cell carries out it’s normal activity but is resting from dividing Also called growth phase or metabolic phase Prepares for next cell division Is divided into three stagesG1 phase - (cells metabolically active, synthesize proteins rapidly, grow vigorously) Lasts from minutes to hours or even yearsG0 phase - Cells cease to divide permanently.S Phase - DNA replication occurs . Two future cells will receive identical copies of the genetic materialG2 phase - Final phase. Enzymes and other proteins needed for division are synthesized and moved to their proper sitesM phase - Mitosis –Prophase, metaphase, anaphase and telophase occurs Cytokinesis – division of cytoplasm – Dr Anshu P Gokarn
    10. 10. Dr Anshu P Gokarn
    11. 11. How cancer develops Normal cell Transformation carcinogen Step 1 Initiation (change in cellular genetic material primes the cell to become cancerous) Step II Promotion (cell becomes cancerous) Normal feedback mechanisms mediating cell growth are defective. Faulty cells contact-signaling process (transduction defect) Dr Anshu P Gokarn
    12. 12. Progression of a normal cell to cancer Tumour formation is a multi-step process Genes mutation occursGenetic changes confer a selective growth or survival advantage No response to normal regulatory signalsGrow in an uncontrolled manner, resulting in malignant disease Dr Anshu P Gokarn
    13. 13. Cell transformation from normal to cancer Dead cell apoptosis DNA repair Mutation Repair absent or faulty Cancer cell Dr Anshu P Gokarn
    14. 14. Part III  A. Molecular basis of cancer  B. Carcinogens  C. The risk factors involvedDr Anshu P Gokarn
    15. 15. Dr Anshu P Gokarn
    16. 16. How normal cell proliferation occurs : Growth factor binds to specific receptor Activates several signal transducing proteins on the inner surface of the plasma membrane Signal reaches nucleus via 2nd messengers Activation of Nuclear Regulatory Factors initiate DNA transcription (via transcription factors). Cell enters cell division. Alterations/Mutations in any of these steps cause Cancer Dr Anshu P Gokarn
    17. 17. Some more factors… Systems that regulate apoptosis may be altered to cause cancer. Cell adhesion proteins can also undergo mutation and contribute to metastasis. Several genes altered during conversion of a cell from normal to malignant. Dr Anshu P Gokarn
    18. 18. Carcinogenic genesGenes may be either : Effectors of transformation also known as Oncogenes(eg. signal pathway molecules) or Facilitators of transformation – also known as tumor suppressor genes They cause increase occurrence of mutations in other genes e.g. p53 gene DNA repair genes Apoptosis genes Telomerase genesDr Anshu P Gokarn
    19. 19. Some cell cycle regulators 1. Integral membrane tyrosine kinases ( erbB and others ) 2. growth factors ( sis and hst ) 3. ras and src gene families 4. Membrane associated tyrosine kinases, serine- threonine kinases ( mos and raf ) 5. nuclear oncoproteinsThese proteins are expressed in most cells, but when a mutation occurs, this expression is abnormal and cancer can arise. Dr Anshu P Gokarn
    20. 20. Cellular genes controlling malignancyProtooncogenes – Tumor suppressorPositively influence genes – negatively influence cellgrowth growth Mutation Oncogenes cancer Dr Anshu P Gokarn
    21. 21. Proto-oncogenes  Control cell proliferation and differentiation  Expressed in all subcellular compartments (nucleus, cytoplasm, cell surface)  Act as protein kinases, growth factors, growth factor receptors, or membrane associated signal transducers  Mutations in proto-oncogenes alter the normal structure and/or expression patternDr Anshu P Gokarn
    22. 22. Oncogenes Mutated types of normal Wild Type Genes (proto-oncogenes) promote cancer development Act in a dominant fashion – a mutation is needed in only a single allele for activation – also referred to as gain of function mutations For oncogenes to be tumorigenic, they must be activated in some way. Three known mechanisms of transforming oncogene activation: translocations amplification point mutations Dr Anshu P Gokarn
    23. 23. Oncogene mechanisms of activation Changes to oncogenes confer advantage to affected cells leading to transformation. Categorized into two groups Changes to the structure of an oncogene results in an abnormal gene product (protein) with abnormal function Changes to the regulation of gene expression which results in excessive or inappropriate production of the structurally normal growth-promoting protein Dr Anshu P Gokarn
    24. 24. Oncogene mechanisms of action Extracellular growth factor Growth factor receptor Signal transduced and transmitted via cytosol to the nucleusCell replication and transcription Dr Anshu P Gokarn
    25. 25. Normal regulation of a gene that promotes cell division Dr Anshu P Gokarn
    26. 26. Growth Factors Mutations of genes encoding growth factors can render them oncogenic (eg platelet derived growth factor). Tumors possessing receptors for PDGF are subject to autocrine stimulation Growth factor gene itself may not be altered / mutated but the products of other oncogenes such as ras cause over-expression of growth-factor genes. Large number of growth-factors eg. TGF-α produced. TGF-α binds to endothelial growth factor to induce cell proliferation Whole process occurs outside the cell Dr Anshu P Gokarn
    27. 27. Growth Factor Receptor  Mutations/Pathologic over-expression of growth factor receptors have been detected in several tumors.  Over-expression : eg. EGF receptor family  c-erb B-1 is over expressed in squamous cell carcinoma of lungs  c-erb B-2 in breast cancers, adino-carcinoma of lungs, ovaries and salivary glands.  HER-2 and PDGF are amplified in human cancer cells. These are the other types which can be over- expressed.Dr Anshu P Gokarn
    28. 28. Cytoplasmic Oncogenes Two important members in this category are c-ras and c-abl ras Gene Family includes k-ras, h-ras and m-ras Mutations in these three members of the ras gene family – quite common Structure of ras eg. k-ras mutation prevalent in pancreatic cancer & colonic cancer. Mutation in all three types in thyroid cancerDr Anshu P Gokarn
    29. 29. Cytoplasmic Oncogenes abl Gene altered in 90% of CML Gene activated by chromosomal rearrangement with another gene called bcr resultng in expression of hybrid bcrabl protein eg. Philadelphia Chromosome (reciprocal translocation of long arm f chromosome 22 occurs) abl possesses tyrosine kinase activity which is activated in the bcrabl fusion protein.Dr Anshu P Gokarn
    30. 30. Nuclear Oncogenes Bind to DNA elements in the promotors of specific genes, enhancing (or occassionally inhibiting) gene expression Eg. eos, jun, erb A, mic Mic gene family consists of c-mic, N-mic and L-mic – c-mic plays a part in regulating apoptosis Alterations in mic and bcl-2 (other oncogene indicated in apoptosis) affects the balance between cell division an death Combined with aberrant growth stimuli, it may result in growth of malignant cells.Dr Anshu P Gokarn
    31. 31. Tumor Suppressor Genes Have normal, diverse functions to regulate cell growth in a negative fashion (restrain neoplastic growth; act as cellular “brakes”) Act in a recessive fashion – physical or functional loss of both alleles frees the cell from constraints imposed by their protein products – also referred to as loss of function mutations Signal transduction regulation--NF1 Transcription regulation--Rb and p53 Cell surface/cell matrix molecules--NF2, APC, and DCC – regulate cell adhesionDr Anshu P Gokarn
    32. 32. Tumor Suppressor Genes Products of TSGs receive and process growth inhibitory signals from their surroundings. The result is the same as for unchecked stimulation of cell growth: neoplastic growth deregulation Some products are responsible for normal cell morphology, cell-cell interactions, and cell-matrix interactions Dr Anshu P Gokarn
    33. 33. Tumor Suppressor Genes Mechanisms of inactivation – Structural inactivation  Deletions  Insertions  Inactivating point mutations – Functional inactivation (analogous to regulatory alterations as seen in oncogenes: normal gene, abnormal function eg Rb) In one clonal population it is possible to find a combination of two mechanisms of inactivation, a different one for each alleleDr Anshu P Gokarn
    34. 34. The p53 gene….. Tumor suppressor gene, present in most human cancersFunction of p53 gene : To halt the cell in its cycle before DNA replication of the chromosomal DNA has been damaged. This pause allows time for DNA repair, preventing mutations from becoming permanent.Uses Ex: to assess cancer origin, to define cancer cell immuno-phenotype, to detect cellular products( hormones, cytokines, etc. ), to predict tumor behavior with specific markers. Dr Anshu P Gokarn
    35. 35. The role of p53 in development of cancerIn normal cells, p53regulates cell growth bycontrolling cell proliferationand cell death.Mutations in p53 lead toloss of growth suppressivefunctions, leading touncontrolled growth. Dr Anshu P Gokarn
    36. 36. Growth Inhibitory Factors Mutations in genes encoding soluble factors that bind to cell membrane, transmit growth inhibitory signals, favour uncontrolled cell growth eg. Breast cancer – 1 (brca-1 protein) Increased mutations of brca-1 have increased risk of breast and ovarian cancersDr Anshu P Gokarn
    37. 37. DNA Repair Genes “Humans literally swim in a sea of environmental carcinogens.” Cells can repair damage caused by ionizing radiation, sunlight, dietary/chemical carcinogens and replication errors which occur spontaneously in dividing cells. If errors accumulate, cells are at risk of neoplastic transformation Dr Anshu P Gokarn
    38. 38. Apoptosis Regulating Genes Apoptosis is programmed cell death There are both proapoptotic genes (cell death agonists such as bax, bcl-xS, bad, bid) and antiapoptotic genes (cell death antagonists such as bcl-2, bcl-xL) The prototypic gene in this category is bcl- 2Dr Anshu P Gokarn
    39. 39. Cancer: apoptosis Apoptosis (programmed or physiological cell death) Process in which single cells are removed from midst of living tissue without disturbing architecture or function or eliciting an inflammatory response. Normal inbuilt response is present in its genetic material. Deregulated apoptosis : pathogenesis of neoplasms Apoptosis : End result of chemotherapeutic drug action Dr Anshu P Gokarn
    40. 40. bcl-2 family Antiapoptosis Proapoptosis (Death antagonists) (Death agonists) bcl-2 ba x Cell accumulation ApoptosisDr Anshu P Gokarn
    41. 41. bcl-2 family Antiapoptosis Proapoptosis(Death antagonists) (Death agonists) bax bcl-2 bcl-xS bcl-xL bad bidDr Anshu P Gokarn
    42. 42. Telomerase Genes  With each cell division, shortening of specific tracts of DNA at the ends of chromosomes occurs  These tracts are called telomeres  Telomeres are composed of repetitive DNA sequences  Once shortened beyond a certain point, cells die  Telomere shortening, therefore, acts as a clock that counts cell divisionsDr Anshu P Gokarn
    43. 43. Telomerase Genes  In germ cells, telomere shortening is prevented by the enzyme complex telomerase  Telomerase adds back any repetitive telomere sequences lost after a cell division  Most somatic cells lack telomerase  For a cell to divide indefinitely, it must prevent telomere shortening  Tumor cells do this by activating telomerase Dr Anshu P Gokarn
    44. 44. Molecular Basis of MultistepCarcinogenesis  No single gene can transform cells in Normal cell proliferation vitro  Every human cancer analyzed reveals multiple genetic alterations involving activation of several oncogenes and loss of two or more tumor suppressor genes.  The specific temporal order of mutations determines the propensity for tumor development Dr Anshu P Gokarn Aggressive cancer cell
    45. 45. Localization and function of cancer associated genesDr Anshu P Gokarn
    46. 46. How cancer develops (The Pathological changes) Stages of development of cancer Dr Anshu P Gokarn
    47. 47. Cancer :Initiation to metastasis Dr Anshu P Gokarn
    48. 48. Dr Anshu P Gokarn
    49. 49. CarcinogenCarcinogen are chemicals that cause cancerCarcinogen may be:Environmental / Industrial Benzene leukemia Vinyl chloride liver Asbestos lung, pluera Arsenic lungAssociated with lifestyle Alcohol esophagus, mouth and throat Betel nuts mouth, throat Tobacco head, neck, lung, esophagus, bladder Dr Anshu P Gokarn
    50. 50. CarcinogensDrug induced Alkylating agents leukemia, bladder DES liver, vagina (if exposed before birth) Oxymetholone liver Susceptible cell + carcinogen cancerous cellDr Anshu P Gokarn
    51. 51. Dr Anshu P Gokarn
    52. 52. Risk Factors Family history Ex: breast cancer, colorectal cancer Chromosomal abnormalities ex : Down’s Syndrome with acute leukemia Environmental factors Ex : UV radiation / sunlight --- skin cancer ionizing radiation / atomic bomb explosion ---- leukemia smoking ---- lung cancerDr Anshu P Gokarn
    53. 53. Risk factors DietEx : 1. Smoked / pickled food cancer stomach more 2. High fiber diet - less colorectal cancer AlcoholEx: liver cancer Occupational hazardEx :asbestos with lung cancer Geographic location :Ex : Japanese : colon / breast cancer - less stomach cancer ---- - more Dr Anshu P Gokarn
    54. 54. Risk Factors Viral infection Ex: cytomegalovirus : Kaposi’s sarcoma Hepatitis B virus : liver cancer HIV virus : lymphomasParasitic infectionEx: schistosoma : bladder cancerImmune statusEx : immunosuprressants / immunosuppressed status More chances Dr Anshu P Gokarn
    55. 55. PART IVDr Anshu P Gokarn
    56. 56. Types of tumors  Benign tumor Tumor is localized,cannot spread to other sites,amenable to local surgical removal,patients life is not at danger, capsule present  Malignant tumor c/a cancer Adhere to any part that they seize in an obstinate manner Lesion can invade / destroy surrounding areas, can metastasize, patient’s life is at risk Capsule is absentDr Anshu P Gokarn
    57. 57. Characteristics of benign and malignant tumors  Differentiation (lack of differentiation a hallmark of malignant cells)  Rate of growth ( in malignant tumors correlates with their level of differentiation)  Local invasion (most benign tumors have a fibrous capsule around them which separates them from the host tissue)  metastasis Dr Anshu P Gokarn
    58. 58. Comparison characteristics Benign malignant Well differentiated. Lack of differentiation1.Differentiation Structure typical of Structure atypical tissue of origin Progressive / slow Erratic/ slow to rapid2. Rate of growth Standstill / regression Cohesive and expansile; Locally invasive; well demarcated;no invades surrounding3. Local invasion infiltration into tissue surrounding Dr Anshu P Gokarn
    59. 59. comparisoncharacteristics benign malignant4. Metastasis Absent Frequently present5. Bleeding Absent present6. survival No threat to life Serious threat to life Dr Anshu P Gokarn
    60. 60. Benign tumorDr Anshu P Gokarn
    61. 61. Malignant tumor (spreading)Dr Anshu P Gokarn
    62. 62. Structure of a tumor Stroma (blood vessels, connective tissue) Parenchyma (Decides the biological behaviour)Dr Anshu P Gokarn
    63. 63. Structure of a tumorDr Anshu P Gokarn
    64. 64. Dr Anshu P Gokarn
    65. 65. Nomenclature Benign  Fibrous – fibroma  Cartilagenous – chondroma  Epithelial -- microscopic / macroscopic appearance/ cell of origin Ex: Adenoma -- generally displays glandular appearance Papilloma – located on the surface finger like processes Polyp --- mass projecting above mucosal surface ex: gut Cystadenoma -- hollow cystic massesDr Anshu P Gokarn
    66. 66. Nomenclature Malignant  Arising from mesenchyme --- sarcomas Fibrous tissue --- fibrosarcoma Chondrocytes --- chondrosarcoma  Arising from epithelium ----carcinomas squamous cell carcinoma adenocarcinomaDr Anshu P Gokarn
    67. 67. Nomenclature Melanoma in skin  Poorly differentiated carcinoma  Mixed Tumors ex: salivary glands Exceptions to the rule  Lymphoma  Melanoma  Mesothelioma malignant  seminomaDr Anshu P Gokarn
    68. 68. Nomenclature Malignant  Arising from white blood cells Leukemias Ex : Acute Lymphoblastic Leukemia  Arising from monocytes, macrophages Lymphomas Ex : Hodgkin’s diseaseDr Anshu P Gokarn
    69. 69. NomenclatureLung cancer- Tumors arising from the respiratory epithelium(bronchi, bronchioles, alveoli) Treatment Decisions Of Lung Cancers Depends On The Histological Appearance of the tumors Dr Anshu P Gokarn
    70. 70. According to WHO classification……Four major cell types make 88% of all primary lungneoplasmsThey are:Squamous / epidermoid carcinomaSmall cell also called as oat cell carcinomaAdenocarcinoma (including bronchioalveolar)Large cell (large cell anaplastic) carcinoma The remainder include undifferentiated carcinomas, carcinoids, bronchial gland tumors (including adenoid cystic and mucoepidermoid carcinomas) and the rarer tumors.Dr Anshu P Gokarn
    71. 71. Differences between Small cell type and Non- small cell type Small cell type Non small cell type  (scant cytoplasm,small  (Abundant cytoplasm, hyperchromatic nuclei, pleomorphic nuclei, indistinct nucleoli, diffuse prominent nucleoli, sheets of cells glandular/squamous architecture)  At presentation they have spread so much that surgery  Localized not helpful.  Managed primarily by  Amenable to surgery and chemotherapy and/or radiotherapy but not radiotherapy. chemotherapy. Dr Anshu P Gokarn
    72. 72. Benign Neoplasms of the Lung Represents less than 5 % of all primary tumors  Bronchial adenomas  Hamartomas  Chondromas  Fibromas  Lipomas  Haemangiomas etc.Dr Anshu P Gokarn
    73. 73. Cancer of stomach 85% of stomach cancers are adenocarcinomas 15% - lymphomas / leiomyosarcomas Adenocarcinomas --- Diffuse type (individual cells infiltrate and thicken the stomach Intestinal type (neoplastic cells form gland like tubular structure) Dr Anshu P Gokarn
    74. 74. Tumors of the small intestine Benign tumorsAdenomas – Islet cell adenoma (From the pancreas) Brunner’s gland adenoma( from the duodenal mucosal glands)Polypoid adenomasLeiomyomas – from smooth muscle of the intestineLipomas – In the distal ileum and at ileocecal valveAngiomas – They cause intestinal bleeding Dr Anshu P Gokarn
    75. 75. Tumors of the small intestine Contd…..Malignant tumors Ampullary carcinomas – arise from biliary / pancreatic ducts Adenocarcinomas – Most common carcinoma of small bowel (50% incidence) Lymphomas – may be primary / secondary  Primary -ex : Non-Hodgkin’s Lymphoma, Involves the ileum, duodenum and jejunum in decreasing order of frequency.  Secondary lymphomas – involvement of the intestine by a lymphoid malignancy extending from involved retroperitoneal or mesenteric lymph nodes Carcinoid Tumors – From distal duodenum to the ascending colon Leiomyosarcomas Dr Anshu P Gokarn
    76. 76. Tumors of the liver Benign liver tumors Hepatocellular adenomas – In right lobe of the liver Focal nodular hyperplasia- predominantly in women Solid tumor in the right lobe with a fibrous core Hemangioma Malignant tumors Hepatocellular carcinomas Dr Anshu P Gokarn
    77. 77. Breast cancer Ductal adenocarcinoma - most common Lobular carcinoma - the second malignant breast tumour Medullary carcinoma is rare Hyperplasia is a proliferation without criteria of malignancy Fibroadenomas are benign breast tumours Dr Anshu P Gokarn
    78. 78. Solid tumors Comprise a group of malignancies arising from the various systems or organs with distinct behaviour patterns, requiring different management Multimodal approach followed in management of solid tumors Surgery - the primary modality for most of the solid tumors Radiotherapy also can be used as a primary modality followed by adjuvant therapy Dr Anshu P Gokarn
    79. 79. Solid tumors Contd….. Chemotherapy systemic, local or regionalRegional chemotherapy - intra-tumoral, intracavitary or intra-arterialSystemic chemotherapy – to prevent early disseminated aggressive lesionsDr Anshu P Gokarn
    80. 80. Dr Anshu P Gokarn
    81. 81. Various types of cancers  Haematological malignancies Acute Lymphocytic Leukemia Multiple myeloma Acute Granulocytic leukemia Hodgkin’s Disease Acute myelomonocytic Low grade(nodular) leukemia lymphomas Chronic granulocytic leukemia High grade lymphomas Chronic Lymphocytic Burkitt’s tumor leukemia Mycosis Fungoides Dr Anshu P Gokarn
    82. 82. Various types of tumors Solid tumors Adrenocortical carcinoma  Head and neck Bronchogenic carcinoma squamous cell small cell or oat cell  Hepatocellular Squamous cell, large cell carcinoma anaplastic and  Malignant insulinoma adenocarcinoma or islet cell carcinoma  Malignant melanoma Cervix squamous cell  Ovary Colon carcinoma  Pancreatic Endometrial carcinoma adenocarcinoma Gastric adenocarcinoma  Prostate Dr Anshu P Gokarn
    83. 83. Various types of cancers  Pediatric solid tumors  Wilm’s tumor  Ewing’s sarcoma  Embryonal Rhabdomyosarcoma  Retinoblastoma  Neuroblastoma  Osteogenic sarcomaDr Anshu P Gokarn
    84. 84. Dr Anshu P Gokarn
    85. 85. Metastases  Development of secondary implants discontinuous with the primary tumor, possibly in remote areas.  Not all cancerous cells have an equal ability to metastasize Ex:  basal cell carcinoma and cancers of CNS invade locally but rarely metastasize  Bone sarcomas have already metastasized to lungs at discoveryDr Anshu P Gokarn
    86. 86. MetastasesOccurs by following routes1. Hematogenous2. Lymphatic3. Seeding of cancer cells4. Direct implantation Common sites of metastases Dr Anshu P Gokarn
    87. 87. Metastases Hematogenous Favoured by sarcomas (carcinomas are by no means shy about using it ! ) Liver and lungs – most frequently affected Spread by this route very fast Some tumors have propensity to invade veins Dr Anshu P Gokarn
    88. 88. MetastasesLymphatic spread More typical of carcinomas Pattern of lymph node involvement depends on site of involvement, natural lymphatic pathways for drainageex: lung carcinomas of respiratory passage first metastasize to the regional bronchial lymph nodes; then to tracheo - bronchial / hilar lymph nodes Cells may traverse all the lymph nodes to enter the vascular compartment Dr Anshu P Gokarn
    89. 89. MetastasesSeeding of cancers Invasion of natural body cavities Ex: carcinoma of colon can penetrate wall of the gut and reimplant at distant sites. Cancer ovary disseminates through peritoneal cavityDirect spread With surgeon’s gloves Or With surgical instruments Rarely seen in practiceDr Anshu P Gokarn
    90. 90.  What happens to the patient ?Dr Anshu P Gokarn
    91. 91. Signs and symptoms Pain Loss of weight / muscle wasting Loss of appetite/anaemia Ulceration at the site Bleeding Rapid growth in size Immunosuppression –repeated infections Depending on the location of the tumor pitutary adenoma - hypopituitarism Renal carcinoma - renal ischaemia/hypertension Hormone production --Neoplasm of endocrinal gland Dr Anshu P Gokarn
    92. 92. Signs andsymptoms Dr Anshu P Gokarn
    93. 93. Diagnosis of cancer History Age Sex Family, personal history Geographic location Screening Radiological examination ---- MRI CT- Scan X ray chest Dr Anshu P Gokarn
    94. 94. Diagnosis of cancerScreening To detect possibility of cancer Early detectionDisadvantage Though not definitive reduction in number of deaths Costly Psychological or physical repurcussions High number of false positive/ false negative results seen Dr Anshu P Gokarn
    95. 95. Diagnosis of cancerScreening tests widely usedIn women Pap staining --- cancer cervix Mammogram – breast cancerIn men Prostate specific antigen ---- prostate cancerOther testsXray chestSputum cytology lung cancerStool examination for occult blood rectal cancerRectal examination rectal cancerpelvic examination cervical cancer Dr Anshu P Gokarn
    96. 96. Diagnosis of cancer Molecular / Morphologic methodsTissue Biopsy Indicated almost all types of cancers Advantages Invasive method but highly diagnostic Disadvantage Margins may not be representative / centre may be necrotic . Selection of appropriate site necessary Dr Anshu P Gokarn
    97. 97. Diagnosis of cancer Frozen section biopsy Advantages  determines nature of lesion  Helps evaluate the margins of excised cancer  Quick method  Patient spared the trauma of repeated operationDr Anshu P Gokarn
    98. 98. Diagnosis of cancerFine needle aspiration cytology Indicated For readily palpable lesions of breast, thyroid,lymph nodes, salivary glands Advantages : obviates need for surgery Deeper structures can be examined Disadvantages Sampling errors due to small sample size may occur Dr Anshu P Gokarn
    99. 99. Diagnosis of cancer Cytologic smears  Indicated in: Carcinoma cervix, endometrial carcinoma, bronchogenic carcinoma,bladder, prostate,joints,, abdominal tumors, pleural tumors  Advantages 100 % true positive diagnosisDr Anshu P Gokarn
    100. 100. Diagnosis of cancer Biochemical methods 1. Biochemical assays Indications  To determine prognosis  To detect new cases  Tumor associated enzymes  Hormones  Tumor markers : alpha fetoprotein, carcinoembryonic antigen 2. RadioimmunoassayDr Anshu P Gokarn
    101. 101. Tumor Markers Normal metabolic constituents / biochemical products found in abnormal amount / at inappropriate time of life Aids in detecting viable tumor tissue in the bloodEx : Fetal proteins re-expressed in adult life Tumor markers used to monitor progress of individual patients of malignancyEx : alpha-fetoprotein for testicular tumors Dr Anshu P Gokarn
    102. 102. Radioimmunoassay Highly specific antibodies raised against tumor antigens and labelled with flourescein stain /. Used in immunohistochemical techniques to detect tumor cell products such as enzymes, hormones, receptors Used to differentiate between benign and malignant tumors To differentiate between histological subtype of similar tumors To select the most appropriate therapy Dr Anshu P Gokarn
    103. 103. Dr Anshu P Gokarn
    104. 104. Grading of cancer  Grading Helps to estimate  The aggressiveness of the tumor  Level of malignancy  To predict the prognosis Done depending on the degree of anaplasia Grade I -- IVDr Anshu P Gokarn
    105. 105. Staging Based on size of primary lesion Extent of spread to regional lymph nodes Presence/absence of lymph nodes CT Scan/ MRI/Exploratory laparotomy to conduct staging Of more value than gradingDr Anshu P Gokarn
    106. 106. Staging Method TNM classification T = extent of primary tumor N = regional lymph node involvement M = Metastases Dr Anshu P Gokarn
    107. 107. TNM classification  T0 ---- excised tumor  T1,T2,T3, – increase in size of primary lesion  N0, N1,N2,N3—indicate advancing nodal involvement  M0, M1 – Presence/ Absence of metastases Dr Anshu P Gokarn
    108. 108. TNM Classification: ex: Breast cancer Primary Tumor  TX primary tumor cannot be assessed  TO No evidence of primary tumor  Tis Carcinoma in situ: intraductal carcinoma, lobular carcinoma in situ or Pagets disease of the nipple with no tumor  T1 tumor 2 cm or less in greatest diameter  T1a 0.5 cm or less in greatest diameter  T1b > 0.5 cm but < 1 cm in greatest diameter  T1c > 1cm but < 2 cm in greatest diameter  T2 Tumor > 2cm but < 5 cm in greatest diameter.  T3 Tumor>5 cm in greatest diameter.  T4 Tumor any size with direct extension into chest wall of skin  T4a Extension to chest wall .  T4b Oedema  T4c Both(T4a and T4b)  T4d Inflammatory carcinoma Dr Anshu P Gokarn
    109. 109. TNM Classification: ex: Breast cancer Regional Lymph Nodes  NX Regional lymph nodes cannot be assessed (ex: previously removed)  N0 No regional Lymph Node metastasis  N1 Metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures.  N3 Metastases to ipsilateral internal mammary node(s) Distant Metastases  MX Presence of distant metastases cannot be assessed  M0 No distant metastases  M1 Distant metastases Dr Anshu P Gokarn
    110. 110. Investigations to define TNM classification Tumor  Palpation  Inspection including endoscopy  Radiology  Cytology / aspiration /biopsy Nodes  Palpation  Aspiration  Biopsy  Radiology (CT scanning) Dr Anshu P Gokarn
    111. 111. Investigations to define TNM status Metastases  Biochemical screening(ex : liver function tests)  Radionuclide scans(ex : liver,brain, bones)  Ultrasound of liver  Radiology (Xray chest, CT scan- liver, brain, thorax)  Laparoscopy  LaparotomyDr Anshu P Gokarn
    112. 112. PART - VDr Anshu P Gokarn
    113. 113. Cancer treatment Types :  Radiotherapy  Chemotherapy  Immunotherapy  Endocrine Therapy  SurgeryDr Anshu P Gokarn
    114. 114. ChemotherapyThe treatment of cancer with drugs which killmalignant cells or modify their growth and leavehost cells unharmed or at least recoverable.AIMTo Cure Or Prolong RemissionPalliationAdjuvant Chemotherapy – drugs are used to mopup any residual malignant cells (micrometastases)after surgery or radio-therapy.Dr Anshu P Gokarn
    115. 115. Purine Pyrimidine PALA-I nhibits pyrimidine synthesis synthesis synthesisPentosan- Inhibitsadenisine deaminase Hydroxyurea- inhibits ribonucleotide reductase6-mercaptopurine, 6- Ribonucleotide thioguanine 5-Fluorouracil- inhibits TMPInhibits purine ring Deoxyribonucleotides s synthesis biosynthesis Gemcitabine,Cytarabine,FludaraInhibits nucleotide bine, -Inhibits DNA synthesis bioconversions DNAMethotrexate- inhibits Platinum analogues,alkylatingdihydrofolate reduction- agents,Mitomycin,,cisplatin,blocks TMP and purine Procarbazine,Dacarbazine- forms RNA adducts with DNAsynthesis L-asparginase- deaminatesCamptothecin,Etoposide,T asparagine- inhibits proteineniposide,Daunorubicin – Proteins synthesisblocks topoisomerasefunction Paclitaxel, Vinca alkaloids, Enzymes microtubules colchicine- inhibits function of microtubule Dr Anshu P Gokarn
    116. 116. Anti tumor drug action to the cycleDNA synthesis (G2) Premitotic (S) interval S-Phase specific Cytosine arabinoside (M) Mitosis Hydroxurea Vincristine, vinblastine, S Phase specific, self Paclitaxel limiting 6 Mercaptopurine Methtrexate G 0 (resting (G 1) phase)Dr Anshu P Gokarn
    117. 117. Anti tumor drug action to the cycle Phase Non-Specific  Alkylating drugs  Nitrosoureas,  Anti tumor antibiotics  Procarbazine,  Cis-platinum,  DacarbazineDr Anshu P Gokarn
    118. 118. Treatment Of CancerDRUG ACTION Cycle Specific : only active cycling cells killed Toxicity is generally expressed in S -phase e.g. anti-metabolite Cycle Non-Specific : kills cells in both resting or active cycling phase (i.e. tumor with low growth fraction - e.g. solid tumors). Non cycling cells are allowed to re-enter the cycle between drug courses. e.g. alkylating agents; doxorubicin; anthracyclines; MOPP regime Dr Anshu P Gokarn
    119. 119. Alkylating agents  Nitrogen mustards ex: Mechlorethanamine, cyclophosphamide, Melphalan, Uracil mustard, Chlorambucil  Ethylenimines ex: Triethylenemelamine (TEM) Triethylene Thiophosphamide (Thio-TEPA)  Alkyl Sulfonates ex: BusulfanDr Anshu P Gokarn
    120. 120. Alkylating agents Mechanism of action  Cells are destroyed by alkylation  Alkyl groups are added to constituents of DNA inhibiting DNA synthesis  Interference with the replication and transcription of Messenger RNA occurs Indications  Hodgkin’s disease  Lymphomas, chronic leukemias  Bronchial, ovarian carcinoma  seminomasDr Anshu P Gokarn
    121. 121. Alkylating agents - Cyclophosphamide  Mechanism of action similar but thrombocytopenia is less severe while alopecia like side effects are more.  The drug does not produce any CNS side effects.  Essential component for various drug combinations for Non-Hodgkin’s lymphoma.  Administered by both oral and Intravenous route  Can be given as single agent for Burkitt’s Lymphoma Dr Anshu P Gokarn
    122. 122. Alkylating agents (busulfan)  More effective on the myeloid series of cells  Causes depression of platelet and granulocyte production Indication  In chronic myeloid leukemiaDr Anshu P Gokarn
    123. 123. Nitrosureas EX: carmustine, Lomustine, Streptozotocin Alkylates the DNA and kills cells in all phases of cell cycle Have high lipophilicity , so can be given in Brain malignancies. Indicated in gastrointestinal neoplasms and brain tumors. Significant response in Hodgkin’s disease May cause renal failure and myelosuppression. Streptozotocin does not cause myelosuppression.Dr Anshu P Gokarn
    124. 124. AntimetabolitesII) Folic acid antagonistsEx: methotrexate Purine analoguesEx : 6- mercaptopurine, Azathioprine Pyrimidine analoguesEx : cytosine arabinoside, 5- fluorouracil Dr Anshu P Gokarn
    125. 125. Antimetabolites Mechanism of action  Blocks the action of the metabolite by preventing the combination of the metabolite with it’s enzyme Or  Itself combines with the enzyme to get transformed into a metabolically inactive compound which is harmful to the cellDr Anshu P Gokarn
    126. 126. Antimetabolites Folic acid antagonists : Methotrexate Folic acid Methotrexate TetraHydrofolic Folate reductase + acid No THF synthesis DNA synthesis No DNA synthesis Indications  Acute Lymphatic Leukemia  Choriocarcinoma  Soft tissue sarcoma  Breast cancer  Acute Myeloid LeukemiaDr Anshu P Gokarn
    127. 127. Antimetabolites: (Purine antagonists)  Interferes with the synthesis and interconversion of purines 6- Mercaptopurine 6-mercaptopurine ribonuclideinhibits inhibits Purines synthesis DNA Dr Anshu P Gokarn
    128. 128. Purine antagonists Indications  Acute Leukemia mainly in children  Choriocarcinoma  Chronic Myelogenous leukemia (CML)Dr Anshu P Gokarn
    129. 129. Pyrimidine antagonists(5- Fluorouracil) Fluorinated analogue of pyrimidine Binds to thymidylate synthetase to prevent the production of thymine(basic component of DNA) Incorporates in place of uracil in RNAIndications Carcinoma of colon, ovaries, rectum, stomach, breastCytosine arabinoside Pyrimidine analogue used in inducing remission in acute myeloid leukemia Dr Anshu P Gokarn
    130. 130. ProcarbazineMechanism of action Undergoes metabolic activation to generate the cytotoxic reactants which methylate DNA. Exposure to Procarbazine leads to damage of the DNA, RNA and the protein synthesis which occurs in vivoIndications Used in combination with other drugs of the MOPP regime in Hodgkin’s disease. Has shown activity against brain tumors, small cell carcinoma of the lung, myeloma and melanoma Dr Anshu P Gokarn
    131. 131. Hydroxyurea Mechanism of action  Interferes with the activity of ribonucleoside diphosphate reductase .  This enzyme converts ribonucleotide to deoxyribonucleotides and is the rate limiting step in the biosynthesis of DNA. Indication  Used as a myelosuppressant in myeloproliferative disorders ex: chronic granulocytic leukemia, polycythemia vera and essential thrombocytosisDr Anshu P Gokarn
    132. 132. Gemcitabine : newer antimetabolite. Mechanism of action Weak inhibitor of DNA polymerase Potent inhibitor of ribonucleotide reductase Incorporates into DNA and leads to DNA strand termination. Indications First line therapy in pancreatic acncer and non small cell lung cancerDr Anshu P Gokarn
    133. 133. Radioactive isotopes Radiations emitted by these isotopes produce ionization in the cells thereby disrupting the cellular metabolism. Cell destruction follows Indications Radioactive iodine for thyroid cancer Radioactive gold for malignant pleural/ peritoneal effusions, in prostatic / pelvic cancersEx : Radioiodine, Radiogold, RadiophosphorusDr Anshu P Gokarn
    134. 134. AntibioticsMechanism of action Blocking DNA dependent RNA synthesis (actinomycin D, Rubidomycin) Causing breaks in single / double stranded DNA (bleomycin)IndicationsActinomycin D - Wilm’s tumor, choriocarcinoma ,Hodgkin’s lymphomaMitomycin ---- CML, Hodgkin’s DiseaseRubidomycin --acute leukemia in childrenDoxorubicin ---Remission in ALL, lymphoblasticlymphosarcoma Dr Anshu P Gokarn
    135. 135. Antibiotics (contd…..) Bleomycin ---- epidermoid carcinoma of skin, respiratory passage, oral cavity, Mithramycin --embryonal cell carcinoma of testes, in hypercalcaemia due to malignancy, Paget’ disease Mitoxantrone Analogue of doxorubicin Has low cardiotoxicity potential Indicated in acute granulocytic leukemia, breast cancer.Dr Anshu P Gokarn
    136. 136. Antimitotic plant products (Vinca alkaloids)Act by:Inhibiting mitosisBinds to tubulin and prevents the formation of mitotic spindleUsesVinblastine inHodgkin’s disease(remission in 50- 60% cases)Methotrexate resistant choriocarcinoma, lymphosarcomaVincristine inAcute Lymphatic LeukemiaVinorelbine inNon small cell lung carcinomas along with cisplatinIn breast cancerCauses lesser neurotoxicity and modest thrombocytopeniathan other vinca alkaloids. Dr Anshu P Gokarn
    137. 137. Antimitotic plant products (Paclitaxel)Mechanism of actionBinds to microtubules and inhibits their depolymerization(molecular disassembly) into tubulin.Paclitaxel blocks a cells ability to break down the mitoticspindle during mitosis (cell division)Paclitaxel inhibits mitosis but unlike vinca alkaloids promotesmicrotubule formation.IndicationsIn Cisplastin resistant tumors of ovaryCancers of breast, lung, oesophagus, head and neck Dr Anshu P Gokarn
    138. 138. DocetaxelMechanism of ActionLike paclitaxel, it prevents the breakdown of mitotic spindleClinical trials indicate its about twice as effective as paclitaxelIndication:Breast cancerNon small cell Lung cancerOther uses:Head and neck cancer, Small cell lung cancerMesothelioma, Ovarian cancer, Prostate cancerOrothelial transitional cell cancer Dr Anshu P Gokarn
    139. 139. Natural Products (Camptothecins)Irinotecan, Topotecan Combines with the Topo-isomerase I and inhibits its function An intermediate complex formed creating single stranded DNA break(cleavable complex) This relieves the DNA torsion Camptothecins stabilize the cleavable complex Accumalation of single stranded breaks in DNA which after series of reactions becomes irreversible leading to cell death Active in S phaseIndications Ovarian cancer, Small cell lung cancer, Colon cancer Dr Anshu P Gokarn
    140. 140. Natural Products (Epipodophyllotoxins)Etoposide Form a ternary complex with Topoisomerase II and DNA Results in double stranded DNA breaks and resealing of the break that follows the binding of DNA with Topoisomerase is inhibited Enzyme remains bound to the free end of the broken DNA strand leading to accumalation of DNA breaks and cell death. Cells in S /G2 phase most susceptibleIndications In testicular cancer, small cell lung, breast cancers. Hodgkin’s disease, Non- Hodgkin’s Lymphoma, Acute granulocytic Leukemia, Kaposi’s sarcoma Dr Anshu P Gokarn
    141. 141. Hormones and Hormone antagonistsMechanism of action Act in a different manner from the cytotoxic drugs and can be combined with them in certain malignancies Are slow in their effect Inhibit cell growth and differentiationEx androgens in breast cancer estrogens in prostate cancer Stimulation of differentiation of cells which regain the body’s ability to respond to regulatory mechanismEx: estrogens in breast cancer in postmenopausal women Dr Anshu P Gokarn
    142. 142. Hormone and hormone antagonists Selective lysis of leukemic lymphocytesEx : in ALL (Acute Lymphocytic Leukemia) Inhibition of circulating concentration of a substance which stimulates the malignant cellsEx: Thyroxine suppresses thyroid cancers by inhibiting TSH levels Androgens in Mammary tumors in post-menopausal women Particularly useful in bone metastases because they promote recalcification Flutamide Nonsteroidal compound used in metastatic cancer o prostate Dr Anshu P Gokarn
    143. 143. Hormones and hormone antagonistsTamoxifen Nonsteroidal oestrogen it competes with the circulating estrogen for binding to estrogen receptors At low concentrations – estrogen receptor positive cells are blocked by the drug (cytostatic effect) At higher concentrations – (cytotoxic effects) Estrogen receptor positive/ negative cells are destroyed.Indication Postmenopausal women with breast cancer Dr Anshu P Gokarn
    144. 144. Hormone and hormone antagonistsSteroids Direct lympholytic effect Suppress mitosis in lymphocytes (due to this effect used in ALL / Malignant lymphoma) Prevents accelerated erythrocyte destruction (prevents anaemia ) Counter haemolytic/Haemorrhagic) complications due to thrombocytopenia in CML/ CLL In cerebral edema due to intracranial tumors metastases To control hypercalcemia due to certain tumors or following drug therapy In combination with cytotoxic drugs to produce symptomatic relief and sense of well being Dr Anshu P Gokarn
    145. 145. L- Asparginase Acts by depleting asparginase from the host and denying the malignant cells the metabolite Indications  In reticulum cell carcinoma  Lymphoblastic leukemia CisPlatinum  Gets converted into active form in the cell  Behaves like alkylating agent and attacks the DNA Indications  Ovarian and testicular tumorsDr Anshu P Gokarn
    146. 146. Newer agents : Carboplatin Mechanism of action is similar to cisplatin.However: Carboplatin is less reactive than cisplatin. Relatively well tolerated in clinical practice. Carboplatin is an effective remedy in patients with responsive tumors but unable to tolerate cisplatin because of impaired renal function, refractory nausea, significant hearing impairment, or neuropathy.. Can be used in high dose therapy.Indications In bladder cancer, head and neck cancer. Dr Anshu P Gokarn
    147. 147. Newer agents : Oxaliplatin Unlike carboplatin and cisplatin it has a high volume of distribution. Unlike cisplatin, oxaliplatin in combination with 5-FU is active in colorectal cancer. Oxaliplatin, does not yield a cross-resistance. Less toxic than cisplatin Indications Ovarian cancer, germ cell cancer, cervical cancer, colorectal cancer.Dr Anshu P Gokarn
    148. 148. Newer agents : Nedaplatin Nedaplatin – A recent addition to platinum compounds. Along with 5FU effective in squamous cell carcinoma of oral region.1 Indicated in head and neck, testicular, lung, oesophageal, ovarian, and cervical cancer. 2 Yields cross resistance with other platinum compounds .2 Less toxic than cisplatin.21. Ita M et al. Oral Oncol 2003 Feb;39(2): 144-92. Desoize B, Madoulet CCrit Rev Oncol Hematol 2002 Jun;42(3):317-25 Dr Anshu P Gokarn
    149. 149. Drugs commonly used to treat major types of cancer: Hematological Malignancy Leukemia: (ALL)Cancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityAcute Induction: Daunorubicin ThioguanineLymphocytic Vincristine + Doxorubicin TeniposideLeukemia prednisone Cyclophaosphamide Methotrexate for cytarabineIncidence : 2.1% CNS prophylaxisof all cancers Maintenance –and cancer Methotrexate +deaths mercaptopurine Dr Anshu P Gokarn
    150. 150. Drugs commonly used to treat major types of cancer: Hematological MalignancyLeukemia: (Acute granulocytic Leukemia) Cancer Type/ Drugs used Alternative/ Other drugs with Incidence secondary drugs reported activity Acute Doxorubicin or Amsacrine Azacitidine granulocytic daunorubicin + Mitoxantrone Mercaptopurine leukemia cytarabine Etoposide OR Cytarabine + Thioguanine OR Cytarabine, vincristine + Prednisone Dr Anshu P Gokarn
    151. 151. Drugs commonly used to treat major types of cancer: Hematological Malignancy Leukemia: AMLCancer Type/ Drugs used Alternative/ Other drugs withIncidence secondary drugs reported activityAcute Doxorubicin / Etoposidemyelomonocytic daunorubicin +or monocytic cytarabineleukemia OR Cytarabine + thioguanine OR citarabine, vincristine + prednisone Dr Anshu P Gokarn
    152. 152. Drugs commonly used to treat major types of cancer: Leukemia and Multiplemyeloma Leukemia : CLLCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityChronic Hydroxyurea Busulfan MercaptopurineGranulocytic Interferon alpha PlicamycinleukemiaChronic Chlorambucil PrednisoneLymphocytic CyclophosphamideLeukemia Dr Anshu P Gokarn
    153. 153. Drugs commonly used to treat major types of cancer: Hematological malignancy Multiple MyelomaCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityMultiple Myeloma Melphalan OR Doxorubicin Vincristine+ Cyclophosphamide vincristine doxorubicin+ + Prednisone Dexamethasone Dr Anshu P Gokarn
    154. 154. Drugs commonly used to treat major types of cancer: Hematological MalignancyCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityHodgkin’s disease ABVD MOPP Lomustine (Doxorubicin, regime(chlormusti Carmustine bleomycin, ne, vincristine,Incidence: Chlorambucil vinblastine, procarazine,0.5% of all cancers Thiotepa dacarbazine) prednisone)and 0.3% of cancer Etoposidedeaths Dr Anshu P Gokarn
    155. 155. Drugs commonly used to treat major types of cancer: Hematological MalignancyCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityNodular lymphoma Cyclophosphamid fludarabine Lomustine(Non Hodgkin’s e, vincristine, CarmustineLymphoma) prednisone Interferon alpha 2.4% of all cancersBurkitt’s tumor cyclophosphamid carmustine methotrexate(Non Hodgkin’s eLymphoma)2.4% of all cancersMycosis fungoides Methotrexate Mechlorethamine Dr Anshu P Gokarn
    156. 156. Drugs commonly used in Pediatric solid tumors, brain tumors, germ cell tumors and sarcomasCancer Type/ Incidence Drugs used Alternative / Other drugs secondary with reported drugs activityWilm’s Tumor Dactinomycin + Doxorubicin CyclophosIncidence: 1.6% of all vincristine -phamidecancers and 1.8% ofcancer deathsEwing’s sarcoma Cyclophosphamide+ Dactinomycin0.2% of all cancers doxorubicin+ vincristineEmbryonal Doxorubicin Dactinomycin Thioteparhabdomyosarcoma Cyclophosphamide Methotrexate Vincristine alternating with cisplatin + etoposide Dr Anshu P Gokarn
    157. 157. Drugs commonly used to treat major types of cancerCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityRetinoblastoma cyclophosphamide CarboplatinNeuroblastoma Cyclophosphamide Doxorubicin Etoposide OR vincristine Cisplatin or carboplatin Vinblastine PrednisoneOsteogenic Doxorubicin+ Cisplatin or Melphalansarcoma cisplatin, Methotrexate + Mitomycin0.2 % of all folinic acidcancers Dr Anshu P Gokarn
    158. 158. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityAdrenocortical mitotanecarcinomaBladder Cisplatin or Methotrexate , Fluorouracil,Incidence: 4.6% of doxorubicin vinblastine, cyclophosphamideall cancers and Thiotepa mitomycin3.4% of all cancer Methotrexatedeaths vinblastineColon carcinoma Fluorouracil mitomycin Tegafur11.6% of ll cancers Semustine Doxorubicin Dr Anshu P Gokarn
    159. 159. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityBronchogenic Doxorubicin+ Etoposide + Procarbazine,carcinoma small cyclophosphamide+ cisplain Altretaminecell or ‘oat cel’ vincristineOR Paclitaxel16.8% of all Cyclophosphamidecancers + lomustine+ methotrexateSquamous cell, Cisplatin + Methtrexate, Mitomycinlarge cell vincristine OR cyclophosphamideanaplastic and cisplatin + Methotrexateadenocarcinoma etoposide16.8% of allcancers Dr Anshu P Gokarn
    160. 160. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs with secondary reported activity drugsEndometrial carcinoma Megestrol OR Doxorubicin Fluorouracil,1.5% of all cancers and Medroxyprogest cyclophosphamide0.7% of all cancer deaths eroneGastric adenocarcinoma Fluorouracil Semustine, Tegafur5% of all cancer deaths Mitomycin mitomycinand 5.8% of cancer DoxorubicindeathsHepatocellular Doxorubicin Fluorouracil, Tegafurcarcinoma etoposide0.5% of all cancer deaths cisplatin Dr Anshu P Gokarn
    161. 161. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityCervix squamous Cisplatin Bleomycin,mitom Methotrexate,cell ycin, Fluorouracil,1.8% of all cancers Vincristine,and 1.2 % of Cyclophosphamidecancer deaths doxorubicinHead and Neck Cisplatin+ Bleomycin Methotrexate, Vinblastinecancer OR methotrexate OR Paclitaxel Epirubicin fluorouracil+ leucovorin Doxorubicin carboplatinMalignant Streptozotocin + DacarbazineInsulinoma doxorubicin OR2.7% of all cancers fluorouraciland 4.2 5 of allcancer deaths Dr Anshu P Gokarn
    162. 162. Drugs commonly used to treat major types of cancers Solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs with secondary reported activity drugsMalignant Melanoma Dacarbazine Cisplastin Hydroxycarbamide1.5% of all cancers and Semustine0.8% of all deathsOvary Cisplatin + Doxorubicin FluorouracilChloraIncidence: 2.3% of all cyclophosphamide OR mbucil, Thiotepacancers and 2.7% of + Doxorubicin altretamine Melphalan,cancer deathsProstate Stilbestrol Cyclophosph EstramustineIncidence: 5% of all amidecancers and 6.2% of Doxorubicincancer deaths Dr Anshu P Gokarn
    163. 163. Nonmelanoma skin cancer:Incidence : 12.2% of all cancers Cancer Type/ Incidence Drugs used 1. Basal cell carcinoma 5 Fluorouracil – tretament of superficial variety Intralesional intereferon useful 2. Squamous cell carcinoma 13 Cis retinoic acid -1 mg orally daily + interferon (3 million units s.c.) Combinations with cisplatin may help in few cases Dr Anshu P Gokarn
    164. 164. Likely therapies in future for malignant melanoma  Melanomas often express cell-surface antigens which may be recognized by host immune cells.  Number of such antigens present such as:  MAGEs – 1,-2,-3  Tyrosinase –an enzyme involved in melanin synthesis  MART antigen  These antigens may make it possible to develop vaccination strategies against melanoma. Dr Anshu P Gokarn
    165. 165. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs secondary drugs with reported activityPancreatic Fluorouracil Mitomycin Tegafuradenocarcinoma Doxorubicin2.7% of all cancer deathsSarcomas(Bone) Doxorubicin + Cyclophosphamide0.2% of all cancer and Dacrabazine Vincristinemethotrcancer deaths exate IfosfamideTesticular Vinblastine + Melphalan0.5% of all cancers and 1 Ifosfamide+ Doxorubicin% of cancer deaths cisplatin OR Bleomycin etoposide+ bleomycin+ cisplatin Dr Anshu P Gokarn
    166. 166. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityBrain neoplasms Carmustine or PCV(Procarbazine Plicamycin1.3% of all cancers lomustine +Lomustine+Vincri stine)Choriocarcinoma Methotrexate OR Chlorambucil Dactinomycin Etoposide+ cisplatinRenal cell Medroxyprogester Vinblastine Interferon alpha1.6% of all cancers oneand 1.8% of allcancer deaths Dr Anshu P Gokarn
    167. 167. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugsIncidence secondary drugs with reported activityBreast CMF+ P Doxorubicin+ Vinblastine, (cyclophosphamide, vincristine if CMF thiotepa, methotrexate, fluorouracil + P used as Melphalan,Incidence: , prednisone) OR primary otherwise Mitomycin11.1 % of all Doxorubicin combination ofcancers and drugs not used0.3% of cancer Cyclophosphamide previously/ singledeaths Additive (where agents not used hormones indicated): previously Stilbesterol, testolactone,tamoxifen,me gestrol, depending on menopausal and tumor hormone receptor status Dr Anshu P Gokarn
    168. 168. Drugs commonly used to treat major types of cancer: solid tumors Cancer Type/ Drugs used Other drugs with Incidence reported activity Thyroid cis[platin 0.4% of all cancers doxorubicin Larynx Cisplatin+ Bleomycin OR Vinblastine methotrexate oR 0.8% of all cancers fluorouracil Dr Anshu P Gokarn
    169. 169. Drugs commonly used to treat major types of cancer: solid tumors Cancer Type/ Drugs used Other drugs with Incidence reported activity Salivary glands Cisplatin+ Bleomycin Vinblastine 0.1% of all cancers OR methotrexate oR fluorouracil Gall Bladder Radiotherapy has 0.5% of al cancers not yielded good results Esophagus Cisplatin 2.2 % of all Paclitaxel cancers Dr Anshu P Gokarn
    170. 170.  PART - VIDr Anshu P Gokarn
    171. 171. Newer approaches to cancer Therapy  Measuring initial tumor growth factors or oncogenes helps in: 1. Selecting the patients for more intensive therapy. Ex: epidermal growth factor receptor in bladder and breast cancer. Nuclear oncoprotein p53 in breast cancer. 2. Helps in identifying patients who may show relapse or good response. Dr Anshu P Gokarn
    172. 172. Newer approaches to cancer therapy In Cytotoxic treatment  Most of the drugs interfere with DNA metabolism  Additionally they possess activity on the newer targets for therapy.  Major advances with germ cell tumor, lymphomas and leukemias but less success with common solid tumors like lung, breast and colorectal cancer Dr Anshu P Gokarn
    173. 173. Advances in Cytotoxic Drug TreatmentDr Anshu P Gokarn
    174. 174. Newer approaches to cancer therapy  1. Topoisomerase inhibitors What are Topoisomerases ?  Nuclear enzymes involved in multiple cellular processes like DNA replication and separations of daughter chromosomes.  Are of two types – Type I and Type II Dr Anshu P Gokarn
    175. 175. Type II Topoisomerase inhibitors Act mainly by inhibiting Topoisomerase II Drug in this class:  Epipodophyllotoxins (Etoposide) – In Lung cancer  Anthracyclines (Doxorubicin) – In breast cancer  Amsacrine derivatives  Anthrapyrazole group (CI-941) Dr Anshu P Gokarn
    176. 176. Topoisomerase Type I inhibitors Less widely available Ex: Camptothecin Unaceeptable gastroinrestinal toxicity observed Newer types being developed Ex: Analogue of camptothecin – 9 amino- camptothecin Has significant activity in colon cancer xenografts an area where Topoisomerase II inhibitors have minimal impact. Dr Anshu P Gokarn
    177. 177. Newer approaches to cancer therapy 2. New Antimetabolites: Gemcitabine  Anti-Folates like methotreaxte have been the most widely used till date.  Nowadays drugs which inhibit thmidylate synthase being developed.  Recently Gemcitabine developed  Gemcitabine gets converted to metabolites that inhibit DNA polymerase.  Active on Non Small Cell Lung cancer and breast cancer. Dr Anshu P Gokarn
    178. 178. Newer approaches to cancer therapy 3. Modulation of drug resistance  Normally mdr1 gene encodes a glycoprotein which acts as an energy dependent efflux pump for many cytotoxic drugs.  Many new drugs modulate this glycoprotein  Ex: antiestrogens  These drugs modify the activity of p- glycoprotein which is present in the renal and biliary canaliculi. Suppression of this p-glycoprotein may lead to altered pharmacokinetics of the cytotoxic drug. Dr Anshu P Gokarn
    179. 179. Dr Anshu P Gokarn
    180. 180. New Drug Targets Inhibitors of Signal Transduction and second messenger systems Angiogenesis Receptor targeting Monoclonal Antibodies Immunotherapy agianst Tumor antigens or mutant oncogenes Molecular targets Dr Anshu P Gokarn
    181. 181. Molecular Therapy……… Drugs developed using past paradigms attack both cancerous and healthy cells, often causing devastating short- and long-term side effects. Moreover, individual patient responses to conventional agents vary, even in cases where cancers appear to be identical Molecularly targeted therapies hold the promise of being more highly selective, drastically reducing the incidence of side effects in patients. Dr Anshu P Gokarn
    182. 182. Research Avenues for Molecular Targeting Influence the cancer cell to re-regulate itself, or assume a more normal state. Turn on self-destruct pathways that cause a cancer cell to commit suicideStimulate the bodys immunesystem to reject the cancer Prevent the cell from acquiring the capacity to repeatedly replicate itself. Interfere with a cells capacity to use surrounding tissue to support its growth - e.g., through angiogenesis Dr Anshu P Gokarn
    183. 183. Application of gene therapy to cancer Strategy: to introduce novel genes into cancer cells to convert them into "foreign" tissue grafts so they will be rejected by the patients own immune system. Following gene therapy, the cancer cells will be recognised as a genetically unrelated graft in the cancer patients and therefore will be rejected by the patients own immune system. Two Phase I clinical trials employing this strategy had been completed. Preliminary results are encouraging. A Phase 2 clinical trial is presently in progress. Dr Anshu P Gokarn
    184. 184. Gene Therapy (contd……) Novel non-viral gene delivery lipid vehicles to deliver genes to cancer cells are also being designed and synthesized by this research group. The aim is to improve the efficiency of which cancer cells can take up novel exogeneous genes. Dr Anshu P Gokarn
    185. 185. Gene Therapy (contd…..)Techniques that are possible 1. Immunomodulation by using tumor infiltrating lymphocytes This strategy mostly used in malignant Melanoma. 2. Certain genes are transcribed in malignant and fetal tissues but are not transcribed in adult tissue Ex: α fetoprotein in hepatomas and germ cell tumors Carcinoembryonic antigen in a range of adenocarcinomas particularly colonic tumor Vectors used to construct promoters of these particular proteins. Dr Anshu P Gokarn
    186. 186. Oligonucleotides Involves down regulation of expression of important genes such as oncogenes which may be overexpressed in cancer cells. Achieved by three techniques1. Antisense approach2. Targeting specific mRNAs3. Antigene approach aimed at blocking transcription at its genetic location. Dr Anshu P Gokarn
    187. 187. Antisense approach: Principle Translation is inhibited by degradation of mRNA by RNAase H OR Inhibition of binding of ribosomal subunits. Dr Anshu P Gokarn
    188. 188. Antisense approach Normal flow of genetic information where a gene is transcripted into an mRNA and translated into a corresponding protein Antisense oligonucleotide hybridization to the complementary target and causes a block of protein translation Antisense oligonucleotides are taken up by the cell, hybridize to their target mRNA and block protein expression Dr Anshu P Gokarn
    189. 189. Inhibitors of signal transduction and second messenger systems Mutation (ras) Over-expression of growth factor G proteins regulating receptors adenylate cyclase Increased intracellular signalling by second messenger systems like protein kinase C/ C-AMP dependent protein kinase Trials on for Bryostatin – antagonises protein kinase CC-AMP analogues ex: 8 Chlorocyclic AMP– inhibits tumor growth with little tissue toxicity Dr Anshu P Gokarn
    190. 190. Inhibitors of signal transduction and second messenger systems  Activation of Tyrosine kinases has a transforming role.  Epidermal growth factors inhibitors ex: tyrosine analogues, may be useful. Dr Anshu P Gokarn
    191. 191. What is a telomere The DNA molecule of a typical chromosome contains a linear array of genes (encoding proteins and RNAs) interspersed with non-coding DNA. Included in the non-coding DNA are:1. long stretches that make up the centromere and2. long stretches at the ends of the chromosome, the telomeres.When telomeres are completely or almost completely lost, cells mayreach a point at which they crash and die. Dr Anshu P Gokarn
    192. 192. Telomerase Inhibitors Telomerase is the enzyme that replenishes shortened telomeres and allows cells to reproduce indefinitely. Found in only a few normal human cells, telomerase is present in as many as 90% of human cancers. This makes telomerase an attractive candidate for highly selective cancer drugs Certain normal human cells can only undergo 30-50 doublings before their telomeres are too short and doubling stops. Cancer cells must undergo about 80 doublings before a tumor mass is large enough to be detected Dr Anshu P Gokarn
    193. 193. Telomerase Inhibitors B.-S. Herbert, A. E. Pitts, et al. at the University of Texas Southwestern Medical Center have shown that inhibitors of telomerase can remortalize transformed human breast epithelial cells and human prostate cancer cells in culture, ultimately leading to their cell death. The telomerase inhibitors used in this study are 2-0- MeRNA oligonucleotides directed towards the essential RNA component (hTR) of human telomerase. Dr Anshu P Gokarn
    194. 194. Receptor Targeting External domain of the receptor – the new target Recombinant DNA technology used Either single molecule prepared or fusion protein with other molecule prepared. High specificity and affinity provided Ex: IL-6 receptor in Myeloma IL-2 receptor in lymphomas C-erb-2 / epidermal growth factor receptor – breast cancer. In fusion proteins – anticancer component provided by diphtheria / pseudomonas exotoxin Phase I studies in bladder cancer Dr Anshu P Gokarn
    195. 195. Angiogenesis inhibitorsTumor invasiveness and metastasisrequire neovascularization (formation ofnew blood vessels)Tumor cells cannot grow as a massabove 2 to 3 mm because diffusion isinsufficient for oxygen and glucoserequirements, unless the tumor induces ablood supply. AngiogenesisMechanism of induction of a new bloodsupply from pre-existing vascular bed Drugs which inhibit angiogenesis are angiogenesis inhibitors Dr Anshu P Gokarn
    196. 196. Angiogenesis inhibitors….. Like:  Suramin analogues  Antibodies to proliferating endothelium  Angioinhibins  Collagenase inhibitorsAngiogenesis inhibitors can be used with hypoxically active drugs for better effects. Hypoxically active drugs – drugs activated under reducingconditions to generate toxic metabolites that can bind to DNA and Dr Anshu P Gokarn generate strand breaks.
    197. 197. Angiogenesis inhibitors in clinical trials Thalidomide and TNP-470, a synthetic analogue of fumagillin have shown efficacy in Kaposi,s sarcoma. 2- methoxyestradiol – in phase I trial for Breast cancer; has shown efficacy against melanoma. Thrombospondin 1 in basal cell and squamous cell carcinoma Col –III is a synthetic metalloproteinase inhibitor (in phase I trial) SU 6668 inhibits VEGF, FGF, and EGF receptor signalling. (in phase II trial ) Dr Anshu P Gokarn
    198. 198. Common targets for angiogenesis inhibitorsAttack Points for angiogenesis inhibitors include specific cell surface and intracellular targets 1. Initial drugs including pentosan polysulphate, were heparin like. 2.Blocking a receptor’s autophosphorylation interferes with subsequent signal transmission 3. Some occupy a particular growth factor 4. Blocks cell surface proton pumps which interferes with several receptors. 5. Proliferating endothelial cells require specific cell surface contacts such as those mediated by Integrin αγβ3 6. Blockade of the process may induce endothelial cell death. 7. Body has its own tissue inhibitors of Dr Anshu P Gokarn matrix metalloproteinases(TIMPs)
    199. 199. Newer developments in monoclonal Antibodies  Two step strategy used  Initially antibody allowed to localize itself for several days.  Then second binding protein which recognizes the first and has the therapeutic agent attached is administered.Ex: biotin on the first antibody and streptavidin asthe second protein. Dr Anshu P Gokarn
    200. 200. Dr Anshu P Gokarn
    201. 201. Monoclonal antibodies Rituximab and Trastuzumab are monoclonal antibodies approved by FDA Rituxan – for treatment of B-cell Non-Hodgkin’s Lymphoma that has not responded to chemotherapy. Herceptin – in treatment of metastatic breast cancer These antibodies are also being tested in lymphomas, leukemias, colorectal cancer, lung cancer, brain tumors ,and prostate cancers. Dr Anshu P Gokarn
    202. 202. ADEPT MechanismADEPT – Antibody dependent enzyme prodrug therapyToxin is generated by1 enzyme attached to the antibody from a nontoxic Step an Step 2precursor.Advantage is that cytotoxic drug produced locally that will be active againsttumor cels that have not bound the antibody well. Repeated daily doses can begiven Dr Anshu P Gokarn
    203. 203. Immunotherapy Antibodies designed specially to recognize a specific cancer When coupled with natural toxins, drugs or radioactive substances, the antibodies will seek out their target cancer cells and deliver their lethal load Alternatively toxins combined with lymphokines and routed to cells equipped with receptors for Lymphokines. Dr Anshu P Gokarn
    204. 204. Immunotherapy against tumor antigens or mutant oncogenes Endogenous antigens presented by HLA class I molecules. Selective loss of HLA (Human leukocyte antigens) alleles occurs in many epithelial tumors. Upregulation of HLA with combined therapy with interferons may prove to be beneficial. Beneficial specially when vaccine technology is used for immunization against tumor antigens or mutant oncogenes like p 53, H-ras, mutant K- ras. Dr Anshu P Gokarn
    205. 205. Dr Anshu P Gokarn
    206. 206. Vaccines in cancer Dendritic cells are potent initiators of anti-tumor responses. They involve the activation of cytotoxic T cells which eliminate the tumor cells. Dendritic cells are being primed with Tumour cell lysates, tumour peptides, or DNA, to induce tumour-specific immunity against various human cancers. These DCs are expected to be valuable tool in the immunotherapeutic treatment of patients with metastatic tumor Dr Anshu P Gokarn
    207. 207. Smart drugs searching out problem cells Specially designed toxins are linked with agents that bind selectively with components on the surface of cancer cells . A single piece molecule with two step mode of action has been developed One component of the molecule carries the tumor identifier and the other carries the active agent. Two tumor cell identifiers (IL-13 and SS1) are being developed to selectively seek out, recognize, attach to and deliver active drug to destroy cancer cells while leaving healthy cells intact. Dr Anshu P Gokarn
    208. 208. Neopharm ,FDA and Nationalcancer institute have developedtwo highly selective tumor targetingagents1.Tumor targeted cytotoxin calledas IL-13-PE38 Normal cell Antimesothelin monoclonal2.antibody called as SS1-PE 38The PE-38 component of both thedrugs is a naturally occuringcytotoxin.It destroys the cancer cell after it is Cancer cellintroduced into the cell. Dr Anshu P Gokarn
    209. 209. IL-13 targets receptors in thekidney , brain, berast, head andneck and Kaposi’s sarcomaSS1 seeks out and attaches tosites normally present in largenumbers on the surface ofspecific cancer cells.IL13-PE38 (delivered systemically)- fro treating renal cancerIL13-PE38 (delivered intratumorally)- for treating glioblastoma (braincancer)SS1-PE38(delivered systemically)- antimesothelin monoclonal antibodydelivery system Dr Anshu P Gokarn
    210. 210. Rasburicase – approved by the FDAAnticancer therapy leads to tumor lysisLeads to accumalation of uric acid in plasmaLeads to tumor lysis syndrome which may lead to acute renalfailure.Rasburicase helps convert uric acid into a solublebyproduct(allantoin) which is readily excreted by the kidneys. Dr Anshu P Gokarn
    211. 211. Biological Response Modifiers They are antibodies, cytokines and other immune system substances that can be produced in the laboratory for use in cancer treatment. They include:1. Interferons2. Interleukins3. Colony stimulating factors4. Monoclonal antibodies and5. Vaccines Dr Anshu P Gokarn
    212. 212. Interferons They are cytokines which occur naturally in the body. Three major types:1. Interferon alpha2. Interferon beta3. Interferon gamma They improve the way a cancer patients immune system reacts to cancer cells. Additionally they also slow their growth or promote their development into more normal behaviour. Interferon Alpha used in – hairy cell leukemia, malignant melanoma, CML, AIDS related Kaposi’s sarcoma. May also be useful in metastatic kidney cancer and Non- Hodgkin’s Lymphoma Dr Anshu P Gokarn
    213. 213. Biological Response Modifierslevamisole Acts by modulating cell mediated immune response Restores/ augments cutaneous delayed hypersensitive responseBCG Boost’s the production of antibodies Direct injection of tuberculosis bacteria into Melanoma decreases the size of tumor Dr Anshu P Gokarn
    214. 214. Interleukins Interleukins are also cytokines produced naturally in the body IL-2 (Aldesleukin) is the most widely used It stimulates the growth and activity of many immune cells like lymphocytes that can destroy cancer cells. IL-2 indicated in metastatic kidney cancer and metastatic melanoma Dr Anshu P Gokarn
    215. 215. Colony Stimulating Factors(CSF) Also called as Haematopoeitic growth factors They encourage the bone marrow stem cells to divide and develop into white blood cells, platelets and red blood cells. CSF are particularly useful when combined with high dose chemotherapy Some ex; G-CSF (Filrastim) and GM-CSF(sargramostin) Dr Anshu P Gokarn
    216. 216. Imatinib Mesylate Inhibits specific protein tyrosinekinase which is targeted to plateletderived growth factor. It specifically inhibits constitutivelyactive fusion protein arising from thePhiladelphia chromosome of CML andc-kit(CD117) in GISTImpairs BCR-ABL mediated transfer of phosphates to itssubstrates.BCR-ABL is a protein unique to leukemia cells and its tyrosine kinase activity is essential for its ability to induce leukemia BCR-AABL mutation is present in almost all patients with CML, Dr Anshu P Gokarn
    217. 217. What are protein Kinases?  Enzymes that transfer phosphate from adenosine triphosphate to specific amino acids on substrate proteins (Phosphorylation).  Phosphorylation of these proteins leads to activation of signal transduction pathways.  Signal transduction pathways play a critical role in cell growth, differentiation and death.Several protein kinases are deregulated and overexpressed inhuman cancers and serve as an attractive target for anticancertherapy. Dr Anshu P Gokarn
    218. 218. Disrupted regulation of oncogene : bcrabl gene responsible for CML Dr Anshu P Gokarn

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