Anticancer drugs - drdhriti


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A Power point presentation on "Anticancer Drugs" compiled for theory lecture to the Undergraduate level Medical Students

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  • Thymidylate synthase: Deoxyuridilic acid to deo0xythymidylic acid – direct failure of DNA synthesis. Cytarabine – blocks generation of cytidylic acid
  • Anticancer drugs - drdhriti

    1. 1. Anticancer Drugs Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Advances in Cancer Chemotherapy Treatment options of cancer:  No Treatment: Before 1940  Surgery: before 1955  Radiotherapy: 1955~1965  Chemotherapy: after 1965  Immunotherapy and Gene therapy
    3. 3. Goals of Therapy  Cure or induce prolonged ‘remission’ so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persist - Acute Lymphoblastic Leukaemia, Wilm`s tumor, Ewing`s sarcoma etc. in children, Hodgekin`s lymphoma, testicular teratoma and choriocarcinoma  Palliation: Shrinkage of evident tumour, alleviation of symptoms and prolongation of life - Breast cancer, ovarian cancer, endometrial carcinoma, CLL, CML, small cell cancer of lung and Non- Hodgekin lymphoma  Insensitive or less sensitive but life may be prolonged - Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer
    4. 4. Aim of Therapy – contd.  Adjuvant therapy: One of the main basis of treatment now  For mopping up of residual cancer cells including metastases after Surgery, Radiation and immunotherapy etc.  Routinely used now  Mainly in solid tumours
    5. 5. Cancer Chemotherapy – 5 years survival rate Childhood Acute Lymphoblastic Leukemia 50 - 80% Acute Adult Lymphoblastic Leukemia 20 - 60% Childhood Acute Myeloblastic Leukemia 20 - 60% Adult Acute Myeloblastic Leukemia 10 - 20% Breast Cancer 5 - 20% Hodgkin’s lymphoma 40 - 80%
    6. 6. General Principles of Chemotherapy of Cancer 1. Analogous with Bacterial chemotherapy – differences are  Selectivity of drugs is limited – because “I may harm you”  No or less defence mechanism – Cytokines adjuvant now 1. All malignant cells must be killed to stop progemy – surival time is related to no. of cells that escape Chemo attack 2. Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy 3. Drug regimens or combined cycle therapy after radiation or surgery (Basis of treatment now in large tumour burdens) 4. Complete remission should be the goal – but already used in maximum tolerated dose – so early treatment with intensive regimens 5. Formerly single drug – now 2-5 drugs in intermittent pulses – Total tumour cell kill – COMBINATION CHEMOTHERAPY
    7. 7. COMBINATION CHEMOTHERAPY - SYNERGISTIC  Drugs which are effective when used alone  Drugs with different mechanism of action  Drugs with differing toxicities  Drugs with different mechanism of toxicities  Drugs with synergistic biochemical interactions  Optimal schedule by trial and error method  More importantly on cell cycle specificity
    8. 8. Cell Cycle and Clinical Importance • All cells—normal or neoplastic—must traverse before and during cell division • Malignant cells spend time in each phase - longest time at G1, but may vary • Many of the effective anticancer drugs exert their action on cells traversing the cell cycle - cell cycle-specific (CCS) drugs • Cell cycle-nonspecific (CCNS) drugs - sterilize tumor cells whether they are cycling or resting in the G0 compartment • CCNS drugs can kill both G0 and cycling cells - CCS are more effective on cycling cells
    9. 9. Cell cycle clinical importance – contd.  Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs  Information is valuable in knowing - mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs  CCS – effective against hematologic malignancies and in solid tumors with large growth fraction  CCNS drugs – solid tumors with low growth fraction solid tumors  CCS drugs are given after a course of CCNS
    10. 10. Drugs Based on Cell Cycle  CCNS: Nitrogen Mustards, Cyclphosphamide, chlorambucil, carmustine, dacarbazine, busulfan, L- asparginase, cisplatin, procarbazine and actinomycine D etc.  CCS:  G1 – vincristine  S – Mtx, cytarabine, 6-thioguanine, 6-MP, 5-FU, daunorubicin, doxorubicin  G2 – Daunorubicin, bleomycin  M – Vincristine, vinblastne, paclitaxel etc.
    11. 11. The Neoplastic Cell Burden  May have up to 1012 tumor cells throughout the body at the time of death  109 (100 crore) cells at the time of diagnosis  Debulking – 90% done  Still 10% left i.e. 109 became108 or 10 crores (log kill = 1)  There would still be up to 8 logs of tumor cells  Inherent resistance to drug, Pharmacological sanctuary (CNS and testes), G(0) cycle  An effective drug is capable of killing 99.999% tumor cells - clinical remission and symptomatic improvement (log kill 5) – still 0.001% cells  Therefore, scheduling of these agents is particularly important  In common bacterial infections – host defense mechanism  Immunological  Single clonogenic malignant cell – produce progeny kill host cells 10,00000000000 X 0.01/100 (0.0001) = 10,000000 = remains
    12. 12. The Log kill Hypothesis  Relationship of tumor cell number to time of diagnosis, symptoms, treatment, and survival  Actions of CCS drugs follow first order kinetics: a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells)  Kill a constant fraction of the cells in a population, independent of the absolute number  Magnitude of a tumor cell kill is a logarithmic function: 4 log kill means reduction from1012 to 108
    13. 13. Approaches to Drug Treatment • DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) • LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e. kill rate>growth rate) • GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.
    14. 14. Clinical Considerations 1. Early intensive start to the treatment is helpful 2. Complete remission is the goal of chemotherapy 3. Combined chemotherapy is useful - Drug regimens or effective designing of number of cycles can reduce large tumour burden and delayed emergence of resistance 4. Combined chemotherapy can be curative when applied to minute residual tumour cell population after surgery or radiation 5. Treatment must continue past the time when cancer cells can be detected using conventional techniques
    15. 15. Resistance  Intrinsic and Acquired  Intrinsic: Some tumor types, e.g. malignant melanoma, renal cell cancer, and brain cancer, exhibit primary resistance, i.e. absence of response on the first exposure, to currently available standard agents  Acquired:  Single drug: change in the genetic apparatus of a given tumor cell with amplification or increased expression of one or more specific genes  Multidrug resistance:  Resistance to a variety of drugs following exposure to a single variety of drug  increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (P-glycoprotein) involved in drug efflux
    16. 16. Toxicities  Harmful to normal tissues too  Steep dose response curve  Low therapeutic index  Particularly harmful to rapidly multiplying normal tissues: GI mucosa, Bone Marrow, RE system and gonads and hair cells  Effects are in dose dependent manner
    17. 17. Toxicities 1. Bone marrow deression – limits treatment 2. Buccal mucosa erosion – due to high epithelial turnover (stomatitis, bleeding gums) 3. GIT: Diarrhoea, shedding of mucosa, haemorrhage  Nausea, vomiting – CTZ direct stimulation 1. Skin: alopecia 2. Gonads: oligospermia, impotence, amenorrhoea and infertility 3. Lymphoreticular system: Lymphocytopenia and inhibition of lymphocyte function – loss of host defence mechanism – susceptibility to infections 4. Carcinogenicity 5. Teratogenicity and Hyperuricemia
    18. 18. Countering the Toxicities  Intermittent therapy  Folinic acid rescue  Systemic Mesna (sodium-2-mercaptoethane sulfonate) administration and irrigation by acetylcysteine – detoxify toxic metabolites  Ondansetron  Hyperurecaemia: uricosuric agents like allopurinol  Platelet and granulocyte transfusion  Granulocyte colony stimulating factors (GM-CSF/G- CSF) – recovery of garnulocytopenia
    19. 19. Anticancer Drugs
    20. 20. Classification  According to chemical structure and sources of drugs  Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others  According to biochemistry mechanisms of anticancer action:  Block nucleic acid biosynthesis  Direct influence the structure and function of DNA  Interfere transcription and block RNA synthesis  Interfere protein synthesis and function  Influence hormone homeostasis  According to the cycle or phase specificity of the drug:  Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents (CCSA)
    21. 21. Mechanism of Anticancer Drugs  Block nucleic acid (DNA, RNA) biosynthesis  Directly destroy DNA and inhibit DNA reproduction  Interfere transcription and block RNA synthesis  Interfere protein synthesis and function  Influence hormone homeostasis
    22. 22. Block nucleic acid (DNA, RNA) biosynthesis Antimetabolites:  Folic Acid Antagonist: inhibit dihydrofolate reductase (methotrexate)  Pyrimidine Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine)  Purine Antagonist: inhibit interconversion of purine nucleotide (6-mercaptopurine and 6-Thioguanine)  Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea)
    23. 23. Influence the Structure and Function of DNA  Alkylating Agent: mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, Mephalan, Busulfan, Nitrosoureas and Thio-TEPA  Platinum: cis-platinium, carboplatin and imatinib  Antibiotic: bleomycin and mitomycin C  Topoismerase inhibitor: camptothecin analogues and podophyllotoxin and antibiotics like actinomycin D, daunorubicin and doxorubicin
    24. 24. Interfere Protein Synthesis  Antitubulin: vinca alkaloids (vincristine and vinblastin) and taxanes (paclitaxel and docetaxel) Bind tubulin, destroy spindle to produce mitotic arrest  Influence amino acid supply: L-asparaginase .
    25. 25. Influence hormone homeostasis These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth  Estrogens and estrogen antagonistic drug (EE, SERM- tamoxifene)  Androgens and androgen antagonistic drug (flutamide and bicalutamide)  Progestogen drug (hydroxyprogesterone)  Glucocorticoid drug (prednisolone and others)  Gonadotropin-releasing hormone inhibitor: nafarelin, triptorelin  aromatase inhibitor: Letrozole and anastrazole
    26. 26. Alkylating agents  Nitrogen Mustards: A) Mechlorethamine B) Cyclophosphamide, Isofamide C) Chlorambucil and others  Nitrosoures (carmustine)  Alkyl sulfonates (Busulfan)
    27. 27. Alkylating Agents Mechanism of Action:  Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA)  The specific type of chemical bonding involved is alkylation  After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites  Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.
    28. 28. Nitrogen Mustards  Mechlorethamine:  Uses: Given IV  Part of MOPP (Mechlorethamine – oncovine-prednisolone and procarbazine) in Hodgekin`s lymphoma and disease  ADRs: Severe Vomiting, myelo and immunosuppression  Extravasation – severe local toxicity  Cycolphosphamide:  Transformed into active aldophosphamide and phospharamide  Administered orally  Used in Hodgkin's lymphoma, breast and ovary cancers  Ifosphamide has longer half life and used mainly I n testicular tumour
    29. 29. Nitrogen Mustards – contd.  Chlorambucil: given orally, active against lymphoid tissues (Ch. Lymphatic leukaemia and non- Hodgkin's lymphoma)  Busulfan: given orally, active against CML  Carmustine: given IV, effective against brain tumors and also in Hodgkin's lymphoma  Dacarbazine: Different from other alkylating agents – action against RNA and protein synthesis  Used against Melanoma and Hodgkin's lymphoma
    30. 30. Antimetabolites  Folic acid Antagonists: MTX  Purine Antagonists: 6MP and 6TG  Pyrimidine Antagonists: 5FU and cytarabine General Characteristics:  Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis.  Myelosuppression is the dose-limiting toxicity for all drugs in this class
    31. 31. Methotrexate – Folate Antagonist  MOA:  The structures of MTX and folic acid are similar  MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase  the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis  Leucovorin rescue:  Administered as a plan in MTX therapy  Leucovorin (Folinic acid) is directly converted to tetrahydrofolic acid - production of DNA cellular protein inspite of presence of MTX  Used to rescue bone marrow and GIT mucosal cells  Resistance:  Reduction of affinity of DHFR to MTX  Diminished entry of MTX into cancer cells  Over production of DHFR enzyme
    32. 32. Methotrexate – contd.  Kinetics:  Given orally/IM /IV and also intrathecally and good oral absorption  CSF entry - intrathecal  Indications:  Choriocarinoma - was the first demonstration of curative chemotherapy  Tumors of head and neck  Breast cancer  Acue lymphatic leukemia  Meningeal metastases of a wide range of tumors  ADRs: 1) Myelosuppression - severe leukopenia, bone marrow aplasia, and thrombocytopenia 2) GIT disturbances 3) renal toxicity (crystalluria)
    33. 33. Purine Antagonists – 6MP, 6TG 6-Mercapapurine (6-MP) and others  Exact mechanisms of action are still uncertain – inhibit purine base synthesis  Used in childhood Acute lymphatic Leukaemia for maintenance and remission and may also be in combination with MTX in choriocarcinoma  Metabolized by xanthine oxidase (inhibited by allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th  Well tolerated, mild myelosuppression and hepatotoxicity on long term administration
    34. 34. Antimetabolites (Pyrimidine Antagonists) - 5 FU  MOA:  Fluorouracil is an analogue of thymine  Converted to 5-fluoro-2deoxy-uridine monophosphate (5-FdUMP)  5-FdUMP inhibits thymidylate synthase and blocks conversion of deoxyuridilic acid to deoxythymidylic acid – failure of DNA synthesis  Indications: solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck  ADRs:  nausea and vomiting, myelosuppression, and oral and gastrointestinal ulceration. Nausea and vomitting are usually mild  Mucosal damage and myelosuppression
    35. 35. Antibiotics  Anthracyclines (doxorubicin and dau norubicin), Dactinomycin, Bleomycin, and mitomycin  Anthracyclines:  Enters themselves into DNA and causes DNA break  Activates TopoisomeraseII and cause break in DNA strands  Generates excess free radicals causing production of superoxide – damage to DNA  Known to damage cardiac cells also (unique)  Resistance developes due to increased eflux of drug  Uses: Doxo- Breast, ovary, lung, [prostate and acute lymphatic leukaemia  Dauno- ALL and AML
    36. 36. Read yourself  Cisplatin and L-asparginase