Skip to main content
UploadLanguage (EN)Support
BusinessMobileSocial MediaMarketingTechnologyArt & PhotosCareerDesignEducationPresentations & Public SpeakingGovernment & NonprofitHealthcareInternetLawLeadership & ManagementAutomotiveEngineeringSoftwareRecruiting & HRRetailSalesServicesScienceSmall Business & EntrepreneurshipFoodEnvironmentEconomy & FinanceData & AnalyticsInvestor RelationsSportsSpiritualNews & PoliticsTravelSelf ImprovementReal EstateEntertainment & HumorHealth & MedicineDevices & HardwareLifestyle
Karun Kumar, profile picture
Uploaded byKarun Kumar
PPTX, PDF15,221 views

Anti-cancer drugs

The document discusses anti-cancer drugs, detailing their mechanisms, toxicities, and applications in treating various malignancies, particularly focusing on cytotoxic drugs that aim to kill or inhibit cancer cell growth. It emphasizes the general and specific toxic effects of these drugs on rapidly dividing cells, including the implications for oral health during chemotherapy. It also categorizes different classes of cancer drugs, including alkylating agents, antimetabolites, microtubule inhibitors, and targeted therapies, along with their uses and side effects.

Health & Medicine◦
Related topics:
Anti-Cancer Drugs•
Downloaded 160 times
Anti-cancer drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology
Anticancer Drugs • Either kill cancer cells or modify their growth • Selectivity of majority of drugs is limited. They are one of the most toxic drugs used in therapy • In addition to their prominent role in leukaemias and lymphomas, drugs are used in conjunction with surgery, radiotherapy and immunotherapy in the combined modality approach for many solid tumors, especially metastatic
• In malignant diseases, drugs are used with the aim of 1. Cure or prolonged remission  Primary treatment modality 2. Palliation  Shrinkage of tumour, alleviation of symptoms and life is prolonged 3. Adjuvant chemotherapy  Drugs are used to mop up any residual malignant cells after surgery or radiotherapy
General toxicity of cytotoxic drugs • Majority of the cytotoxic drugs have more effect on rapidly multiplying cells 1. Bone marrow  Depression of bone marrow results in granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia 2. Lymphoreticular tissue  Lymphocytopenia and inhibition of lymphocyte function results in suppression of cell mediated as well as humoral immunity
3. GIT  Stomatitis, diarrhoea, shedding of mucosa, haemorrhages, nausea and vomiting 4. Skin  Alopecia occurs due to damage to the cells in hair follicles. Dermatitis is another complication 5. Gonads  Inhibition of gonadal cells causes oligozoospermia and impotence in males; inhibition of ovulation and amenorrhoea are common in females 6. Foetus  Cytotoxic drugs given to pregnant women damage the developing fetus → abortion, fetal death, teratogenesis
7. Carcinogenicity  Leukemias, lymphomas and histiocytic tumors appear with greater frequency many years after the use of cytotoxic drugs 8. Hyperuricemia  This is secondary to massive cell destruction (uric acid is a product of purine metabolism). Gout and urate stones in the urinary tract may develop. • In addition to these general toxicities, individual drugs may produce specific adverse effects 1. Vincristine causes neuropathy 2. Doxorubicin causes cardiomyopathy 3. Cyclophosphamide produces alopecia and cystitis
Oral complications of cancer chemotherapy • Oral mucosa is susceptible to cytotoxic drugs because of high epithelial cell turnover • Many chemotherapeutic drugs produce oral lesions • Oral mucositis  Early manifestation of toxicity. The gingival tissue and oral mucosa are regularly subjected to minor trauma during chewing and breaches are common • Oral microbial flora is large and can be the source of local (e.g. periodontal abscess) as well as bloodborne infection
• Neutropenia and depression of immunity caused by the cytotoxic drug indirectly ↑ oral inf. chance • Thrombocytopenia due to bone marrow depression may cause gingival or mucosal bleeding • Chemotherapeutic drugs frequently produce Xerostomia (which accelerates development of dental caries) angular cheilitis • Dysgeuesia • Administered to children during tooth development, cancer chemotherapy may cause hypoplasia of tooth, blunting of roots and even tooth agenesis
Prevention of oral/dental complications 1. Thorough dental checkup before starting the regimen 2. Any carious cavities, periodontal lesions, impacted last molars and other potential sources of infection should be appropriately treated 3. All sharp cusps or dentures should be smoothened to avoid injury 4. Good oral hygiene should be maintained throughout the course 5. Topical use of fluoride can retard caries development
6. Stomatitis and oral ulcers can be treated with chlorhexidine mouthwash 7. Nystatin or Clotrimazole lotion may be used for Candida infection 8. As mucositis progresses, oral lesions become increasingly painful and may interfere with eating. Topical application of sucralfate and misoprostol may afford some relief 9. Benzocaine lozenges or lidocaine gel can reduce pain but may interfere with taste and increase the risk of injury to oral mucosa. Opioid analgesics may have to be prescribed
10. Systemic antibiotics to cover organisms like Pseudomonas, Klebsiella, E.coli are often needed in addition to those for common oral pathogens (GPC & anaerobes) when chemotherapy related oral inf. develop 11. In a patient receiving chemotherapy, any dental procedure should be undertaken only after giving due regard to his/her immune and haemostatic status and in consultation with the patient’s physician 12. Appropriate prophylactic antibiotic to eliminate the risk of infection is important, since infections can easily set in or get disseminated in subjects compromised by the chemotherapy
Classification
Cancer drugs—targets
Alkylating agents • Produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds • Have cytotoxic and radiomimetic (like ionizing radiation) actions • Many are cell cycle nonspecific, i.e. act on dividing as well as resting cells • Cyclophosphamide  M/c used, effective in a wide range of tumors & has prominent immunosupp. acn.
Other alkylating agents 1. Chlorambucil  Selective for lymphoid tissue and is used for maintenance therapy in chronic lymphocytic leukaemia and Hodgkin’s disease 2. Busulfan  Selective for myeloid elements and DOC for chronic myeloid leukaemia 3. Melphalan  Effective in multiple myeloma 4. Lomustine  Highly lipid soluble (brain tumors and meningeal leukemia) 5. Dacarbazine  Used in malignant melanoma 6. Procarbazine  Component of the MOPP regimen for Hodgkin’s and related lymphomas
Carmustine Lomustine
Nitro gen must ards
Platinum coordination complexes Cisplatin  Has alkylating and radiomimetic properties 1. Used for many solid tumours including lung, bladder, esophagaus, stomach, head and neck as well as metastatic testicular and ovarian carcinoma 2. Needs to be infused i.v. 3. Highly emetogenic 4. Strong antiemetic pretreatment is required
• Carboplatin  Less reactive 2nd gen. platinum complex that is better tolerated • Oxaliplatin  3rd gen. complex which is active against many tumors that have developed resistance to Cisplatin
Cisplatin Carboplatin Oxaliplatin
Antimetabolites • Analogues related to the normal components of DNA or of coenzymes involved in nucleic acid synthesis • Competitively inhibit utilization of normal substrate or get themselves incorporated forming dysfunctional macromolecules • Folate antagonist  Methotrexate
Methotrexate • Inhibits dihydrofolate reductase (DHFRase)—blocking the conversion of dihydrofolic acid (DHFA) to tetrahydrofolic acid (THFA) which is an essential coenzyme required for one carbon transfer reactions in de novo purine synthesis and amino acid interconversions • Methotrexate primarily inhibits DNA synthesis, but also affects RNA and protein synthesis • It exerts major toxicity on bone marrow
Mtx
• Aspirin and sulfonamides ↓ its renal tubular secretion  ↑ toxicity • The toxicity of Mtx cannot be overcome by folic acid, because it will not be converted to the active coenzyme form • However, Folinic acid (N5 formyl THFA, cirtrovorum factor) rapidly reverses the effects • High dose Mtx with ‘folinic acid rescue’ has been employed in many difficult to treat neoplasms
Uses of Methotrexate • Inhibit – Immunosuppressant • C – Crohn’s disease • A – Abortion • N – Non Hodgkin Lymphoma • C – Choriocarcinoma • E – Ectopic pregnancy • R – Rheumatoid arthritis
• Pemetrexed This is a new congener of methotrexate that has found use in mesoepithelioma and nonsmall cell lung cancer
Purine antagonists • Mercaptopurine (6-MP) and thioguanine (6-TG) are converted in the body to the corresponding monoribonucleotides which inhibit purine synthesis and utilization of purine nucleotides • They are specially useful in childhood acute leukaemia, choriocarcinoma and in some solid tumours
• Azathioprine has marked effect on T lymphocytes, suppresses cell mediated immunity (CMI) and is used primarily as immunosuppressant in organ transplantation, rheumatoid arthritis, etc. • Azathioprine and 6MP are metabolized by xanthine oxidase; their metabolism is inhibited by allopurinol; dose has to be reduced to ¼–½ if allopurinol is given concurrently.
• Thioguanine is not a substrate for xanthine oxidase; its dose need not be reduced if allopurinol is given • Fludarabine is a newer antipurine that is active even in some slow growing and recurrent cancers • Toxicity 1. Bone marrow depression 2. Mucositis 3. Jaundice 4. Hyperuricaemia
Pyrimidine antagonists • Fluorouracil (5-FU) is converted in the body to the corresponding nucleotide which blocks the conversion of deoxyuridilic acid to deoxythymidylic acid  Selective failure of DNA synthesis occurs • Concurrent i.v. infusion of leucovorin (folinic acid) enhances efficacy of 5FU • Cisplatin is also synergistic • Most treatment protocols for 5FU employ it alongwith Leucovorin and Cisplatin
• 5FU has been particularly used for many solid tumours—breast, colon, urinary bladder, liver, head and neck, etc. • Capecitabine is an orally active prodrug of F.U., which is especially active against colorectal and breast cancers • Cytarabine is phosphorylated in the body to the corresponding nucleotide which inhibits DNA synthesis by DNA polymerase • Uses  Acute leukaemia in children & adults, Hodgkin’s disease and non Hodgkin lymphoma
Microtubule damaging agents • Vinca alkaloids  Mitotic inhibitors, bind to microtubular protein—‘tubulin’, prevent its polymerization and assembly of microtubules, cause disruption of mitotic spindle and interfere with cytoskeletal function • Chromosomes fail to move apart during mitosis: metaphase arrest occurs • Cell cycle specific & act in the mitotic phase
• Vincristine (oncovin)  Childhood acute leukemia, lymphosarcoma, Hodgkin’s disease, Wilms’ tumour, Ewing’s sarcoma and carcinoma lung • A/E  Peripheral neuropathy and alopecia. Bone marrow depression is minimal • Vinblastine  Employed with other drugs in Hodgkin’s disease and testicular carcinoma • Bone marrow depression is more prominent, while neurotoxicity and alopecia are less marked than with Vincristine • Vinorelbine  Semisynthetic Vinblastine analogue which is primarily used in non small cell lung cancer
Taxanes • Paclitaxel binds to β tubulin and enhances its polymerization  Inhibition of normal dynamic reorganization of the microtubule network that is essential for interphase and mitotic functions • The indications of paclitaxel are metastatic ovarian and breast carcinoma after failure of first line chemotherapy. It has also shown efficacy in advanced cases of head and neck cancer, small cell lung cancer, esophageal adenocarcinoma, etc. • Toxicity  Reversible myelosuppression and ‘stocking and glove’ neuropathy
Stocking & glove neuropathy
• Docetaxel  More potent congener • Indications 1. Breast & ovarian cancer refractory to 1st line drugs 2. Small cell cancer lung 3. Pancreatic carcinoma 4. Gastric carcinoma 5. Head/neck carcinoma • Toxicity  Neutropenia, but neuropathy is less frequent
Estramustine • Complex of estradiol with a nitrogen mustard has weak estrogenic, but no alkylating property • Binds to β tubulin preventing its organization into microtubules (exerts antimitotic action) • Indication  Advanced or metastatic prostate cancer
Topoisomerase-2 inhibitor • Etoposide arrests cells in the G2 phase and causes DNA breaks by affecting DNA topoisomerase 2 function • Uses 1. Testicular tumors 2. Lung cancer 3. Hodgkin’s and other lymphomas 4. Carcinoma bladder
Topoisomerase-1 inhibitors • Topotecan & Irinotecan act in a manner similar to Etoposide but interact with a different enzyme DNA topoisomerase 1 • Uses  Metastatic carcinoma of ovary and small cell lung cancer after primary chemotherapy has failed • Toxicity  Bone marrow depression, especially neutropenia • Irinotecan  Metastatic/advanced colorectal carcinoma, cancer lung/cervix/ovary, etc. • Dose limiting toxicity  Diarrhoea
Antibiotics • Products obtained from microorganisms and have prominent antitumour activity • Intercalate b/w DNA strands & interfere with its template function • Actinomycin D (Dactinomycin) is highly efficacious in Wilms’ tumour, rhabdomyosarcoma and a few other malignancies • A/E  Vomiting, stomatitis, diarrhoea, desquamation of skin, alopecia and bone marrow depression
• Daunorubicin (Rubidomycin)  Acute leukaemia • Doxorubicin  Acute leukaemia & solid tumours • Dauno & Doxo are capable of causing breaks in DNA strands by activating topoisomerase 2 and generating quinone type free radicals • Toxicity  Cardiotoxic (arrhythmias, cardiomyopathy, heart failure; marrow depression, alopecia, stomatitis
Doxo Dauno
• Bleomycin  Chelates copper or iron, produces superoxide ions and intercalates between DNA strands—causes chain scission and inhibits repair • Uses  Testicular tumour, Squamous cell carcinoma of skin, oral cavity, head and neck, and esophagus; also useful in Hodgkin’s lymphoma • Toxicity  Mucocutaneous toxicity and pulmonary fibrosis, but little myelosuppression
Miscellaneous cytotoxic drugs • Hydroxyurea blocks the conversion of ribonucleotides to deoxyribonucleotides (interferes with DNA synthesis); exerts S phase specific action • Uses  chronic myeloid leukaemia, psoriasis, polycythaemia vera and in some solid tumours. • Toxicity  Myelosuppression • L-Asparaginase  Induce remission in childhood lymphoblastic leukaemia • Toxicity  Liver damage & allergic reactions
Targeted drugs • These are recently developed drugs which attack cancer specific target biomolecules or processes • Targeted drugs can be divided in 2 major types: 1. Specific monoclonal antibodies  Attack cell surface targets or tumor antigens;given parenterally 2. Synthetic compounds which penetrate cells and affect cancer specific enzymes or processes (active orally)
1. Tyrosine protein kinase inhibitors  Imatinib & Nilotinib (Inh. ‘Bcr–Abl’ expressed by chronic myeloid leukaemia cells and related tumours) 2. EGF receptor inhibitors  Epidermal growth factor (EGF) acts on a transmembrane receptor tyrosine kinase to regulate growth and differentiation of epithelial cells.
• Gefitinib and Erlotinib  Penetrate cells & bind to the tyrosine kinase domain of EGF receptor and prevent phosphorylation of regulatory proteins. Effective in lung & pancreatic cancers • Cetuximab  Chimeric monoclonal antibody directed to the extracellular domain of the EGF receptor. Its binding interferes with transmembrane signalling. • Weekly i.v. infusion of Cetuximab suppresses advanced/metastatic squamous carcinoma of head and neck and EGF positive colorectal cancer
3. Angiogenesis inhibitors • Vascular endothelial growth factor (VEGF)  Most important stimulus for neovascularization • Bevacizumab  Binds to the VEGF rec. interrupting angiogenic signalling • Sunitinib  Synthetic VEGF receptor 2 inhibitor • Certain cancers over express VEGF receptor and are susceptible to these drugs
4. Proteasome inhibitor • Bortezomib is a unique boron containing compound that binds to and inhibits ‘proteasomes’, which are packaged complexes of proteolytic enzymes which control cell cycle by degrading intracellular signalling proteins • Bortezomib thus disrupts many intracellular signalling pathways, the most important of which involves the nuclear factor kB (NFkB) • Multiple myeloma and few other neoplasms overexpress NFkB and are suppressed by this drug
Bortezomib
5. Specific monoclonal antibodies • Monoclonal antibodies (MAbs) are sourced from hybridomas created by fusing a continuously proliferating cell line with antibody producing B lymphocytes sensitized against a particular antigen • Malignant cells express certain unique antigens on their surface
• MAbs directed to these antigens have been produced and tested • MAbs kill the target cells by following mechanisms :- 1. Direct signaling of apoptosis 2. Antibody dependent cellular toxicity (ADCC) 3. Compliment dependent cytotoxicity (CDC)
Formation of monoclonal antibodies
Nomenclature of Monoclonal Antibodies • Divided into 4 parts  Prefix + Target subsystem + Origin subsystem + Suffix • Suffix for all monoclonal antibodies is mab • Depending on the source of origin, various names are given, e.g. u stands for human, xi for chimeric • Target is identified by specific letters, e.g. vi for virus, ci for circulation • Prefix is different for each monoclonal antibody
• Rituximab  Chimerized MAb that binds to the CD20 B cell antigen which is expressed on the surface of B lymphocytes and B cell lymphomas • Rituximab promotes apoptosis in B cell lymphoma, non Hodgkin lymphoma and chronic lymphocytic leukaemia • Has yielded survival benefit to the patients with these malignancies
Hormonal drugs • Palliative • Glucocorticoids 1. Used in 1. Acute childhood leukemia and lymphomas 2. Hodgkin’s disease 3. Hormone responsive breast cancers 2. Induce remission rapidly but relapses occur inevitably
3. Control complications like hypercalcaemia, haemolysis and bleeding due to thrombocytopenia 4. Afford symptomatic relief by antipyretic and mood elevating action 5. Potentiate antiemetic action of Ondansetron or Metoclopramide
• Estrogens  Symptomatic relief in carcinoma prostate; superseded by GnRH agonists used along with an antiandrogen • Selective estrogen receptor modulators (tamoxifen), Selective estrogen receptor down regulator (Fulvestrant) and Aromatase inhibitors (Letrozole, etc.)  Adjuvant and palliative therapy of carcinoma breast, as well as for prevention of breast cancer • Antiandrogen  Flutamide & Bicalutamide antagonize androgen action on prostate carcinoma & have palliative effect in advanced/metastatic cases
MOA of Tamoxifen
Antiandrogens
• 5-α reductase inhibitor  Finasteride & Dutasteride in advanced carcinoma prostate. • GnRH agonists  Adjuvant/palliative effect in advanced estrogen/androgen dependent carcinoma breast/prostate • Progestins  Temporary remission in some cases of advanced, recurrent (after surgery/radiotherapy) & metastatic endometrial carcinoma
General Principles In Chemotherapy Of Cancer 1. Selectivity of drugs for the tumor cells is limited: toxicity is high. As such, measures to enhance selectivity need to be employed 2. A single clonogenic malignant cell is capable of producing progeny that can kill the host 3. In any cancer, subpopulations of cells differ in their rate of proliferation and susceptibility to cytotoxic drugs. • These drugs kill cancer cells by first order kinetics, i.e. a certain fraction of cells present are killed by one treatment
4. Drug regimens or treatment cycles which can effectively palliate large tumor burdens may be curative when applied to minute residual tumor cell population after surgery and/or irradiation. This is the basis of the combined modality approach 5. Whenever possible, complete remission should be the goal of cancer chemotherapy: drugs are often used at maximum tolerated doses. Intensive regimens used at an early stage in the disease yield better results. 6. Generally a combination of 2–5 drugs is given in intermittent pulses to achieve total tumor cell kill, giving time in between for normal cells to recover
• Synergistic combinations and rational sequences are devised by utilizing: 1. Drugs which are effective when used alone 2. Drugs with different mechanisms of action 3. Drugs with differing toxicities 4. Empirically by trial and error; optimal schedules are mostly developed by this procedure 5. Kinetic scheduling: on the basis of cell cycle specificity or nonspecificity of drugs
1. Cell cycle nonspecific  Kill resting as well as dividing cells, e.g. mechlorethamine, Cyclophosphamide, Chlorambucil, Carmustine, Dacarbazine, L asparaginase, Cisplatin, Procarbazine, Actinomycin D. 2. Cell cycle specific  Kill only actively dividing cells. Their toxicity is generally expressed in S phase. • These drugs may show considerable phase selectivity
Cancer drugs—cell cycle
7. Tumors often become resistant to the drug used repeatedly due to selection of less responsive cells 8. Measures employed to ameliorate the toxicity of anticancer drugs are: 1. Use of biological response modifiers like recombinant granulocyte colony stimulating factor (GCSF) and granulocyte macrophage colony stimulating factor (GMCSF)  Molgramostim, Filgrastim, hasten recovery of neutrophil count following myelosuppressant chemotherapy
2. Amifostine provides free thiol radical and reduces renal toxicity of cisplatin as well as xerostomia due to radiotherapy 3. Folinic acid rescue can reduce methotrexate toxicity 4. Cystitis caused by Cyclophosphamide can be blocked by Mesna administered along with it 5. Ondansetron ± dexamethasone, lorazepam, aprepitant protect against cisplatin (and other emetic drugs) induced vomiting 6. Hyperuricaemia due to destruction of bulky tumours can be reduced by allopurinol
Therapy of choice for various cancers Diagnosis Treatment of choice ALL (Acute lymphocytic leukemia) Induction  Vincristine + Prednisolone + Daunorubicin + Asparaginase + Intrathecal Methotrexate Consolidation  Hyper-CVAD [Cyclophosphamide + Vincristine + Adriamycin (Doxorubicin) + Dexamethasone] alternated with Cytarabine + Methotrexate
Diagnosis Treatment of choice AML (Acute myeloid leukemia) Cytarabine + Daunorubicin/Idarubicin CML (Chronic myeloid leukemia) Imatinib (or Nilotinib or Dasatinib) CLL (Chronic lymphocytic leukemia) FCR [Fludarabine, Cyclophosphamide, Rituximab] (<70 years) Chlorambucil (>70 years) Hodgkin’s disease ABVD [Adriamycin + Bleomycin + Vinblastine + Dacarbazine]
Diagnosis Treatment of choice Non-Hodgkin’s Lymphoma CHOP-R [Cyclophosphamide + Hydroxydaunorubicin (Doxorubicin) + Oncovin (Vincristine) + Prednisone + Rituximab] Breast cancer Endocrine : Tamoxifen (Pre- menopausal) Aromatase inhibitor (Post-menopausal) Adjuvant chemoterapy: Doxorubicin + Cyclophosphamide + Docetaxel ± Trastuzumab
Toxicity of chemotherapeutic agents