Anti cancer drugs

Introduction, genesis, pathophysiology of cancer and various treatments along with detailed mechanism of action and adverse effects.

1. Anti-Cancer Drugs Done By : Mukul Tambe Friday, February 15, 2019 1

2. Contents Introduction. Genesis of a cancer cell. Cell cycle. Causes. Classification of cancers. Anti-Cancer drugs classification. Mechanism of action. References. Friday, February 15, 2019 2

3. Introduction Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of the body’s own cell. There are two types of tumors : 1. Benign tumor 2. Malignant tumor Benign tumor : It is not a cancer cell it will not spread to other cells. Malignant tumor : It is a cancer cell which can spread to neighboring tissues and enters into blood cells. Friday, February 15, 2019 3

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5. Genesis of a Cancer cell A normal cell turns to cancer cell because of one or more mutations in its DNA which can inherited or acquired. The development of cancer is a complex multistage process, involving not only more than one genetic change but usually also other epigenetic factors like hormonal action. There are two main categories of genetic change: The activation of proto-oncogenes to oncogenes. The inactivation of tumor suppressor genes. Friday, February 15, 2019 5

6. Activation of proto-oncogene to oncogene : Genes that normally control cell division , apoptosis, differentiation but converted to oncogenes by viral or carcinogen action. Inactivation of tumor suppressor genes : Normal cells contain genes that have ability to suppress the malignant but due to mutations the loss of tumor suppressor genes can be critical in carcinogenesis. Friday, February 15, 2019 6

7. Cell cycle G o phase : Resting phase. G 1 phase : Mech. Ensures that everything is ready for DNA synthesis. S phase : DNA replication occurs during this phase. G 2 phase : Mech. Ensures that everything is ready to enter the Mitosis phase and divide. M phase : Cell growth stops at this stage. Friday, February 15, 2019 7

8. Cell cycle is regulated by two factors: 1. Positive regulators of cell growth. 2. Negative regulators of cell growth. Increase in positive regulators cause tumor which further divided by Mutations. Negative regulators cause cell injury. Cancer cells can manifest from normal cells by following: 1.Uncontrolled proliferation. 2.Dedifferentiation and loss of function. 3.Invasiveness. 4.Metastasis. Friday, February 15, 2019 8

9. Normal cell mitosis Friday, February 15, 2019 9

10. Cancer cell mitosis Friday, February 15, 2019 10

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12. Causes Majority cancers(90-95%) are caused by Environmental factors. Remaining (5-10%) are caused by inherited genetics. Cancers are caused by some viruses they are Oncoviruses which include human papiloma virus, Epstein-Barr virus, Hepatitis B and C virus. Some types of bacteria Helicobacter pylori. Friday, February 15, 2019 12

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15. Classification of Cancer Based on type of cell : Carcinoma : Derived from Epithelial cells. Sarcoma : Cancer arising from connective tissue. Lymphoma and Leukemia : These two classes arise from hematopoietic cells. Germ cell tumor : Arise from pluripotent cells. Blastoma : Cancers derived from immature precursor cells or embryonic tissue. Friday, February 15, 2019 15

16. Anti-Cancer drugs Anticancer drugs Cytotoxic Drugs Hormones and their (killing the antagonists Cancer cells) (suppressing the cancer cells by altering the hormonal mileau) Friday, February 15, 2019 16

17. Alkylating Agents Antimetabolites Natural Products Cytotoxic Drugs Platinum compounds Monoclonal antibodies Miscellaneous Agents Friday, February 15, 2019 17

18. Alkylating Agents Nitrogen mustards : Cyclophosphamide, Ifosfamide, Estramustine , Melphalan Chlorambucil, Mechlorethamine. Ethylenimines : Thiotepa. Methlmelamine : Altretamine. Alkyl sulfonates : Busulphan Treosulfan Nitrosoureas : Lomustine, Carmustine, Semustine, Streptozocin. Triazenes : Dacarbazine , Temozolamide. Friday, February 15, 2019 18

19. Antimetabolites Folate Antagonist : Methotrexate, Pemetrexed. Purine antagonists : 6-mercaptopurine, 6- thioguanine, Azathioprine Fludarabine, Pentostatin Cladribine. Pyrimidine antagonists : 5-fluorouracil Floxuridine Cytarabine Gemcitabine Capecitabine Azacitidine Friday, February 15, 2019 19

20. Natural Products Vinca alkaloids : Vincristine, Vinblastine, Vinorelbine. Taxanes : Paclitaxel, Docetaxel Epipodophyllotoxin : Etoposide, Teniposide. Camptothecins : Topotecan, Irinotecan. Enzymes : L- Asparaginase Antibiotics : Dactinomycin, Doxorubicin, Daunorubicin Epirubicin, Idarubicin, Aclarubicin, Bleomycin, Mithramycin, Mitomycin, Methoxantrone Friday, February 15, 2019 20

21. Platinum compounds : Cisplatin, Carboplatin Oxaliplatin. Monoclonal Antibodies : Transtuzumab, Alemtuzumab Tositumab, Rituximab, Cituximab Gemtuzumab, Bevacizumab. Miscellaneous Agents : Hydroxyurea, Procarbazine Interferon- α , Imatinib, Gefitinib Erlotinib, Bortezomib. Friday, February 15, 2019 21

22. Glucocorticoids Anticorticoids Androgens & Antiadrogens Hormones and their antagonists Estrogens & Antiestrogens Progestins Aromatase inhibitors Gn RH superagonists Friday, February 15, 2019 22

23. Glucocorticoids : Prednisolone, Dexamethasone. Anticorticoid : Aminoglutethimide, Trilostane. Androgens : Testosterone, Fluoxymestrone. Antiandrogens : Flutamide, Nilutamide, Bicalutamide, finasteride, Dutasteride. Estrogens : Ethinyl estradiol, Diethylstilbestrol, Fosfestrol. Antiestrogens : Tamoxifen, Toremifene, Fluvestrant. Progestins : Hydroxyprogesterone acetate, Megestrol, Norethisterone, Medroxyprogesterone. Aromatase inhibitors : Anastrozole, Letrozole, Exemestane. Gn RH superagonists : Laprorelin, Naferelin, Goserelin, Buserelin, Triptorelin. Friday, February 15, 2019 23

24. MECHANISM OF ACTION Friday, February 15, 2019 24

25. Vinca alkaloids and taxanes acts on M phase because of mitotic spindles formation. Epipodophyllotoxins, Campthothecins, Anti cancer antibiotics acts on G 2 phase. Anti metabolites acts on S phase. Friday, February 15, 2019 25

26. Alkylating agents Formation of Carbonium ion is main step. ↓ Attacks lone pair of electron in DNA. ↓ Cross linked with DNA. Most of cytotoxic anticancer alkylating agents are bifunctional i.e., they have two alkylating groups . Friday, February 15, 2019 26

27. Nitrogen mustards : Cyclophosphamide is most commonly used alkylating agent. Its is given orally or I.V. and also given through I.M. Toxic effects: Nausea. Vomiting. Bone marrow depression and Haemorrhagic cystitis. Estramustine is a combination of mustine with an estrogen. It has both cytotoxic and hormonal action . Friday, February 15, 2019 27

28. Nitrosoureas: They are lipid soluble and cross BBB. Most of nitrosoureas have a severe cummulative depressive effect on bone marrow that starts 3-6 weeks after initiation of treatment. Alkyl sulfonates : Busulphan has a selective effect on bone marrow depressing the formation of granulocytes and platelets in lower dose and RBC in higher dose. It is used in chronic granulocytic leukaemia. Friday, February 15, 2019 28

29. Triazenes : Dacarbazine is a pro drug is activated in liver and the resulting compound is subsequently cleaved in the target cell to release an alkylating derivative. Unwanted effects include severe nausea and vomiting. Friday, February 15, 2019 29

30. Anti metabolites Pteridine ↓ Dihydro pteridine ↓ Dihydro pteroic acid synthase Dihydro pteroic acid ↓ Dihydro folate reductase.(DHFR) Dihydro folate ↓ DHFR Tetrahydrofolate AMP synthase Thymidilate synthase Purines Pyrimidines Friday, February 15, 2019 30

31. Folate antagonist acts on DHFR and inhibit the formation of dihydro folate. Unwanted effects : Depression of Bone marrow. Damage of the epithelium of GIT. Pyrimidine antagonists inhibit Thymidilate synthase results in the inhibition of DNA synthesis. Cytarabine inhibit DNA polymerase. Unwanted effects: Bone marrow depression. Nausea. Vomiting. Friday, February 15, 2019 31

32. Gemcitabine new analogue of cytarabine has unwanted effects like influenza and mild myelotoxicity. Purine antagonist inhibit Adenosine monophosphate synthase. Fludarabine is metabolised to triphosphate and inhibits DNA synthesis. It is myelosuppressive. Pentostatin has different M.O.A. It inhibit adenosine deaminase enzyme which catalyses deamination of adenosine to inosine. It has significant effects on cell proliferation. Friday, February 15, 2019 32

33. Natural Products Vinca alkaloids : They act by binding to tubulin and inhibiting its polymerization into microtubules which prevents the spindle formation in mitosing cells and causes arrest at metaphase. Their effects are only because of changes in mitosis. Vincristine has mild myelosuppressive activity but causes paraesthesias. Vinblastine is less neurotoxic but causes leucopenia. Vinorelbine is a new Vinca alkaloid. Friday, February 15, 2019 33

34. Taxanes : Stabilizes microtubules and inhibit mitosis. Paclitaxel is given by I.V. and Docitaxel is given through orally. These are used in treating Breast cancers. Paclitaxel+Carboplatin is the choice of treatment for Ovarian cancer. Unwanted effects: Bone marrow suppression. Cummulative Nephrotoxicity. Friday, February 15, 2019 34

35. Epipodophyllotoxins : It acts by inhibiting mitochondrial function and nucleoside transport and having effect on Topoisomerase-II. Unwanted effects are Nausea, Vomiting, and hair loss. Campthothecins : These are bind and inhibit Topoisomerase-I. Diarrhoea and reversible Bone marrow depression. Friday, February 15, 2019 35

36. Anti-Cancer Antibiotics : It shows action by inhibiting Topoisomerase-II. Epirubicin is less cardiotoxic than doxorubicin. Bleomycin is most effective in G 2 phase and mitosis but it is also active against non dividing cells. Mitomycin cross links the DNA and degrade DNA through the generation of free radicals. Friday, February 15, 2019 36

37. Monoclonal antibodies These are immunoglobulins produced by cell culture to react with antigen expressed on cancer cells. Rituximab is a monoclonal antibody that attaches to CD20 protein on B cells and kills complement mediated lysis. Unwanted effects hypertension, chills, and fever during initial infusion. Trantuzumab is a humanised monoclonal antibody. Unwanted effects similar to Rituximab. Friday, February 15, 2019 37

38. Platinum compounds Cisplatin is a water soluble coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups. It action is similar to alkylating agents. When enters the cell chlorine dissociates leaving complex that reacts with water and interacts with DNA. It causes cross linking of DNA. Cisplatin given through I.V. It has low myelotoxicity but severe nausea and vomiting. Friday, February 15, 2019 38

39. Hormones and their antagonists Glucocorticoids : It has inhibitory effect on lymphocyte proliferation and used in leukaemia. Tamoxifen used in Breast cancer. Gonadotropin releasing hormone analouges are for Breast cancer and Prostate cancer. Anti androgens for Prostate cancer. Friday, February 15, 2019 39

40. References Pharmacology by H.P.Rang and M.M.Dale 5 th edition page no. 693. Friday, February 15, 2019 40

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