CANCER CHEMOTHERAPY

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CANCER CHEMOTHERAPY:

PRESENTED BY RAVINDER NAIK .D NIPERA 1113 PC 01 CANCER CHEMOTHERAPY

Introduction :

Cancer also known as malignant neoplasm and malignant tumour . characteristics Uncontrolled proliferation Dedifferentiation Invasiveness Metastasise The appearance of these abnormal characteristics reflects altered patterns of gene expression in the cancer cells, resulting from genetic mutations. Introduction

PATHOGENESIS:

A normal cell turns into a cancer cell because of one or more mutations in its DNA, which can be acquired or inherited. Carcinogenesis is a complex multistage process, usually involving more than one genetic change as well as other, epigenetic factors (hormonal, co-carcinogen and tumour promoter effects, etc.) There are two main categories of genetic change that are important. 1. The activation of proto- oncogenes to oncogenes . 2. The inactivation of tumour suppressor genes. PATHOGENESIS

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The changes that lead to malignancy are a result of point mutations, gene amplification or chromosomal translocation, often caused by viruses or chemical carcinogens.

Treatment :

Treatment Radiation Immunotherapy Surgery Chemotherapy Cancer

Chemotherapy :

Chemotherapeutic agents play main role in treatment of cancer. One of the major difficulties in treating cancer is that tumour growth is usually far advanced before cancer is diagnosed. Most anticancer drugs are antiproliferative -most damage DNA and thereby initiate apoptosis. They also affect rapidly dividing normal cells and are thus likely to depress bone marrow, impair healing and depress growth. Most cause nausea, vomiting, sterility, hair loss and teratogenicity . Chemotherapy

Drugs :

Cytotoxic drugs : they act directly on cells A . Alkylating agents Nitrogen mustards : Mechlorethamine , Cyclophosphamide , Chlorambucil , Melphalan Ethylenimide : Thio -TEPA Alkyl sulfonate : Busulfan Nitrosoureas : Carmustine , Lomustine Triazine : Dacarbazine Drugs

Contd…:

B. Anti metabolites Folate antagonist : Methotrexate Purine antagonist : 6-Mercaptopurine, 6-Thioguanine , Azathioprine , Fludarabine . Pyrimidine antagonists : 5-Fluorouracil, Cytarabine C. Vinca alkaloids : Vincristine , Vinblastine . D. Taxanes : Paclitaxel , Docetaxel . E. Epipodophyllotoxin : Etoposide F. Campothecin : Topotecan , Irinotecan . G. Antibiotics : D’actinomycin , Doxorubicin, Daunorubicin , Bleomycin,Mitomycin C H. Miscellaneous : Procarbazine , cisplatin , Imatinib Contd …

Contd…:

II. Hormones Glucocorticoids : Prednisolone,Dexamethasone . Estrogens : Fosfestrol , Ethinylestradiol . SERMs : Tamoxifen , Tormifene . Aromatase inhibitors : letrozole , Anastrazole , Exemestane . Anti androgens : Flutamide , Bicalutamide 5- α reductase inhibitor : Finasteride , Dutasteride GnRH analogues : Triptorelin,Naferelin . Progestins : Hydroxyprogesterone acetate. Contd …

Alkylating agents:

MOA : Disturbs DNA synthesis and cell division. The capacity of these drugs to interfere with DNA integrity and function and to induce cell death in rapidly proliferating tissues provides the basis for their therapeutic and toxic properties. Alkylating agents

Mustard gas:

Each 2-chloroethyl side-chain undergoes an intramolecular cyclisation with the release of a Cl - . The highly reactive ethylene immonium derivative so formed can interact with DNA and other molecules. Mustard gas

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Cyclophosphamide : is probably the most commonly used alkylating agent. Prodrug . Can also be used as an immunosuppressant. Haemorrhagic cystitis is its potential adverse effect. This is caused by its metabolite Acrolein , and it can be ameliorated by N- acetylcysteine (MESNA). Carmustine & Lomustine : Highly lipophilic . Can cross BBB. Nitrosoureas have a severe cumulative depressive effect on the bone marrow

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Busulfan : Has a selective effect on the bone marrow, depressing the formation of granulocytes and platelets in low dosage and of red cells in higher dosage. It has little or no effect on lymphoid tissue or the gastrointestinal tract. It is used in chronic granulocytic leukaemia. Cisplatin : When it enters the cell, Cl - dissociates, leaving a reactive complex that reacts with water and then interacts with DNA. It causes intrastrand cross-linking. Nephrotoxicity and Myelotoxicity . Dacarbazine : Prodrug Unwanted effects include myelotoxicity and severe nausea and vomiting

Anti metabolites :

Anti metabolites

MTX ::

Nephrotoxic , bone marrow depressant. Folic acid is also administered along with MTX. 5-fluoruracil : An analogue of uracil . interferes with DTMP synthesis It is converted into a 'fraudulent' nucleotide, fluorodeoxyuridine monophosphate (FDUMP). This interacts with thymidylate synthetase but cannot be converted into DTMP. Capecitabine is metabolized to fluorouracil. MTX :

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6-Mercapapurine ( 6-MP ) inhibit purine base synthesis, although their exact mechanisms of action are still uncertain. Myelosuppression is generally mild with thioguanine . Long-term mercaptopurine use may cause hepatotoxicity . Cytarabine : Cytarabine has a narrow clinical spectrum . Primarily used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia. High doses of cytarabine can damage the liver, heart, and other organs.

Antibiotics : :

Adriamycin and Daunorubicin : Adriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine . They are DNA intercalating agents that block the synthesis of DNA and RNA . Myelosuppression and cardiotoxicity are the common side effect of antibiotics used to treat cancer. Tubulin -Binding Agents Vinca Alkaloids: The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly, causing cells to arrest in the late G2 phase by preventing formation of mitotic filaments for nuclear and cell division. Antibiotics :

Taxanes :

Paclitaxel and docetaxel are derived from the bark of the yew tree. They act on microtubules, stabilising them (in effect 'freezing' them) in the polymerised state, achieving a similar effect to that of the vinca alkaloids. Neurotoxicity , bone marrow suppression and hypersensittvity reactions. Irinotecan and Topotecan isolated from the stem of the tree Camptotheca acuminata , bind to and inhibit topoisomerase I, high levels of which occur throughout the cell cycle Taxanes

Horomones :

Tumours derived from hormone-sensitive tissues may be hormone- dependent,an effect related to the presence of steroid receptors in the malignant cells. Their growth can be inhibited by hormones with opposing actions, by hormone antagonists. 1. Glucocorticoids : such as prednisolone and dexamethasone have marked inhibitory effects on lymphocyte proliferation and are used in the treatment of leukaemias and lymphomas. 2. Oestrogens : Diethylstilbestrol and ethinyloestradiol are two oestrogens used clinically in treatment of androgen-dependent prostatic tumours. Horomones

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3. Progestogens : such as megestrol , norethisterone and medroxyprogesterone have been useful in endometrial neoplasms and in renal tumours. 4. Gonadotrophin hormone analogues : inhibit gonadotrophin release. These agents are therefore used to treat advanced breast cancer in premenopausal women and prostate cancer. 5. Antioestrogens : Tamoxifen , is remarkably effective in some cases of hormone-dependent breast cancer tamoxifen competes with endogenous oestrogens for the oestrogen receptors and therefore inhibits the transcription of oestrogen-responsive genes.

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6 . Aromatase inhibitors : such as anastrozole , letrozole and exemestane , which suppress the synthesis of oestrogen from androgens, are also effective in the treatment of breast cancer. 7. Antiandrogens : flutamide , cyproterone and bicalutamide , may be used either alone or in combination with other agents to treat tumours of the prostate. 8. Adrenal hormone synthesis inhibitors : Trilostan and (rarely today) aminoglutethimide which inhibit the early stages of sex hormone synthesis. They have effects in postmenopausal breast cancer 9. RADIOACTIVE ISOTOPES: they have an important place in the therapy of certain tumours; for example, radioactive iodine ( 131 I) is used in treating thyroid tumours

Monoclonal antibodies : :

Immunoglobulins Two monoclonal antibodies are currently in clinical use: rituximab and trastuzumab . It lyses B lymphocytes by binding to the calcium channel-forming CD 20 protein and activating complement. It also sensitises resistant cells to other chemotherapeutic drugs. trastuzumab induces cell cycle inhibitors p21 and p27 in Tumour cells. Monoclonal antibodies :

Miscellaneous ::

Imatinib mesylate : is a small-molecule inhibitor of signalling pathway kinases . It not only inhibits platelet-derived growth factor (a receptor tyrosine kinase ) but also a cytoplasmic kinase . Miscellaneous :

Novel targets ::

Tyrosine kinase inhibitors Angiogenesis and metalloproteinase inhibitors Cyclo-oxygenase inhibitors p53 as anticancer target Antisense oligonucleotides : Are synthetic sequences of single-stranded DNA complementary to specific coding regions of mRNA, which can inhibit gene expression. Gene therapy Novel targets :

References :

Rang and Dale’s Pharmacology 6 th edition. Essentials of medical pharmacology by K.D.Tripati Lippincott’s Illustrated reviews in pharmacology Goodman & gilman’s The Pharmacological Basis of Therapeutics References

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Thank you….

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