Cytotoxic Drugs

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General Principles Of Cancer Chemotherapy & Cytotoxic Drugs: 

General Principles Of Cancer Chemotherapy & Cytotoxic Drugs

INTRODUCTION : 

Cytotoxic drugs are therapeutic agents intended for, but not limited to, the treatment of cancer. These drugs are known to be highly toxic to cells, mainly through their action on cell reproduction. Cytotoxic drugs are increasingly being used in a variety of healthcare settings, laboratories and veterinary clinics for the treatment of cancer and other medical conditions such as rheumatoid arthritis, multiple sclerosis and auto-immune disorders. INTRODUCTION

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Cytotoxic drugs are toxic compounds and are known to have carcinogenic, mutagenic and/or teratogenic potential. With direct contact they may cause irritation to the skin, eyes, and mucous membranes, and ulceration and necrosis of tissue.

General principles: 

The purpose of treating cancer with chemotherapeutic agents is to prevent cancer cells from multiplying, invading, metastasizing, and ultimately killing the host. The goal in selecting an effective drug, therefore is to find an agent that has marked growth inhibitory or controlling effect on the cancer cell with minimal toxic effect on the host. General principles

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Treatment strategies Goal of treatment Indications for treatment Tumor susceptibility and the growth cycle Cell-cycle specificity of drugs Tumor growth rate Treatment regimens and scheduling Log kill Treatment protocols Combinations of drugs Advantages of drug combinations Treatment protocols

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Problems associated with chemotherapy Resistance Multidrug resistance Toxicity Common adverse effects Minimizing adverse effects

Chemotherapeutic agents: 

Alkylating agents Antimetabolites Natural products Hormones and their antagonists Miscellaneous agents Chemotherapeutic agents

Alkylating agents : 

Nitrogen mustard: cyclophosphamide , ifosfamide , mechlorethamine , melphalan , chlorambucil . Nitrosoureas : carmustine , lomustine , semustine . Alkyl sulfonates : busulfan Metal salts : cisplatin , carboplatin Others : thiotepa , dacarbazine . Alkylating agents

Antimetabolites : 

Folate antagonists : methotrexate Purine antagonists : 6 mercaptopurine , 6-thioguanine, pentostatin , fludarabine . Pyrimidine antagonists : 5-fluorouracil , cytarabine . Antimetabolites

Natural products i)Antibiotics : 

Dactinomycin Doxorubicin Bleomycin Daunorubicin Mitomycin Idarubicin Plicamycin Natural products i )Antibiotics

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ii)Mitotic inhibitors: Plant alkaloids : vincristine , vinblastine , vinorelbine . iii)Microtubule polymer stabiliser : paclitaxel , docetaxel . iv) Podophyllum derivatives: etoposide , teniposide . v) Enzyme : asparaginase

Hormones and their antagonists: 

Androgens : fluoxymesterone and others Corticoseroid : prednisone , dexamethasone Estrogen : diethylstilbestrol Progestin : megestrol acetate, medroxyprogesterone acetate. Antiestrogens : tamoxifen Antiandrogens : flutamide Leutinizing hormone- releasing hormone agonist: leuprolide , goserelin . Hormones and their antagonists

Miscellaneous drugs: 

Substituted urea: hydroxyurea Methylhydrazine derivative : procarbazine Adrenocortical suppressant: mitotane Steroid synthesis inhibitor: aminoglutethimide Substituted melamine: altretamine Miscellaneous drugs

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Cytotoxic agent can be roughly categorized based on their activity in relation to the cell cycle.

Phase specific drugs: 

Effective only in particular phase of cell cycle. Phase specific drugs Cell phase TYPE CHEMOTHERAPEUTIC AGENTS G1 ENZYME CORTICOSTEROID L-ASPARAGINASE PREDNISONE G1/S PURINE ANTAGONISTS CLADRIBINE DNA SYNTHESIS (S) PYRIMIDINE AG FOLIC ACID AG PURINE AG SUBS. UREA CYTARABINE METHOTREXATE THIOGUANINE ,FLUDARABINE HYDROXYUREA G2 ANTIBIOTIC TOPOISOMERASE II INHB MICROTUBULE P& STAB BLEOMYCIN ETOPOSIDE PACLITAXEL M MITOTIC INHIBITOR VINBLASTINE, VINCRISTINE, VINDESINE

PHASE NON SPECIFIC DRUGS: 

Can kill either dividing cells or nondividing cells at any point in the cell cycle. CELL CYCLE SPECIFIC : alkylating agents( nitrogen mustard), busulphan , dacarbazine , cisplatin , carboplatin . CELL CYCLE NON SPECIFIC : nitrogen mustard, nitrosourea . PHASE NON SPECIFIC DRUGS

Common side effects:: 

Alopecia Nausea, vomitting Pulmonary fibrosis Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis Mucositis Diarrhoea Cystitis Sterility and myalgia . Common side effects:

Antimetabolites : 

Therapeutic uses In combination used in Acute lymphocytic leukemia, Breast cancer, Head and neck carcinoma Usual dose 15–30 mg PO or IM on days 1-5 every 2weeks.( gtc ) 40-80mg/m^2 IV or PO 2-4 times monthly with a 7-14 day interval between doses. Adverse effects- Nausea, vomiting, stomatitis , myelosupperssion , alopecia, renal damage, cirrhosis, pulmonary toxicity Antimetabolites

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Drug interactions: Salicylates , sulphonamides and tetracyclines when taken with mtx , displaces mtx from protein binding sites and increases the level of mtx leading to toxicity. NSAIDS and sulphonamides also potentiate the toxicity by decreasing the excretion of mtx .

6 mercaptopurine: 

Therapeutic uses Used principally in ; Acute lymphoblastic leukemia, Crohn’s disease Usual dose 100mg/m2 po if used alone 50-90 mg/m2 po daily if used with mtx . Adverse effects Bone marrow depression, anorexia, nausea, vomiting, jaundice 6 mercaptopurine

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Drug interactions of mp: Decrease dose by 75% when used concurrently with allopurinol . Increase intervals btwn doses or reduce dose in pts with renal failure.

Alkylating agents:mechlorethamine: 

Therapeutic uses Lymphatic cancer, Hodgkin’s disease, cutaneous t cell lymphomas. Usual dose 6 mg/m 2 IV day 1 and day 8 every 4 weeks (in MOPP regimen for hg). 8-16 mg/m2 by intracavity inj. Adverse effects Nausea, vomiting, bone marrow depression Painful if extravasatn occurs. Alkylating agents:mechlorethamine

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Mechlorethamine is an nitrogen mustard and an analogue of sulfur mustard, with antineoplastic and immunosuppressive activities. Mechlorethamine is metabolized to an unstable, highly reactive ethyleniminium intemediate that alkylates DNA, particularly the 7 nitrogen of guanine residues, resulting in DNA base pair mismatching, DNA interstrand crosslinking , the inhibition of DNA repair and synthesis, cell-cycle arrest, and apoptosis. This agent also exhibits lympholytic properties

Cyclophosphamide : 

Therapeutic uses Burkitt's lymphoma breast,ovary,testis , bladder cancer ALL,CLL Multiple myeloma Usual dose 1000-1500mg/m2 IV every 3-4wks 4000mg/m2 po days 1-5 evry 3-4wks 60-120mg/m2 po daily - Ifosfamide 1.2 g/m 2 per day qd Adverse effects Alopecia, nausea, vomiting, and diarrhea, bone marrow depression, fibrosis of the bladder Cyclophosphamide

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In the liver, cyclophosphamide is converted to the active alkylating metabolites aldophosphamide and phosphoramide mustard by hepatic microsomal enzymes, which bind to DNA, thereby inhibiting DNA replication and initiating cell death. Ifosfamide alkylates and forms DNA crosslinks , thereby preventing DNA strand separation and DNA replication. This agent is a prodrug that must be activated through hydroxylation by hepatic microsomal enzymes

Nitrosoureas : 

Carmustine MOA: The Nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily on cells that are actively dividing. Carmustine is lipid soluble and easily enters the brain. THERAPEUTIC USES: BRAIN TUMORS, HODGKIN’S AND NON HODGKIN’S LYMPHOMA, MULTIPLE MYELOMA, MELANOMA. Usual dose: 200 -240 mg/m 2 IV as a 30 to 45 min infusion every 6-8wks. Dose often is divided and given over 2-3 days. To limit the cumulative dose to 1000mg/m2 to limit pulmonary and renal toxicity. Adverse effects: These include delayed hematopoietic depression, Renal toxicity, pulmonary fibrosis, myelosuppression . Nitrosoureas

Antitumor antibiotics: bleomycin: 

Therapeutic uses Testis,head,neck,anus and Skin cancer Hodgkin’s and non hodgkin’s Usual dose 10-20 units/m2 IV or IM once or twice a Week, 30units IV push weekly for 9-12 wks in comb with other drugs for testis cancer. Adverse effects Myelosuppression,Pulmonary toxicity, alopecia, hyper pigmentation of the hands Fever. Antitumor antibiotics: bleomycin

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A mixture of the sulfate salts of basic glycopeptide antineoplastic antibiotics isolated from Streptomyces verticillus . Bleomycin sulfate forms complexes with iron that reduce molecular oxygen to superoxide and hydroxyl radicals which cause single- and double-stranded breaks in DNA; these reactive oxygen species also induce lipid peroxidation , carbohydrate oxidation, and alterations in prostaglandin synthesis and degradations

Vincristine and vinblastine: 

Mech of action: mitotic inhibition with reversible metaphase arrest due to drug action on microtubular and spindle contractile proteins. TI: breast cancer, H & NH lymphoma, ALL, multiple myeloma, gestational trophoblastic . Usual dose: VLB: 4-18 mg/m2 IV weekly VCR: 1-2 mg/m2(max 2.0-2.4mg) IV weekly. Vincristine and vinblastine

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ADVERSE EFFECTS: Myelosuppression , nausea vomitting , alopecia, nuerotoxicity , stomatitis .

Cisplatin and carboplatin: 

MOA : similar to alkylating agents with respect to binding and cross linking strands of DNA. TI : used in comb with other cytotoxic drugs. Testis, ovary, cervical, bladder, head, neck, and lung carcinomas, non hodgkin’s lymphoma. Usual dose : 40-120mg/m2 IV on day 1 as infusion every 3 weeks. ADR : myelosuppression , nausea and vomiting, renal tubular damage, ototoxicity , anaphylaxis. Cisplatin and carboplatin

Combination chemotherapy regimens: 

Disease &Regimen Breast cancer Cyclophosphamide,methotrexate , 5-FU (CMF) Cyclophosphamide , doxorubicin ( Adriamycin ), 5-FU (CAF) Lung cancer : Cisplatin , etoposide Colorectal cancer : 5-FU, leucovorin Non-Hodgkin's : Cyclophosphamide , doxorubicin, vincristine , prednisone (CHOP) Hodgkin's : Nitrogen mustard, vincristine , procarbazineprednisone (MOPP) , Doxorubicin, bleomycin , vinblastine , dacarbazine (ABVD) Bladder cancer : Methotrexate , vinblastine , doxorubicin, cisplatin (MVAC) Testicular cancer : Cisplatin , etoposide , bleomycin (PEB) Combination chemotherapy regimens

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Thank you……