Anticancer Drugs. Introduction Cancer refers to a malignant neoplasm or new growth. Cancer cells manifest uncontrolled proliferation, loss of function.

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Presentation transcript:

Anticancer Drugs

Introduction Cancer refers to a malignant neoplasm or new growth. Cancer cells manifest uncontrolled proliferation, loss of function due to loss of capacity to differentiate, invasiveness, and the ability to metastasize. Cancer arises as a result of genetic changes in the cell, the main genetic changes being, inactivation of tumor suppressor genes and activation of oncogenes.

Management of cancer There are three approaches for the management of cancer: 1. Radiotherapy 2. Surgery 3. Chemotherapy

Anticancer drugs The anticancer drugs either kill cancer cells or modify their growth. However selectivity of majority of drugs is limited and they are one of the most toxic drugs used in therapy. In malignant diseases, drugs are used with the aim of: 1. Cure or prolonged remission 2. Palliation 3. Adjuvant chemotherapy

Classification of drugs Drugs acting directly on cells (cytotoxic drugs): 1. Alkylating agents Mechlorethamine Cyclophosphamide Ifosfamide Chlorambucil Melphalan

Continue 2. Antimetabolities Methotrexate 6-mercaptopurine 6-thioguanine Azathioprine 5-fluorouracil Cytarabine

Continue 3. Vinca alkaloids Vincristine Vinblastine 4. Taxanes Paclitaxel Docetaxel

Continue 5. Antibiotics Actinomycin D Doxorubicin Daunorubicin Mitoxantrone Bleomycins Mitomycin C

Continue 6. Miscellaneous Hydroxyurea Procarbazine L-asparaginase Cisplatin Carboplatin Imatinib

Continue Drugs altering hormonal milieu 1. Glucocorticoids Prednisolone 2. Estrogens Fosfestrol Ethinylestradiol

Continue 3. Selective estrogen receptor modulators Tamoxifen Toremifene 4. Aromatase inhibitors Letrozole Anastrozole Exemestane

Continue 5. Antiandrogen Flutamide Bicalutamide 6. 5 alpha reductase inhibitors Finasteride Dutasteride

Continue 7. GnRH analogues Nafarelin Triptorelin 8. Progestins Hydroxyprogestrone acetate

General toxicity of cytotoxic drugs Bone marrow depression Lymphoreticular tissue: lymphocytopenia and inhibition of lymphocyte function. Oral cavity: the oral mucosa is particularly susceptible to cytotoxic drugs because of high epithelial cell turnover.

Continue GIT: Diarrhea, shedding of mucosa, hemorrhages occur due to decrease in the rate of renewal of the mucous lining. Drugs that frequently cause mucositis are Bleomycins, Actinomycin, and Methotrexate. Nausea and vomiting are prominent with many cytotoxic drugs, this is due to direct stimulation of CTZ.

Continue Gonads: Inhibition of gonadal cells causes oligozoospermia and impotence in males; inhibition of ovulation and amenorrhea are common in females. Fetus: practically all cytotoxic drugs given to pregnant women profoundly damage the developing of the fetus. Hyperuricaemia: this is a secondary to a massive cell destruction (uric acid is a product of purine metabolism). Gout and urate stones in the urinary tract may develop. Allopurinol is protective by decreasing uric acid synthesis.

Mechanism of actions Alkylating agents and related compounds (e.g. cyclophosphamide, lomustine, thiotepa, cisplatin): These groups of drugs act by forming covalent bonds with DNA and thus impending DNA replication. Antimetabolites (e.g. methotrexate, fluorouracil, mercaptopurine): These drugs blocks or destabilize pathways in DNA synthesis.

Continue Cytotoxic antibiotics (e.g. Doxorubucin, bleomycin, dactinomycin): These drugs inhibit DNA or RNA synthesis or cause fragmentation to DNA chains or interfere with RNA polymerase and thus inhibit transcription. Plant derivatives (e.g. vincristine): Inhibits mitosis

Mechlorethamine It is the first nitrogen mustard, highly reactive and local vesicant, can only be given i.v route. It produces many acute effects like nausea, vomiting, and haemodynamic changes. Dose is 0.1mg/kg i.v daily times 4 days, doses may be repeated at suitable intervals. It is available 1omg dry powder in vial.

Cyclophosphamide It is inactive, produces few acute effects and is not locally damaging. Transformation into active metabolities occurs in the liver and a wide range of antitumour actions is excerted. It has prominent immunosuppressant property. Thus it is one of the most popular anticancer drugs. It is less damaging to platelets, but alopecia and cystitis are prominent. Dose is 2-3mg/kg/day, 10-15mg/kg i.v, every 7-10days, i.m use is also possible.

Ifosfamide Ifosfamide has a longer and dose dependent halflife. It has found utility in bronchogenic, breast, testicular, bladder, headache, neck and some other carcinoma. Ifosfamide causes less alopecia, and is less emetogenic than cyclophosphamide. Dose is available 1g vial, 200mg inj.

Chlorambucil It is very slow acting Alkylating agent specially active on lymphoid tissue. It is the drug of choice for long term maintenance therapy for chronic lymphatic leukemia and some solid tumors also resolve. It has some immunosuppressant property. Dose is 4-10mg daily for 3-6 weeks.

Melphalan It is very effective in multiple myeloma and has been used in advanced ovarian cancer. Bone marrow depression is the most important toxicity. Infections, diarrhea, and pancreatitis are the complications. Dose is 10mg daily for 7 days or 6mg per day for 2-3 weeks. It is available 2, 5, 50mg for i.v injection.

Busulfan It is highly specific for myeloid elements, granulocyte precursors being the most sensitive, followed by those platelets and RBC. It produces little effect on lymphoid tissue and G.I.T. Hyperuricaemia is common and pulmonary fibrosis is a speacific adverse effect. Sterility also occurs. It is the drug of choice for chronic myeloid leukemia. The dose is 2-6mg/day orally.

Dacarbazine It is different from other Alkylating agents in having primary inhibitory action on RNA and protein synthesis (others mainly effect DNA). It is activated in the liver. The most important indication is malignant melanoma, also used Hodgkin's disease. Nausea and vomiting are the prominent side effects. The dose is 3.5mg/kg per day i.v for 10 days. Available 100, 200, 500mg injection.

Methotrexate It is one of the oldest and highly efficacious antineoplastic drugs, inhibits dihydrofolate reductase- blocking the conversion of DHF to THF which is an essential co-enzyme required for one carbon transfer reactions in purine synthesis. Methotrexate is absorbed orally. Little is metabolized and largely excreted in the urine. Methotrexate is apparently curative in choriocarcinoma, mg/day for 5 days orally or 20-40mg i.m or i.v.