Anticancer Drugs 2 PDF

Anticancer drugs 2 DR KHIN THANE OO PROFESSOR, PHARMACOLOGY, MUCM  Learning outcomes 1. List drugs belonging to following groups: Alkylating agents, antimetabolites, anticancer antibiotics, natural products, protein tyrosine kinase inhibitors, hormones and antagonists, platinum compounds...

Anticancer drugs 2 DR KHIN THANE OO PROFESSOR, PHARMACOLOGY, MUCM  Learning outcomes 1. List drugs belonging to following groups: Alkylating agents, antimetabolites, anticancer antibiotics, natural products, protein tyrosine kinase inhibitors, hormones and antagonists, platinum compounds. (Anticancer 1) 2. List cell cycle-specific and cell cycle-nonspecific anticancer drugs. (Anticancer 1) 3. Explain the anticancer action of the following: alkylating agents, taxanes, vinca alkaloids, methotrexate and anticancer antibiotics. (Anticancer 1) 4. List the therapeutic uses of methotrexate. (Anticancer 1) Manipal University College Malaysia 2  Learning outcomes 5. Explain the general toxicities of anticancer drugs. (Anticancer 2) 6. List the specific toxicities of the following anticancer agents: cyclophosphamide, doxorubicin, methotrexate, vincristine, cisplatin and bleomycin. (Anticancer 2) 7. Explain the measures to minimize the toxicities of anticancer drugs. (Anticancer 2) 8. Explain the role of drug combinations in cancer therapy. (Anticancer 2) 9. Name the preferred combination chemotherapy for acute myeloid leukemia, Hodgkin’s disease and non-Hodgkin’s lymphoma. (Anticancer 2)  General toxicities of anticancer drugs 1. Toxic to the rapidly dividing normal cells Bone marrow cells → myelosuppression, thrombocytopenia, leukopenia and suppression of lymphoreticular system leading to increased bleeding, immunosuppression and opportunistic infections Gut mucosa → GI bleeding and ulcers Skin and hair → Alopecia Gonads → Infertility in both sexes Fetus → Fetal death and teratogenic effects Manipal University College Malaysia 4 General toxicities of anticancer drugs 2. Tumor Lysis Syndrome causes hyperuricemia – urate nephropathy, due to uric acid precipitation within the distal tubules and collecting ducts hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury. Manipal University C ollege Malaysia 5  General toxicities of anticancer drugs 3. Hypersensitivity reactions may be in the form of rashes, chills, fever or life-threatening anaphylaxis. cisplatin, paclitaxel, bleomycin etc. commonly cause hypersensitivity reactions. 4. Nausea and vomiting due to activation of dopamine, 5-HT3, serotonin, neurokinin-1 (NK-1), and cholecystokinin, causing an emetic response; stimulation of chemoreceptor trigger zone Manipal University College Malaysia 7  Specific toxicities of anticancer drugs Cyclophosphamide – hemorrhagic cystitis Doxorubicin – cardiotoxicity Bleomycin – pulmonary fibrosis, usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray Vincristine – neuropathy, syndrome of inappropriate antidiuretic hormone secretion Cisplatin – nephrotoxicity and ototoxicity Methotrexate – hepatotoxicity and nephrotoxicity, and megaloblastic anemia Manipal University College Malaysia 9  Minimizing toxicities of anticancer drugs Ondansetron (an antiemetic drug), a 5-HT3 antagonist to controlling cytotoxic drug induced vomiting. Platelet and/or granulocyte transfusion after treatment—to prevent bleeding or infection. Bone marrow transplantation Use of recombinant colony stimulating factor hastens recovery from cytotoxic drug induced myelosuppression. granulocyte-macrophage colony-stimulating factor (GM-CSF) Amifostine used as prophylaxis of cisplatin induced nephrotoxicity. Vigorous hydration of the patient before, during and after cisplatin infusion also reduces nephrotoxicity. Manipal University College Malaysia 1 3  Minimizing toxicities of anticancer drugs Hemorrhagic cystitis caused by cyclophosphamide and ifosfamide can be prevented by systemically administering mesna before chemotherapy drug administration and by irrigating the bladder with N-acetylcysteine. Mesna interacts with the urotoxic metabolite acrolein to reduce the incidence of cyclophosphamide- and ifosfamide-induced haemorrhagic cystitis. Mesna is rapidly cleared by the kidneys and does not reduce the anti-tumour effect of cyclophosphamide or ifosfamide. 8  Doxorubicin's cardiotoxicity is thought to result from oxygen free radicals, production of which is catalysed by a doxorubicin-iron complex. is a life-threatening side effect that impacts patient prognosis and survival Dexrazoxane is an iron chelating agent, acts by removing the iron from the complex, thus preventing cardiac damage. infused i.v. before doxorubicin to reduce risk of cardiotoxicity Minimizing toxicities of anticancer drugs Methotrexate toxicity treated with leucovorin (folinic acid). Folinic acid reverses this toxicity (Leucovorin rescue). to “rescue” the normal cells in the body from the side effects of methotrexate. Folinic acid directly forms THFA bypassing dihydrofolate reductase enzyme pathway.  Minimizing toxicities of anticancer drugs Urate nephropathy can be reduced by allopurinol, alkalinization of urine and plenty of fluids. Reduced by administration of allopurinol Aggressive intravenous hydration, usually with normal saline solution, to flush out the Allopurinol, a xanthine oxidase remnants of uric acid through inhibitor, blocks the conversion the kidneys of xanthine to uric acid Manipal University College Malaysia 20  Minimizing toxicities of anticancer drugs Xerostomia (treated with artificial saliva, amifostine – cytoprotective agent) Drugs given in pulses with 2–3-week intervals for normal cells to recover improve the efficacy of therapy: malignant cells recovering more slowly. Manipal University College Malaysia 21  Role of drug combinations in cancer therapy Enhanced effect by achieving maximal cell killing To broaden the range of attack as drugs in the combination kill heterogeneous cells Reduce resistance by early/rapid cell kill Reduction in the toxicity of individual drugs as lower dose of individual drugs is sufficient to kill cells Manipal University College Malaysia 23  Principles of drug combinations for cancer chemotherapy Drug must be active as a single agent against the tumor being treated Combine drugs with different mechanism of action Avoid combinations with significant toxicity overlap Use intermittent schedule of drug treatment. This will allow normal cells to recover from acute toxic effects of drugs Several cycles of chemotherapy should be given to achieve eradication Adjuvant chemotherapy is given to prevent relapse after surgery or radiotherapy Manipal University College Malaysia 24  Drug combinations Acute Myeloid Leukemia Induction : Cytarabine + Daunorubicin Maintenance: Cytarabine + Daunorubicin/Etoposide Hodgkin’s lymphoma 1. ABVD regimen Doxorubicin (Adriamycin), Vinblastine, and Dacarbazine 2. MOPP regimen Mechlorethamine, Vincristine (Oncovin), Procarbazine, and Prednisone Manipal University College Malaysia 26  Drug combinations Non-Hodgkin’s lymphoma 1. CHOP regimen Cyclophosphamide, Doxorubicin (hydroxydaunorubicin), Vincristine, and Prednisone Manipal University College Malaysia 27  Model questions 1.List cell cycle specific and cell cycle non-specific anticancer drugs. 2.Explain the mechanism of action of vincristine and mention its specific toxicity. 3.Explain the mechanism of action of taxanes. 4.List general toxicities of anticancer drugs with measure to minimize each toxicity. 5.A 40-year old woman with choriocarcinoma is treated with very high doses of methotrexate. The physician anticipated significant hematological toxicity in response to high dose of methotrexate and put her on drug X to overcome its toxicity. a.What could be the anticipated toxicity? b.Identify drug X. Manipal University College Malaysia 28 c.Explain the anticancer action of methotrexate. Model questions 6. Explain the rationale for using drug combinations for cancer chemotherapy. 7. List principles of drug combinations for cancer chemotherapy. 8. Mention the preferred combination chemotherapy for acute myeloid leukemia / Hodgkin’s disease / non-Hodgkin’s lymphoma.