Pharmacology of Antineoplastic Agents1Outline of Lecture Topics:•Antineoplastic Agents:a. Cell Cycle Specific (CCS) agentsb. Cell Cycle Non-Specific (CCNS) agentsc. Miscellaneous (e.g., antibodies) agents2. Mechanisms of action and side effects3. Drug ResistanceKishore Wary, Ph.D.Dept [email protected]://www.ncbi.nlm.nih.gov/pubmedhealth/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/http://clinicaltrials.gov/ct2/results?term=cancer2009 Estimated US Cancer Deaths*ONS=Other nervous system.Source: American Cancer Society, 2009.Men292,540Women269,80026% Lung & bronchus15% Breast9% Colon & rectum 6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 3% Leukemia3% Uterine corpus 2% Liver & intrahepaticbile duct 2% Brain/ONS25% All other sitesLung & bronchus 30%Prostate 9%Colon & rectum 9%Pancreas 6%Leukemia 4%Liver & intrahepatic 4%bile ductEsophagus 4%Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis 3%All other sites 25%Cancer3Cancer* is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems, this process is called metastasis.Categorized based on the functions/locations of the cells from which they originate: •Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas.•Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. •Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes large numbers of abnormal blood cells to be produced and enter the blood. •Lymphoma - cells of the immune system that affects lymphatic system.•Myeloma - B-cells that produce antibodies- spreads through lymphatic system.•Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.(*National Cancer Institute, NCI) http://www.ncbi.nlm.nih.gov/pubmedhealth/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002267/Cancer Therapeutic Modalities (classical)4•Surgery•Radiation•Chemotherapy1/3 of patients without metastasis Respond to surgery and radiation.If diagnosed at an early stage, close to 50% cancer could be cured.50% patients will undergo chemotherapy,to remove micrometastasis. However,chemotherapy is able to cure only about 10-15% of all cancer patients.Cancer ChemotherapyChapter 55. B.G. Katzung5Cancer ChemotherapyChapter 55. B.G. KatzungNew types of cancer treatmentHormonal Treatments: These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division. E.g., Breast cancer – tamoxifen after surgery and radiationSpecific Inhibitors: Drugs targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells. Antibodies: The antibodies used in the treatment of cancer have been manufactured for use as drugs. E.g., Herceptin, avastinBiological Response Modifiers: The use of naturally occuring, normal proteins to stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmabVaccines: Stimulate the body's defenses against cancer. Vaccines usually contain proteins found on or produced by cancer cells. By administering these proteins, the treatment aims to increase the response of the body against the cancer cells.6Cancer Chemotherapy (Background)A. Most of the recent progress using antineoplastic therapy is based on:1. Development of new combination therapy of using existing drugs.2. Better understanding of the mechanisms of antitumor activity.3. Development of chemotherapeutic approaches to destroying micrometastases4. Understanding the molecular mechanisms concerning the initiation of tumor growth and metastasis.5. Recognition of the heterogeneity of tumorsB. Recently developed principles which have helped guide the treatment of neoplastic disease1. A single clonogenic cell can produce enough progeny to kill the host.2. Unless a few malignant cells are present, host immune mechanisms do not play a significant role in therapy of neoplastic disease.3. A given therapy results in destruction of a constant percentage as opposed to a constant number of cells, therefore, cell kill follows first order kinetics.Cancer Chemotherapy7C. Malignancies which respond favorably to chemotherapy:1. choriocarcinoma, 2. Acute leukemia,3. Hodgkin's disease,4. Burkitt's lymphoma, 5. Wilms' tumor,6. Testicular carcinoma,7. Ewing's sarcoma, 8. Retinoblastoma in children, 9. Diffuse histiocytic lymphoma and10.Rhabdomyosarcoma.D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.E. Goal of Antineoplastic AgentsIS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity).H In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (aka therapeutic ratio). Therapeutic Index =LD50-----ED50A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). Cancer ChemotherapyChapter 55. B.G. Katzung8Infrequent scheduling oftreatment courses.Prolongs survival but does not cure. More intensive and frequent treatment.Kill rate > growth rate.Untreated patientsF. The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on patient survival.Early surgical removal of the primary tumor decreases the tumor burden. Chemotherapy will remove persistant secondary tumors.Cancer ChemotherapyChapter 55. B.G. Katzung910General rules of chemotherapyAggressive high-dose chemotherapy•Dose- limiting is toxicity towards normal cells•Cyclic regimens - repeated administrations with appropriate intervals for regeneration of normal cells (e.g., bone marrow cells) •Supportive therapy - to reduce toxicity hematotoxicity – bone marrow transplantation, hematopoietic growth factors Specific antagonists: antifolate (methotrexate) – folate (leucovorin)MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent. dexrazoxane: chelates iron, reduced anthracycline cardiotoxicityamifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents11General rules of