Transcript CC_prins_07
Cancer Chemotherapy Topics 1. 2. 3. 4. Basic principles: cell cycle, tumor growth kinetics, log kill, recruitment, drug targets Mechanisms of drug action Drug resistance mechanisms Toxicity and new approaches Cellular Pathways to Malignancy Tumor Suppressor Genes Cancer Molecular Pathways History of Cancer Chemotherapy Cancer Chemotherapy: Targets for selective toxicity target rapidly dividing cells? cancer cells are not the only replicating cells • e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all rapidly dividing as well not all cells in a tumor are replicating Cancer Chemotherapy: Targets for selective toxicity target rapidly dividing cells? cancer cells are not the only replicating cells • e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all rapidly dividing as well not all cells in a tumor are replicating altered metabolic enzymes (e.g. L-asparaginase to kill cells that can not synthesize asparagine) cell surface receptors (e.g. trastuzumab (Herceptin) blocks HER2 (ErbB) in breast cancer) specific hormonal requirements (e.g. steroid receptor antagonists for breast CA, prostate CA) altered intracellular signaling (e.g. imatinib (Gleevec) targets the Abl kinase which is turned on in chronic myelocytic leukemia) Remissions and complete cures are obtained with specific cancers Hodgkin’s lymphoma choriocarcinoma acute leukemias in children Wilm’s tumor (kidney) testicular cancer breast, prostate CA The cell cycle G1: growth, protein synthesis, RNA synthesis S: DNA synthesis, replication, RNA & protein synthesis G2: DNA repair, chromosome condensation M: mitosis, nuclear division Restriction point: cells traverse R by expression and activation of cyclin/CDK complexes and then are committed to continue through S phase. Cell Cycle Specificity of Selected Drugs Cell Cycle Specific fluorouracil mercaptopurine methotrexate Cycle non-specific • cyclophosphamide, mechlorethamine, nitrosoureas L-asparaginase paclitaxel vincristine/vinblastine alkylating agents: actinomycin D daunorubicin, doxorubicin etoposide, irinotecan cisplatin bleomycin Tumor growth kinetics Log Kill hypothesis Dr. Howard Skipper 1960s postulated that cell death follows 1st order kinetics with anti cancer drugs experiment: treat mouse leukemia with cytosine arabinose • 24 hr of ara-C--mice died • 3 treatment every 4 days--mice lived developed concept of Log Kill Easy Exam Question As part of your research project you are experimenting with the treatment of mice injected with 1012 leukemia cells. You are using a combination of mechlorethamine and vincristine with a log kill of 4. The leukemia grows at a rate of 1 log per week. If you start treatment immediately and give a treatment every 2 weeks, what is the minimum number of treatments required to theoretically cure your mouse patients? A) B) C) D) E) 3 4 5 6 7 Harder Exam question The initial tumor burden is 1010 cells and the drug combination used is known to give a log kill of 3. Assuming a 1 log re-growth per week between treatments and that all the cells are sensitive, which of the following treatment schedules would be expected to give a complete cure (ignoring the fact that cancers don’t always behave predictably)? A. B. C. D. E. 3 treatments at one week intervals 8 treatments at two week intervals 50 treatments at three week intervals 5 treatments at one week intervals none of the above Recruitment non-dividing cells (insensitive to many drugs) rapidly dividing cells (sensitive to drugs) •increase nutrient supply •increase perfusion •reduce crowding: surgery radiation chemo with cycle non-specific drugs (e.g. alkylating agents) Hypoxia in tumor induces expression of angiogenic genes bevacizumab (Avastin) antibody to VEGF Drug Targets in Cancer Chemotherapy 1. DNA a) bondage--alkylating agents (mechlorethamine, cyclophosphamide), cisplatin b) vaporization--bleomycin c) confusion--actinomycin D, doxorubicin, etoposide, irinotecan d) starvation--methotrexate, 6-thioguanine, 5-fluorouracil, cytosine arabinoside,hydroxyurea e) regulation--tamoxifen, aromatase inhibitors 2. Protein synthesis: L-asparaginase 3. Mitotic Apparatus: vincristine, vinblastine, paclitaxel 4. Specific antigens: therapeutic antibodies (e.g. Herceptin, Avastin) 5. Protein kinase inhibitors: Gleevec (imatinib) inhibits BCR-ABL which causes CML(chronic myeloid leukemia)