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- 1. Cancer Chemotherapy-1 Dr. R. Senthil Kumar
- 7. Major approaches to therapy of cancers
- 8. Cell Cycle = Growth, Division
- 12. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)
- 18. Modes of Resistance to Anticancer Drugs Mechanism Drugs or Drug Groups Change in sensitivity (or ↑ level) or ↓ binding affinity of target enzymes or receptors Etoposide, methotrexate, vinca alkaloids , estrogen & androgen receptors Decreased drug accumulation via ↑ expression of glycoprotein transporters, or ↓ permeability Methotrexate, alkylating agents, dactinomycin Formation of drug-inactivating enzymes Purine & pyrimidine antimetabolites Production of reactive chemicals that “trap” the anticancer drug Alkylators, bleomycin, cisplatin. doxorubicin Increased nucleic acid repair mechanisms Alkylating agents, cisplatin Reduced activation of pro-drugs Purine & pyrimidine antimetabolites
- 20. ADR of Antineoplastic Drugs in Humans
- 21. Distinctive Toxicities of Some Anticancer Drugs Toxicity Drug(s) Renal Cisplatin,* methotrexate Hepatic 6-MP, busulfan, cyclophosphamide Pulmonary Bleomycin,* busulfan, procarbazine Cardiac Doxorubicin, daunorubicin Neurologic Vincristine,* cisplatin, paclitaxel Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin, methotrexate Other Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); asparaginase* (pancreatitis) *Less Bone marrow suppression – “marrow sparing”
Notas do Editor
- Etiology: Environmental carcinogens – azo dyes, afltoxins, asbestos, benzene Viruses: herpes , papilloma , HTLV Amplification of oncogenes (proto-onco), deletion of tumor suppressor genes (p53) Shift in the control mechanisms that govern cell proliferation and differentiation Genetics vs. Environment Theory: “Genetics loads the gun; the environment pulls the trigger
- Normal cells… Differentiate, grow, mature, divide Regulated, balanced; cell birth=cell death Regulation: intracell signaling Hyperplasia: new cells prod’d w/ growth stimulus via hormones, endogenous signals Ex: hyperplasia of endometrial tissue during menstrual cycle is normal and necessary BUT if intense, prolonged demand … May cell structural, functional abnormalities Metaplasia : replacement of one cell type by another Thicker cell layer better accommodates irritation Ex: bronchial epithelium chronically irritated ciliated columnar epithelial cells replaced by sev layers cuboidal epithelium Note: Replacement cells normal, just different Reversible Dysplasia : replacement cells disordered in size, shape Incr’d mitosis rate Somewhat reversible, often precancerous Neoplasia : abnormal growth/invasion of cells “ New growth” Neoplasm = tumor Irreversible Cells replicate, grow w/out control The growth cycle of a cell is its major determinant of responsiveness to chemotherapy. A measure of cell growth is the cell cycle. The cell cycle consists of four major phases: G1, S, G2 & M 1. G1 phase - cell prepares to make DNA. 2. S phase - DNA synthesis takes place. 3. G2 phase - synthesis of components needed for mitosis. 4. M phase - mitosis (cell division) occurs.
- Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high growth fraction CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors. CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent) Cycling cells are more sensitive Effective in low growth fraction as well as high growth fraction solid tumors
- Cell cycle specific drugs (CCS) or phase specific : Antimetabolites : Methotrexate, 6-Mercaptopurine Antibiotic : Bleomycin Taxane : Paclitaxel Epipodophyllotoxins : Etoposide, Teniposide Vinca alkaloids : Vinblastine, Vincristine Act mainly on dividing cells Most effective in hematologic and solid tumors with high growth fraction Cell cycle non-specific (CCNS) or phase non specific drugs: Alkylating agents : Cyclophosphamide, Busulfan, Mechlorethamine, Melphalan. Anticancer antibiotics : Doxorubicin, Daunorubicin, Mitomycin, Actinomycin D. Camptothecins : Topotecan, Irinotecan Metal complexes : Cisplatin, Carboplatin CCNS drugs act on dividing as well as resting cells Effective in low growth fraction as well as high growth fraction solid tumors
- Importance of cell cycle kinetics Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction Most effective in hematologic and solid tumors with high growth fraction CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors. CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent) Cycling cells are more sensitive Effective in low growth fraction as well as high growth fraction solid tumors
- DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate ) GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.