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Clinical Applications of Antineoplastic Chemotherapy Chemotherapy 5th-6th decades of 20th century Subsequent integration into treatment protocols Limitations due to resistance, toxicity Understanding of mechanisms through which the drugs work History Paul Erlich coined the term chemotherapy George Clowes at Roswell Park developed rodent lines to test potential drugs Alkylating agents – First class Product of a secret gas programme by USA 1943 use in Hodgkin’s lymphoma Sidney Farber – folic acid analogs Cure of childhood leukaemia and HD-1960 Work with solid tumors – disappointing Nearly 90% drug cures occur in 10% cancer types Felt that this was related to tumor characteristics and drug resistance Tumor features Cancer cells do not divide at faster rate than normal cells Greater number of cells dividing Slow growing tumors – less responsive Faster growing tumors – more responsive and curable Highly aggressive cancer – almost incurable e.g. Non-Hodgkin’s lymphoma Diffuse large cell lymphoma - curable in advanced stages (more aggressive) Indolent lymphoma - responds to treatment but likely incurable in advanced stages (low grade) Increase in growth fraction - negative response to Rx-? emergence of resistance Normal cells Never develop resistance Resistance of tumor cells associated with sensitivity of normal cells Bone marrow and GIT cells are most vulnerable Chemotherapy options Induction for advanced disease As adjunct to local treatment Primary treatment for localized disease when local treatment is not possible Direct instillation to sanctuary sites or site direct perfusion (CNS therapy for acute leukaemia) 1 Chemotherapy – Options Induction Adjuvant Neoadjuvant Palliation Induction chemotherapy Primary treatment of cancer (before surgery) No alternative treatment exists (leukaemia) Adjuvant chemotherapy Use of systemic treatment after local therapy (minimal tumor bulk) Use based on risk of recurrence (presence of microscopic disease) Use based on response of similar tumors at advanced stage Primary chemotherapy Neoadjuvant Used in tumors where alternative treatment is available but is less acceptable Allows organ preservation (osteogenic sarcoma/breast cancer) Can assess efficacy of treatment End points in evaluating response Partial response (PR) Complete response (CR) Relapse free survival (RFS) Freedom from progression (FFP) Combination chemotherapy – Rationale for use Single drugs at tolerable doses unable to cure cancer Allows maximum cell kill with tolerable host toxicity Allows range of drug interaction with tumor cells with different genetic abnormalities May prevent or slow development of drug resistance Only drugs known to be effective as single agents used Drugs causing CR preferred Select drugs whose toxicities do not overlap Optimize dose and schedules Keep interval dosing consistent Shortest possible time for sensitive tissue recovery 2 Bone marrow function – effects of chemotherapy Storage compartment exists Supplies cells to PB for 8-10 days Events in PB lag 7days behind BM Day 9-10 fall in PB counts Nadir-Day 14-18 Recovery –Day 21 Completed recovery – Day 28 Chemotherapy effects Cell death can be due to direct effect Agent may trigger differentiation May cause apoptosis (programmed cell death) Cell death may not take place at time of drug exposure Only a proportion of cells die Chemotherapy-assumptions All tumor cells are equally sensitive Drug accessibility and sensitivity-independent of location of cells and host factors Cell sensitivity remains constant Evidence to the contrary Tumor growth – depends on: Cell cycle time Growth fraction Total number of tumor cells Intrinsic cell death Phases in cell cycle G0 – resting G1 – RNA and protein synthesis S – DNA synthesis G2 – RNA and protein synthesis M – Mitosis As cells mature they differentiate (BM, GIT cells – cell cycle 24-48 hrs) Thus their sensitivity to chemotherapy Phase and cell cycle specificity of drugs Phase specific drugs Cell cycle specific Cell cycle non-specific 3 Cell cycle phase specific Table 1-1. Cell cycle phase-specific chemotherapeutic agents Phase of greatest activity Class Type Gap 1 (G1) Natural product Hormone Antimetabolite Antimetabolite Enzyme Asparaginase Corticosteroid Prednisone Purine analog Cladribine Pyrinidine analog Cytarabine, fluorouracil, gemcitabine Folic acid analog Methotrexate, Purine analog thioguanine, fludarabine Topoisomerase 1 inhibitor Topotecan Substituted urea Hydroxyurea Antibiotic Bleomycin Topoisomerase II inhibitor Etoposide Microtubule polymerization Paclitaxel (Taxol) and stablization Mitotic inhibitor Vinblastine, vincristine vindesine, vinorelbine G1/S Junction DNA synthesis (S) Antimetabolite Antimetabolite Natural product Gap 2 (G) Miscellaneous Natural product Natural product Natural product Mitosis (M) Natural product Characteristic agents Cell cycle specific and non specific drugs Table 1-2. Cell cycle-specific and cell cycle-nonspecific chemotherapeutic agents Class Type Characteristic agents Cell cycle specific Alkylating agent Nitrogen mustard Natural product Alkyl sulfonate Triazene Metal Salt Antibiotic Chlorambucil, Cyclophosphamide Melphalan Busulfan Dacarbazine Cisplatin, carboplatin Dactinomycin, daunorubicin doxorubicin idarubicin Cell cycle-nonspecific Alkylating agent Nitrogen mustard nitrosourea 4 Mechlorethamine Carmustine, lomustine Drug resistance Natural Acquired Categories of resistance Kinetic Biochemical Pharmacologic Kinetics and resistance Relates to cycle and phase specificity Overcome by reducing tumor bulk Use of combinations to include drugs affecting resting cells Schedule drugs to prevent phase escape Biochemical resistance Inability to convert drug to active form Decrease drug uptake Increased efflux Changes in intracellular target Increased inactivation Increased rate of repair of damage DNA bcl-2 overexpression (blocks apoptosis) p53 mutations MDR-drug efflux Use of agents to rescue normal cells so allowing use of higher doses of chemotherapy Pharmacologic resistance Poor or erratic absorption Increased excretion Increased catabolism Drug interactions Poor transport of agents into some tissues (entry of drugs into CNS) Future Understand molecular basis of cancer Understand differences between normal and malignant cells Current chemotherapy regimens may be a crude beginning 5