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CHEMOTHERAPY OF CANCER Chemotherapy in the use of antimitotic drugs for the treatment of malignant diseases. The target organ of the drugs is the DNA which is responsible for cell division. The principles of chemotherapy administration include.
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CHEMOTHERAPY OF CANCER • Chemotherapy in the use of antimitotic drugs for the treatment of malignant diseases. • The target organ of the drugs is the DNA which is responsible for cell division. • The principles of chemotherapy administration include
1. Induction chemotherapy – initial therapy to achieve significant cytoreduction of re- mission acute leukaemia. 2. Casolidation intensification chemotherapy – given to prolong remission duration a overall survival e.g. ALL or AML. 3. Adjuvant chemotherap – to that unknown microscopic disease to prevent local or distant spread.
4. Negadjuvant chemotherapy – Administered before local disease to increase effectiveness. • 5. Maintenance chemotherapy - continuous low-dose chemotherapy to prolong duration of remission and achieve are for those in remission.
6. Salvage chemotherapy-given after failure of other treatments to control disease or provide palliation. • Evaluation of response to chemotherapy (a) Complete response – complete disappearance of disease clinically an imaging or by finding in bone marrow (<5% blast cells name in peripheral blood)
in haematological malignancies for >1month. (b) Partial response – decrease of disease by 50% for >1month (c) Stable disease - <50% response but no progression. (d) Progression >25% increase in disease
Single agent Or Combination Methods of Administration of chemotherapy (a) Continuous low dose (b) Cyclical Combination Chemotherapy Cell kill Drug resistance
Drug Selection • All used drugs must be partially effective against the tumor when used alone. • Drugs of the same group should not be combined to prevent additive toxicity. • Drugs should be used in their therapeutic dose. • Intervals of administration should be regular.
Response to chemotherapy and the cell kill • Hypothesis: A given dose of a drug kill a constant number, regardless of the numbers present at the time of therapy.
Cell kinetics • The cell circle G1 (Go), S, G2, M phases. • Tumor growth is dependent on the proliferating fraction (growth fraction).
Temnporarily Non-dividing Cancer cells Non-dividing Cancer cells Dividing Cancer cell Sensitive to Partially sensitive drugs Pharmacokinetics The effectiveness of an antitumor agent is directly related to the effective concentration (C)
of drug to the target site for along enough time (T) to bring about the desired effect. The optimal CXT must be calculated for the tumor and for the critical normal tissues (GIT, bone marrow) for the safety of the patients. These help to obtain the appropriate doses and schedules which should kill the maximum tumour cells with minimum lethality in normal cells.
(A) Phase-specific agents • (B) Phase-non-specific agents Multiple drug resistance (MDR) • Intrinsic MDR (High level of MDRI gene) • Acquired MDR Mechanisms of Biochemical Resistance
Mechanism (a) Decreased cellular uptake • Increased target enzyme: Dihydrofolate reductase Asparagine synthetase (c) Altered affinity for target enzyme (d) Decreased activation of drug: Decreased phophoribosyl transferase Decreased uridine phospharylase and kinase
(e) Increased deactivation of drug: increased deaminase (f) Increased DNA repair (g) Increased utilization of salvage pathways. Prevention of drug resistance involves the use of combination chemotherapy. Agents with different biochemical pathways are used with the main aim of decreasing the production and
availability of a specific and product vial for tumour cell growth and replication. Three main ways are (a) Sequential blockage of enzymatic pathway for production if essential metabolite (b) Concurrent blockage of parallel essential pathways (c) Inhibition of agents that produce lesions at a different loci in the synthesis of polymeric & molecules.
CHEMOTHERAPEUTIC AGENTS • Alkylating agents • Antimetabolits • Natural product – vinca alkaloids, etoposide, enzymes, antibiotics, camptothecin (topotecan, Irinotecan, Taxanes)
Miscellaneous – Cisplatinum, carboplatin, mitoxantrone, Hydoxy ureas aminoglutethimide • Hormonal agents- antioestrogens oestrogens, aromatase inhibitors gonadotropin- releasing horman analogues antiandrogens.
Side-Effect of Chemotherapy • Nausea & vomiting • Myelesuppression • Alopecia • Sterility • Cardiomyopathy • Renal damage • Neurological damage • Peripheral neuropathy • Hyperpigmentation • Lung fibrosis
Some current treatment protocols (A) Carcinoma of the breast Adriamycin + cyclophosphamide (AC) Taxotere + Epirupicin Taxotene + Herceptin (B) Carcinoma of the colon FOLFOX – Folinic Acid + 5-Fil +Oxaliplatin FOLFIRI - Folinic Acid 5-Fil + Irinotecan ANTI-EMETIC THERAPY