engleski

Pharmacogenetic and tumor drugs

One of the main goals to improve chemotherapy in cancer patients is to increase the safety while not reducing the efficacy of therapy. Cancer chemotherapy is mainly empirical with the majority of cytotoxic agents given at a fixed dosage based on either body surface area or weight. These compounds have a narrow therapeutic index, and there is no simple index for pharmacological effect monitoring. Approximately 7% of patients are affected by adverse drug reactions (ADRs), increasing the overall hospital costs by 1.9% and drug costs by 15%. Among other influences, the interindividual genetic variation has a major impact on drug activity. Genetic variations are the result of multiple mechanisms such as single nucleotide polymorphisms (SNPs) (over 90%), insertion, deletion, tandem repeats and microsatellites. In an attempt to individualize therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies in search for answers to the hereditary basis for individual differences in drug response). Drugs used to treat cancer inhibit cell proliferation by several mechanisms. Alkylating agents (e.g., cyclophosphamide, busulfan, carboplatin) readily form covalent bonds with the DNA bases thus introducing crosslinks in the double helix and preventing DNA replication. Anticancer antibiotics (e.g., daunorubicin) intercalating between the DNA base pairs stabilize the DNA-topoisomerase II complex and stop the reversible ‘ swivelling’ at the DNA replication fork, which is required for effective replication of the DNA template. The steroid hormones (e.g., prednisolone) interfere with DNA synthesis and alter intracellular metabolism due to receptor binding. The vinca alkaloids (e.g., vincristine) prevent the formation of the mitotic spindle, whilst the antimetabolites (e.g., methotrexate, 6-mercaptopurine) directly interfere with DNA formation by inhibiting purine and pyrimidine biosynthesis. This chapter will focus on the impact of genetic polymorphisms, their effects on the activity and response to commonly used anticancer drugs such as mercaptopurine, 5 fluorouracil, cyclophosphamide, platinum agents and camptothecins.

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