The role of pharmacogenetics in chemotherapy: modulation of tumour response and host toxicity.

What may appear to be a strategy for investigating pharmacogenetic variation must be seen in the context of an evolving understanding of the molecular biology of drug metabolism. New biochemical and analytical techniques permit the determination of mechanisms of drug action and the molecular biology of host and tumour factors influencing that action. However, the only example of the application of pharmacogenetics in cancer chemotherapy is that of 6MP in the treatment of ALL. This was based on a solid understanding of both the metabolism of the drug and therapeutic response and the ability to measure the polymorphic enzyme in erythrocytes. Identification of the gene responsible for this enzyme is thought to be near, with subsequent identification of mutant forms completing the pharmacogenetic story for this drug. However, pharmacogenetics appears to be an important component in the variability of both toxicity and tumour response for several chemotherapeutic agents. Determination of the complete molecular basis for this variation will no doubt make a major contribution to the increased understanding of host and tumour pharmacology, with the ultimate aim of optimization of therapy.