The Role of Pharmacogenetics in Cancer Chemotherapy and the Development of Malignancy

The role of pharmacogenetics in the area of cancer chemotherapy and the development of malignancy has not been well defined. Only four chemotherapeutic agents have been evaluated for toxicity or clinical response based on genetic differences in metabolism. These include 5-fluorouracil, 6-mercaptopurine, amonafide, and cyclophosphamide. Severe toxicity of 5-fluorouracil and amonafide due to individual differences in drug metabolism has been reported in the literature. Tumor response in leukemic children may be associated with genetic differences in metabolism of 6-mercaptorpurine. The development of malignancy may be secondary to an individual's ability to detoxify carcinogens found in the environment. For example, the incidence of bladder cancer appears higher in subjects who have occupational exposure to aromatic amines and the slow acetylator phenotype. Some evidence also exists that smokers who are very extensive metabolizers of debrisoquin may be more prone to developing lung cancer. Strong evidence for an association between other cancer types and pharmacogenetics requires more study.