Cancer pharmacogenomics: SNPs, chips, and the individual patient.
There is great heterogeneity in a patient's response to medications, often requiring empirical strategies to define the appropriate drug therapy for each patient. Pharmacogenomics aims to elucidate further the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosage for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. For example, polymorphism in thiopurine methyltransferase (TPMT) results in altered degradation of the commonly prescribed agent 6-mercaptopurine. This genetic variant has significant clinical implications because patients with functionally relevant homozygous mutations in the TPMT gene experience extreme or fatal toxicity after administration of normal doses of 6-MP. In addition, patients heterozygous for mutations in TPMT require slight dosage reduction of 6-MP and experience a greater degree of systemic toxicity from the agent. This and other examples of genetic polymorphism relevant to the treatment of cancer are highlighted to illustrate the promise and pitfalls of the exciting area of cancer therapeutics, with the potential of providing a stronger scientific basis to optimize drug therapy on the basis of each patient's genetic constitution.
McLeod
Howard L
HL
Departments of Medicine, Molecular Biology and Pharmacology, and Genetics, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA. hmcleod@im.wustl.edu
Yu
Jinsheng
J
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D014644:Genetic Variation; D006801:Humans; D008495:Medical Oncology / Q000639:trends; D015122:Mercaptopurine / Q000009:adverse effects / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010347:Patient Care Planning; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase