Trends in Pharmacological Sciences
ReviewTPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?
Section snippets
Pharmacogenetic testing for the administration of oncology drugs
Life-threatening toxicity has been a risk of cancer therapy since the development of nitrogen mustards 1, 2. Because most oncology drugs are administered at the maximally tolerated dose for the population and have a narrow therapeutic index, individuals with altered distribution, metabolism or elimination can suffer life-threatening adverse reactions. The identification of patients ‘too ill’ to benefit from therapy [3] and of methods of supportive care 4, 5 has improved safety, but uncommon
TPMT and 6-MP
6-MP is a prodrug; its principal active metabolites, thioguanine nucleotides (TGNs), preferentially kill rapidly growing cells by inhibiting DNA and RNA synthesis. As a cytotoxic agent, 6-MP is more widely used to treat various autoimmune disorders and prevent organ rejection. Similarly, the 6-MP prodrug azathioprine is used to treat rheumatoid arthritis and prevent renal allograft rejection. However, this review (and the FDA consideration of labeling changes for 6-MP) focuses on the treatment
UGT1A1 and irinotecan
Primarily used to treat advanced colorectal cancer, irinotecan is a prodrug that is converted by carboxylesterase-2 to SN-38 [16], the active DNA topoisomerase I inhibitor that mediates the therapeutic and toxic effects of the drug. SN-38 is mostly eliminated by glucuronidation, the enzymatic conjugation of glucuronic acid to form the more water-soluble metabolite SN-38 glucuronide (SN-38G). Patients with the highest SN-38:SN-38G ratios are at increased risk of one of the most common severe
DPYD and 5-FU
For decades, 5-FU has been a staple of therapy for various solid tumors. In 1985, a 27-year-old woman with breast cancer lapsed into a prolonged stuporous state after two cycles of 5-FU-containing chemotherapy [26] and was found to have elevated concentrations of thymidine and uracil in her body fluids. Based on the pattern of these biochemical abnormalities in different family members and the known pathways of pyrimidine salvage, the investigators proposed that a heritable defect in
Current translation of pharmacogenetic research
The comprehensive development of pharmacogenetic tests entails determining the relative contributions of heritable and environmental factors to the therapeutic index of a given drug for individuals in different populations, and prospective confirmation of the use of this information in selecting and dosing therapy [38]. However, genetic tests for a given therapy might benefit patients before this development process is completed. For TPMT–6-MP and UGT1A1–irinotecan, the FDA convened panels of
The future of cancer pharmacogenetics
It is difficult to predict when and how further pharmacogenetic information will be integrated into the routine management of cancer therapy [39] but current trends indicate three important themes during the next five years.
Concluding remarks
Two clinically useful pharmacogenetic tests for anticancer agents are now available to practitioners; how best to use the information generated by these tests remains to be determined. The tests could be used to screen for patients at risk of severe toxicity from 6-MP or irinotecan before the initiation of treatment or to help clinicians decide among management options when unexpected toxicity from these drugs arises. The available data indicate that these tests will not predict toxicity
Acknowledgements
M.L.M. is supported by US National Institute of General Medical Sciences grant T32 GM07019 in clinical therapeutics. More-detailed information about these drugs and related genes can be found on the Pharmacogenetics and Genomics Knowledge Base (http://www.pharmgkb.org/).
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