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TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?
Michael L Maitland1, Kaveeta Vasisht, Mark J Ratain
1Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, and Cancer Research Center, University of Chicago, Chicago, IL 60637, USA.
Abstract:
The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.
Insights
The FDA now recommends pharmacogenetic testing for anticancer drugs 6-mercaptopurine (6-MP) and irinotecan to help prevent severe side effects. Further research will confirm the clinical benefits and optimal use of these important genetic tests.
Area of Science:
- Pharmacogenomics
- Oncology
- Drug Development
Background:
- The U.S. Food and Drug Administration (FDA) has approved label updates for 6-mercaptopurine (6-MP) and irinotecan.
- These updates incorporate pharmacogenetic testing to mitigate severe toxic events associated with these anticancer drugs.
Purpose of the Study:
- To review gene-drug-phenotype relationships for 6-MP, irinotecan, and 5-fluorouracil.
- To identify characteristics that enable clinically useful pharmacogenetic tests.
- To inform healthcare providers and patients about the potential role of pharmacogenetic testing in cancer treatment.
Main Methods:
- Analysis of existing evidence on pharmacogenetic testing for 6-MP and irinotecan.
- Review of gene-drug-phenotype relationships for relevant anticancer agents.
- Assessment of the FDA's decision rationale for label changes.
Main Results:
- The FDA acknowledges sufficient evidence to recommend pharmacogenetic testing for 6-MP and irinotecan.
- Specific gene-drug-phenotype relationships for 6-MP, irinotecan, and 5-fluorouracil possess properties suitable for clinical pharmacogenetic tests.
- Comprehensive evaluations of clinical benefit and cost-effectiveness are pending.
Conclusions:
- Pharmacogenetic testing is recognized as a potential strategy to reduce severe toxicity from 6-MP and irinotecan.
- Future research is needed to fully elucidate the role of pharmacogenetic testing in toxicity reduction and dose optimization.
- These tests may help identify patient subgroups who can safely receive higher treatment doses for equivalent benefit.
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