Pharmacogenetics of Irinotecan Therapy in Colorectal Cancer
Summary
Irinotecan, a prodrug converted to the active metabolite SN-38, remains a cornerstone of chemotherapy for colorectal cancer. Its metabolism and detoxification are profoundly influenced by genetic variation, most notably in the UGT1A1 gene, which governs glucuronidation of SN-38 and thereby modulates both efficacy and toxicity. Polymorphisms such as UGT1A1*28 and UGT1A1*6 alter enzyme activity, predisposing carriers to neutropenia and delayed diarrhoea. Pharmacogenetic profiling enables genotype-guided dosing to optimise therapeutic exposure while reducing adverse events. Beyond UGT1A1, variation in CYP3A4, ABC transporters and DNA repair pathways contributes to inter-individual variability in drug response and acquired resistance. Integration of germline and somatic markers with therapeutic drug monitoring, alongside evolving biomarkers for early toxicity prediction, heralds a more personalised approach. Prospective clinical trials and health-economic analyses support the clinical viability of genotyping, underscoring its global significance and potential to improve outcomes and cost-effectiveness in diverse healthcare settings.
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Pharmacogenetics of Irinotecan Therapy in Colorectal Cancer publication trend
The graph below shows the total number of articles in pharmacogenetics of irinotecan therapy in colorectal cancer across all publications each year (not limited to Nature Index journals).
Technical terms
Irinotecan: A chemotherapeutic prodrug that, upon hepatic conversion to SN-38, inhibits DNA topoisomerase I and induces lethal DNA strand breaks in cancer cells.
SN-38: The active metabolite of irinotecan, responsible for both antitumour activity and dose-limiting toxicities.
UGT1A1: Uridine diphosphate glucuronosyltransferase enzyme 1A1, which glucuronidates SN-38 to SN-38G, facilitating elimination and reducing toxicity.
Pharmacogenetics: The study of how inherited genetic variants affect individual responses to drugs, encompassing efficacy, toxicity and optimal dosing.
Topoisomerase I: A nuclear enzyme that relieves DNA supercoiling during replication; the principal target of SN-38 in anticancer therapy.
References
- Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us. International Journal of Molecular Sciences (2023).
- Mechanisms and emerging strategies for irinotecan-induced diarrhea. European Journal of Pharmacology (2024).
- UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients. European Journal of Cancer (2022).
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