A novel type of non-PK related genes controls susceptibility to the toxic effects of irinotecan
Dittmar, Ashley J.
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Adverse drug reactions (ADRs) are a major obstacle in cancer chemotherapy. In spite of the advances in the development of anti-cancer drugs, ADRs compromise their potential benefits in many patients by imposing reduction of dose or cessation of treatment. Prediction of susceptibility to ADRs in individual patients could significantly improve treatment outcomes by more effectively choosing which drugs to treat with and which dose is appropriate. Irinotecan (CPT-11) is one of the drugs that causes a significant number of ADRs. Its pharmacokinetics (PK) have been extensively studied and numerous enzymes and transporters that are involved in its activation and processing have been identified. However, the variants of these proteins have not been able to consistently predict ADRs in individual patients. Therefore, additional studies are required for a reliable prediction of toxicity. We used mouse strains with precisely defined limited genomic differences to evaluate genetic control of ADRs to irinotecan. We compared strain distribution of susceptibility to irinotecan ADRs and tested whether there is a correlation with genotype at the major PK genes or with in vivo processing of CPT-11. We have found very large differences in susceptibility of mouse strains to the toxic effects of irinotecan and no correlation with genetic differences at the major PK loci nor with the rate of the drug's activation or inactivation. Our data also suggest that two common irinotecan ADRs, diarrhea and myelosuppression, are controlled by different genes. Linkage analysis was performed in C3H x HcB-24 F2 hybrids to determine which areas of the genome were responsible for irinotecan ADRs and revealed 11 Adri (Adverse drug reaction to irinotecan) loci responsible for systemic, intestinal, and myelotoxicity. We show that a very significant and the largest part of genetic susceptibility to ADRs is controlled by genes other than the presently known PK-related genes. We hypothesize that these genes are possibly involved in downstream pharmacodynamic (PD) processes that have remained largely unexplored. Identification of the genes at the 11 Adri loci in the mouse can point to their human homologues that may likely contribute to irinotecan toxicity and help to optimize the selection of therapy for individual patients.