67 Cytotoxic response as a result of the cross-talk between UGT mediated metabolism and modulation of UGT activity by C-1311 and C-1305 acridinone antitumor agents in selected solid tumor cell lines

Abstract

Results: For ANC nadir, we replicated UGT1A1*93, UGT1A1*28, and SLCO1B1*1b. In both univariate and multivariate models, SLCO1B1*1b had a protective effect against neutropenia, independent of the effect of either UGT1A1*28 or UGT1A1*93. For irinotecan AUC0−24, we replicated ABCC2 −24C>T and HNF1a 79A>C; however ABCC2 −24C>T predicted only a small fraction of the interindividual variability in irinotecan exposure, and HNF1a 79A>C had a 75% lower estimate of effect compared to the discovery cohort. For SN-38 AUC0−24 and the glucuronidation ratio, we replicated UGT1A1*28, UGT1A1*93, and ABCC1 1684T>C; however ABCC1 1684T>C had an 85% lower estimate of effect compared to the discovery cohort. Conclusion: In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of the clinical utility of SLCO1B1*1b and UGT1A1*93 will help further optimize irinotecan therapy for cancer patients.