Relations between strain and gender dependencies of irinotecan toxicity and UGT1A1, CES2 and TOP1 expressions in mice

Innotecan hydrochloride (CPT-11) can display severe toxicities in individual cancer patients CPT-11 is bio-activated through CES, detoxified through UGT1A1 and inhibits TOP1 CPT-11 toxicity and UGT1A1, CFS2 and TOP1 mRNAs and UGT1A1 protein were determined in male and female C57BL/6. B6D2F1 and B6CBAF1, as potential models for tailoring CPT-11 delivery CPT-11 was administered intravenously (40-90mg/kg/day for 4 days at 7h after light onset). The relations between dose and lethal toxicity or body weight loss were steep and similar in C57BL/6 (lethality, p=0 001; weight loss, p=0 002) and B6D2F1 (p=0.01: p=0.03, respectively). but weak in B6CBAF1. Females displayed less toxicity than males (p <0 001) Mean mRNA expression of UGT1A1 was highest in B6CBAF1 (p=0 039) and ill females (p<0 001) Both CES2 and TOP1 varied according to strain and gender (p <0 001) The three gene expression data explained the most severe toxicity of CPT-11 in male B6D2F1, but displayed inconsistent relations with toxicity in the other groups Mean UGT1A1 protein expression was highest in males as compared to females, and so by similar to 8-fold in C57BL/6 as compared to B6D2F1 (p <0.0001) Genetic background and gender significantly altered the molecular prediction of innotecan toxicity by UGT1A1, CES2 and TOP1 mRNA expressions (C) 2009 Elsevier Ireland Ltd. All rights reserved