Relations between strain and gender dependencies of irinotecan toxicity and UGT1A1, CES2 and TOP1 expressions in mice.
Irinotecan 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, CES2 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 (40-90 mg/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 in 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 approximately 8-fold in C57BL/6 as compared to B6D2F1 (p<0.0001). Genetic background and gender significantly altered the molecular prediction of irinotecan toxicity by UGT1A1, CES2 and TOP1 mRNA expressions.
Ahowesso
C
C
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.
Piccolo
E
E
Li
X M
XM
Dulong
S
S
Hossard
V
V
La Sorda
R
R
Filipski
E
E
Tinari
N
N
Delaunay
F
F
Iacobelli
S
S
Lévi
F
F
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis*; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D000077146:Irinotecan; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D012737:Sex Factors; D013045:Species Specificity
D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C500145:Ces2c protein, mouse; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin