Y. Ando et al., Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity:A pharmacogenetic analysis, CANCER RES, 60(24), 2000, pp. 6921-6926
Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea, I
rinotecan is metabolized to form active SN-38, which is further conjugated
and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic pol
ymorphisms of the UGT1A1 would affect an interindividual variation of the t
oxicity by irinotecan via the alternation of bioavailability of SN-38. In t
his case-control study, retrospective review of clinical records and determ
ination of UGT1A1 polymorphisms were performed to investigate whether a pat
ient with the variant UGT1A1 genotypes would be at higher risk for severe t
oxicity by irinotecan, All patients previously received irinotecan against
cancer in university hospitals, cancer centers, or large urban hospitals in
Japan. We identified 26 patients who experienced severe toxicity and 92 pa
tients who did not. The relationship was studied between the multiple varia
nt genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29,
and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leuk
openia (less than or equal to0.9 x 10(9)/liter) and/or grade 3 (watery for
5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26
patients with the severe toxicity, the genotypes of UGT1A1*28 were homozyg
ous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 1
0 (11%) heterozygous were found among the 92 patients without the severe to
xicity. Multivariate analysis suggested that the genotype either heterozygo
us or homozygous for UGT1A1*28 would he a significant risk factor for sever
e toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence inter
val, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered seve
re toxicity. No statistical association of UGT1A1*6 with the occurrence of
severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7, We suggest th
at determination of the UGT1A1 genotypes might he clinically useful for pre
dicting severe toxicity by irinotecan in cancer patients. This research war
rants a prospective trial to corroborate the usefulness of gene diagnosis o
f UGT1A1 polymorphisms prior to irinotecan chemotherapy.