Associations of various gene polymorphisms with toxicity in colorectal cancer patients receiving oral uracil and tegafur plus leucovorin: a prospective study.
BACKGROUND
To assess the predictive value of polymorphism in nine genes, primarily thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT), which relates to 5-fluorouracil (5-FU) metabolism, for toxicity in patients treated with oral uracil/tegafur (UFT) plus leucovorin (LV).


METHODS
We treated 99 patients with stage II or III colorectal carcinoma with oral UFT + LV. Germline DNA from patients was genotyped for 5-FU and folate metabolism-relating genes. CYP2A6, tegafur-activating enzyme, and uridine diphosphate-glucuronosyltransferase 1A1 genetic variation were also assessed. Toxicity was graded by the National Cancer Institute Common Toxicity Criteria, version 2.0.


RESULTS
The multivariate logistic regression revealed that OPRT 638G>C polymorphism was associated with grade 3 diarrhea [odds ratio (OR) 19.84 for patients with the C/C homozygous type compared with patients with wild type, P = 0.014] and polymorphisms of UGT1A1 were associated with hyperbilirubinemia (OR 38.76 for homozygotes and double heterozygotes of *6 or *28 compared with wild type, P = 0.0008). No relationships were observed between TS polymorphisms and any toxicity.


CONCLUSIONS
OPRT polymorphism predicts toxicity, especially grade 3 or greater diarrhea to oral UFT + LV adjuvant chemotherapy, whereas TS does not, in our study cohort. UGT1A1 polymorphism seems to be a risk factor for hyperbilirubinemia due to UFT+LV.
Tsunoda
A
A
Department of Surgery, Kameda Medical Center, Chiba. a.tsunoda@kameda.jp
Nakao
K
K
Watanabe
M
M
Matsui
N
N
Ooyama
A
A
Kusano
M
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005787:Gene Frequency; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D005641:Tegafur / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D002955:Leucovorin; D005641:Tegafur; D014498:Uracil; D000099148:UGT1A1 Enzyme