期刊
PHARMACOGENOMICS JOURNAL
卷 11, 期 1, 页码 61-71出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/tpj.2010.10
关键词
camptothecin/analogs and derivatives; fluorouracil; glucuronosyltransferase; P-glycoprotein; thymidylate synthase; methylenetetrahydrofolate reductase (NADPH2)
资金
- Merck
- Schering-Plough
- Swedish Cancer Society
- Norwegian Cancer Society
- Swedish Science Council (Medicine)
- Swedish Society of Medicine
- Stockholm Cancer Society
- Uppsala University Hospital
- Lion's Cancer fund
- Uppsala University
- Aventis Pharma AB
- Sanofi-Aventis Pharma AB
Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyl-transferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR) = 3.79 (95% confidence interval (CI) = 1.09-13.2), and in patients carrying the UGT1A1*28/*28 genotype, OR 4.43 (95% CI = 1.30-15.2). Patients with UGT1A1*28/*28 had an especially high risk of neutropenia, OR = 6.87 (95% CI = 1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P = 0.027), and survived shorter time, OR = 1.56 (95% CI = 1.01-2.45). The Pharmacogenomics Journal (2011) 11, 61-71; doi: 10.1038/tpj.2010.10; published online 23 February 2010
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据