Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity.
OBJECTIVE
To analyze thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with respect to fluorouracil (FU) sensitivity.


METHODS
The study included a retrospective analysis of 88 patients with metastatic colorectal cancer and a prospective trial with 51 patients also with measurable metastases. All patients were treated with FU and leucovorin. The analysis of gene polymorphism was performed on normal intestinal tissue and lymphocytes.


RESULTS
The response rate was significantly higher in patients with TS 3R/3R or MTHFR 677 TT gene polymorphism compared with the other groups. The difference of response rate translated to a difference in time to progression. Similar results were observed in the retrospective analysis and the prospective confirmatory trial.


CONCLUSIONS
The analysis of gene polymorphism allows delineation of a group of patients (30%) with a response rate to a single drug of approximately 50%. This information should be used in the design of tailored treatment.
Jakobsen
Anders
A
Danish Colorectal Cancer, Group South, Vejle Hospital, 7100 Vejle, Denmark. aja@vs.vejleamt.dk
Nielsen
Jens Nederby
JN
Gyldenkerne
Niels
N
Lindeberg
Jan
J
D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics*
D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil