Methylenetetrahydrofolate reductase polymorphism is associated with folatepool in gastrointestinal cancer tissue

The folate pool in cancer tissue is a critical factor for the effect of 5-F U-based chemotherapy. Methylenetetrahydrofolate reductase (MTHFR) plays a r ole in the metabolism of folate. The gene of MTHFR is polymorphic (C667T, a lanine-to-valine), and this is related to the activity of the enzyme. We an alyzed the association between MTHFR genotype and the folate pool in gastro intestinal cancel tissues. MTHFR genotypes were determined in 67 surgically -resected gastrointestinal cancer tissues by PCR-RFLP analysis. Forty-five patients received no treatment and 22 patients received oral administration of UFT, a combination of Uridine and Tegafur, before surgery. 5,10-Methyle netetrahydrofolate (CH2FH4) and tetrahydrofolate (FH4) were measured by flu oro-dUMP (FdUMP) binding assay as representative values of the folate pool. The number of FdUMP binding sites on Thymidylate synthase (TS) was quantif ied in the samples from UFT-administered patients. The incidences of MTHFR genotype were as follows: Ala/Ala, 27; Ala/Val, 30; Val/Val, 10. In the UFT (-) group, the amount of FH4 in Ala/Val-type cancer tissue was higher than that in Ala/Ala-type (1.50 +/-1.13 versus 0.72 +/-0.64, p<0.05). This relat ionship was also observed on the sum of CN2FH4 and FH4 (2.88<plus/minus>1.8 5 versus 1.75 +/-1.06, p<0.05). Val/Val-type cancer tissue had higher amoun t of either CH2FH4 and FH4 than Ala/Ala-type, although this finding did not reach statistical significance. h the UFT(+) group, no relationship betwee n MTHFR genotype and the free folate poor was observed presumably due to th e influence of the amounts of FdUMP and TS in the tissue. The calculation o f total CH2FH4 from the value of free CH2FH4, free TS and total TS showed a weak genotype-dependent difference in total CH2FH4. The TS inhibition rate also showed a weak genotype-dependent difference. These results suggest a link between MTHFR genotype and the folate pool in gastrointestinal cancer leading to the association of MTHFR genotype with TS inhibition rate upon 5 -FU exposure. The MTHFR genotype might be consider-ed in the design of 5-FU -based chemotherapy, especially in patient-specific strategies with leucovo rin supplementation.