Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients

MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C-->T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C-->T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, I G3 neutropenia, I G3 anemia, 9 G3 mucositis cases and I G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p<0.0001). G3/4 toxicity occurred in 10 of 13 (77%), I of 17 (6%) and I of 13 (8%) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95% CI 4.2-418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p=0.0001) higher than basal levels (mean +/- SD=16.71 +/- 4.72 vs. 12.48 +/- 3.57 mu mol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean +/- SD=9.87 +/- 3.61 mu mol/l and CT mean +/- SD=11.48 +/- 3.13 mu mol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p =0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX-induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX. (C) 2002 Wiley-Liss, Inc.