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, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 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%), 1 of 17 (6%) and 1 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 micromol/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 micromol/l and CT mean +/- SD = 11.48 +/- 3.13 micromol/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.
Toffoli
Giuseppe
G
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy. gtoffoli@cro.it
Russo
Antonio
A
Innocenti
Federico
F
Corona
Giuseppe
G
Tumolo
Salvatore
S
Sartor
Franca
F
Mini
Enrico
E
Boiocchi
Mauro
M
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005838:Genotype; D006402:Hematologic Diseases / Q000139:chemically induced; D006710:Homocysteine / Q000097:blood* / Q000172:deficiency; D006801:Humans; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000209:etiology; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000097:blood / Q000235:genetics*; D010976:Platelet Count; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D006710:Homocysteine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate