Abstract
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% Cl 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 μmol/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 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/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. £ 2002 Wiley-Liss, Inc.
| Original language | English |
|---|---|
| Pages (from-to) | 294-299 |
| Number of pages | 6 |
| Journal | International Journal of Cancer |
| Volume | 103 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Jan 20 2003 |
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Keywords
- Homocysteine
- Methotrexate
- Methylenetetrahydrofolate reductase
- Ovarian cancer
- Pharmacogenetics
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. / Toffoli, Giuseppe; Russo, Antonio; Innocenti, Federico; Corona, Giuseppe; Tumolo, Salvatore; Sartor, Franca; Mini, Enrico; Boiocchi, Mauro.
In: International Journal of Cancer, Vol. 103, No. 3, 20.01.2003, p. 294-299.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients
AU - Toffoli, Giuseppe
AU - Russo, Antonio
AU - Innocenti, Federico
AU - Corona, Giuseppe
AU - Tumolo, Salvatore
AU - Sartor, Franca
AU - Mini, Enrico
AU - Boiocchi, Mauro
PY - 2003/1/20
Y1 - 2003/1/20
N2 - 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% Cl 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 μmol/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 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/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. £ 2002 Wiley-Liss, Inc.
AB - 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% Cl 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 μmol/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 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/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. £ 2002 Wiley-Liss, Inc.
KW - Homocysteine
KW - Methotrexate
KW - Methylenetetrahydrofolate reductase
KW - Ovarian cancer
KW - Pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=0037454801&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037454801&partnerID=8YFLogxK
U2 - 10.1002/ijc.10847
DO - 10.1002/ijc.10847
M3 - Article
C2 - 12471611
AN - SCOPUS:0037454801
VL - 103
SP - 294
EP - 299
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 3
ER -