Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer
Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer
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DOI：
10.2217/14622416.8.11.1561
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发表时间：
2007-11-01
期刊：
影响因子：
2.1
通讯作者：
Milano, Gerard
中科院分区：
文献类型：
--
作者：
Etienne-Grimaldi, Marie-Christine;Francoual, Mireille;Milano, Gerard
5-基于氟尿嘧啶（5 FU）的治疗仍然是结肠直肠癌的主要化疗。氟嘧啶的最佳细胞毒性需要升高的CH 2FH 4肿瘤浓度，由亚甲基四氢叶酸还原酶（MTHFR）控制，该酶将CH 2FH 4不可逆地转化为5-甲基四氢叶酸。MTHFR基因具有多种多态性，其中677 C> T和1298 A> C SNP是最常与酶活性改变相关的两种。由于MTHFR酶活性的下降理论上可能有利于细胞内CH 2FH 4浓度的增加，因此可以假设表现出罕见MTHFR变体的肿瘤可能对5 FU细胞毒性更敏感。因此，实验数据显示，在位置677和1298的罕见MTHFR变体对5 FU更敏感。然而，关于MTHFR基因型对肿瘤CH 2FH 4浓度、5 FU反应性、患者生存率和5 FU相关毒性的影响，临床数据的结果并不一致。这些差异可能是由于个体叶酸状态引起的患者间变异性，以及在目前的结肠直肠癌化疗方案中氟尿嘧啶的作用有限。
5-fluorouracil (5FU)-based treatments remain the main chemotherapy for colorectal cancer. Optimal cytotoxicity of fluoropyrimidines requires elevated CH2FH4 tumoral concentrations, controlled by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which irreversibly converts CH2FH4 into 5-methyltetrahydrofolate. The MTHFR gene is subject to several polymorphisms, of which the 677C > T and 1298A > C SNPs are the two most commonly linked with altered enzyme activity. Since a drop in MTHFR enzymatic activity may theoretically favor an increase in intracellular CH2FH4 concentrations, it can be hypothesized that tumors exhibiting the rare MTHFR variants may be more sensitive to 5FU cytotoxicity. Accordingly, experimental data have shown that rare MTHFR variants in position 677 and 1298 are more sensitive to 5FU. However, results of clinical data do not concord regarding the influence of MTHFR genotype on tumoral CH2FH4 concentration, 5FU responsiveness, patient survival and 5FU-related toxicity. These discrepancies may result from the interpatient variability arising from the individual folate status, as well as from the limited role of fluoropyrimidines in the current chemotherapy regimen administered in colorectal cancer.