叶酰多聚谷氨酸合成酶与甲氨蝶呤敏感性的关系

摘要

Folypolyglutamate synthetase(FPGS) catalyzes the addition of multiple glutamate molecules to compounds with the basic pteroylglutamate structure,such as polyglutamylation-dependent novel antifolates.As the antifolates like methotrexate require polyglutamation by FPGS for activation,FPGS has an established position in the cytotoxic action of methotrexate and has become a essential part in methotrexate resistance.Recent studies have indicated that decreased mRNA expression and activity of FPGS can cause reduction of methotrexate-polyglutamates accumulation,which have been observed as a dominant mechanism leading to methotrexate resistance.Furthermore,single nucleotide polymorphism in FPGS has been displayed significant associations with methotrexate sensitivity and susceptibility of deseases,though the detail mechanism is unknown.This paper is to review the relationship among FPGS enzyme activity,gene polymorphism and methotrexate drug sensitivity.%叶酰多聚谷氨酸合成酶( folypolyglutamate synthetase,FPGS)作为甲氨蝶呤(methotrexate,MTX)类抗肿瘤药物细胞内代谢过程中的关键酶,催化形成活性形式的MTX多聚谷氨酸,其异常是MTX耐药的重要原因之一.近年来研究发现,FPGS表达及活性的降低可使细胞内MTX多聚谷氨酸浓度降低,从而导致MTX耐药.FPGS基因多态性在MTX耐药中也起着重要的作用,但其具体机制尚未完全明了.该文就FPGS酶活性及基因多态性与MTX药物敏感性的关系进行综述.