前体药物甲氨喋呤-α-肽对前列腺癌细胞的细胞毒作用

Observation of cytotoxin effect of prodrugs MTX α peptides on prostatic cancer cells

研究前列腺癌的导向酶前体药物疗法（ＡＤＥＰＴ），在体外观察前体药物甲氨喋呤α肽对前列腺癌细胞生长、凋亡的影响。用固相合成法合成了前体药物甲氨喋呤α苯丙氨酸（ＭＴＸαＰｈｅ）和甲氨喋呤α精氨酸（ＭＴＸαＡｒｇ），并对前列腺癌细胞ＰＣ３、ＰＣ３ｍ进行了细胞毒性及周期动力学分析。用高效液相色谱及质谱分析，ＭＴＸαＰｈｅ可被羧肽酶Ａ（ＣＰＡ）水解并且完全释放出ＭＴＸ。经体外对前列腺癌细胞的毒性试验，前体药物基本上对细胞无毒，经ＣＰＡ水解后其活性ＭＴＸ细胞毒性大于前体药物１００倍以上。对前列腺癌细胞具有显著抑制作用，Ｓ期比率明显低于对照组，Ｇ０／Ｇ１期比率高于对照组，细胞增殖指数明显减低，细胞并发生凋亡。认为ＭＴＸαＰｈｅ是一较理想的前体药物。

In order to study the efficiency of the antibody directed enzyme prodrug therapy (ADEPT),the effect of MTX α peptides on growth and apoptosis of the prostatic cancer cells was studied.Methotrexate a Phenylalanine (MTX α Phe) and Methotrexate a arginine (MTX α Arg) were used as prodrugs synthesised by solid phase methods.The cytotoxin and cell cycle of prostatic cancer cells,PC 3 and PC 3m were determined.MTX α Phe was hydrolyzed into MTX by carboxypeptidase (CPA) using HPLC and Mass Spectrograph.The cytotoxin effect of the products enzymed by CPA was 100 times higher than that of the prodrugs with no obvious cytotoxin on the cells in vitro and former showed an obvious inhibition effects on the cells.Their cell cycle was determined and S phase fraction was lower than the control group,G 0/G 1 fraction was higher and the perliferation index obviously decreased resulting in apoptosis of the cancer cells.MTX α Phe would be considered an excellent prodrug.