Lockett L J, Molloy P L, Russell P J, Both G W
Division of Molecular Science, Commonwealth Scientific and Industrial Research Organisation, North Ryde, 2113, Australia.
Clin Cancer Res. 1997 Nov;3(11):2075-80.
Enzyme-prodrug therapy for the treatment of cancer is an experimental procedure that is under intensive investigation. However, the relative merits of the various systems for use under specific conditions are still being determined. We have compared the efficacy of cell killing by the herpesvirus thymidine kinase (HSVTK)/ganciclovir and the purine nucleoside phosphorylase (PNP)/9-(beta-M-2-deoxy-erythropentofuranosyl)6-methylpurine enzyme/prodrug systems. These were chosen because of their differential dependence on DNA replication for their mechanism of action. The HSVTK and PNP genes, expressed from the identical prostate-specific antigen promoter, were transduced into human prostate and breast cancers cells using the same human adenovirus vector. The kinetics of cell killing in the presence of the respective prodrugs was monitored using a nondestructive assay that measured total cell bioactivity. The PNP/9-(beta-D-2-deoxy-erythropentofuranosyl)6-methylpurine system was clearly superior in its ability to cause cell death in vitro. Cells were killed in about half the time and at a 5-10-fold lower input of virus relative to the HSVTK/ganciclovir system. The PNP system may offer advantages for the treatment of slow-growing tumors in which the daily proliferative rate is low or in situations in which gene delivery or expression is inefficient.
用于癌症治疗的酶-前药疗法是一种正在深入研究的实验性方法。然而，各种系统在特定条件下使用的相对优点仍在确定之中。我们比较了疱疹病毒胸苷激酶（HSVTK）/更昔洛韦和嘌呤核苷磷酸化酶（PNP）/9-(β-D-2-脱氧赤藓戊呋喃糖基)6-甲基嘌呤酶-前药系统的细胞杀伤效果。选择这两种系统是因为它们在作用机制上对DNA复制的依赖性不同。由相同的前列腺特异性抗原启动子表达的HSVTK和PNP基因，使用相同的人腺病毒载体转导入人前列腺癌细胞和乳腺癌细胞。在存在各自前体药物的情况下，使用测量总细胞生物活性的非破坏性测定法监测细胞杀伤动力学。PNP/9-(β-D-2-脱氧赤藓戊呋喃糖基)6-甲基嘌呤系统在体外导致细胞死亡的能力明显更强。相对于HSVTK/更昔洛韦系统，细胞在大约一半的时间内被杀死，并且病毒输入量低5至10倍。PNP系统可能为治疗生长缓慢、每日增殖率低的肿瘤或基因递送或表达效率低下的情况提供优势。
