Berger N A, Berger S J, Gerson S L
Department of Medicine, Ireland Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Anticancer Drug Des. 1987 Oct;2(2):203-9.
DNA repair mechanisms serve as useful targets for modulating the cytotoxic and chemotherapeutic effects of many agents whose mechanism of action involves the induction of DNA damage. For example, the modified base O6-methylguanine can inactivate the repair protein O6-alkylguanine alkyltransferase, thereby sensitizing cells to the cytotoxic effects of clinically useful nitrosoureas such as BCNU. Some of the cytotoxic DNA adducts induced by BCNU are repaired by O6-alkylguanine alkyltransferase; thus, inactivation of the protein by O6-methylguanine converts cells that are relatively resistant to BCNU into sensitive cells. Another cellular enzyme, poly(ADP-ribose) polymerase, responds to DNA strand breaks by cleaving its substrate, NAD+, and using the resultant ADP-ribose moieties to synthesize homopolymers of ADP-ribose. The use of agents such as benzamide derivatives to inhibit enzyme function results in the accumulation of DNA strand breaks and potentiates the tumoricidal effects of some DNA strand-breaking agents such as bleomycin. Poly(ADP-ribose) polymerase can also affect pyridine nucleotide metabolism in a manner that initiates biochemical alterations leading directly to cell death. Thus, the amount of NAD used in the synthesis of poly(ADP-ribose) is dependent on the number of DNA strand breaks present in the cells. DNA damage can sufficiently activate the enzyme to rapidly consume NAD and consequently deplete ATP levels, resulting in the cessation of all energy-dependent functions and cell death. Understanding this biochemical pathway that leads to cell death provides a new basis for modulating chemotherapy. For example, agents such as Tiazofurin and/or 6-aminonicotinamide can each be used to alter pyridine nucleotide metabolism, lower NAD pools and potentiate the cytotoxic effects of other chemotherapeutic agents whose primary target is the induction of DNA damage.
DNA修复机制是调节许多药物细胞毒性和化疗作用的有用靶点，这些药物的作用机制涉及诱导DNA损伤。例如，修饰碱基O6-甲基鸟嘌呤可使修复蛋白O6-烷基鸟嘌呤烷基转移酶失活，从而使细胞对临床上有用的亚硝基脲如BCNU的细胞毒性作用敏感。BCNU诱导的一些细胞毒性DNA加合物可由O6-烷基鸟嘌呤烷基转移酶修复；因此，O6-甲基鸟嘌呤使该蛋白失活，可将对BCNU相对耐药的细胞转化为敏感细胞。另一种细胞酶聚（ADP-核糖）聚合酶通过切割其底物NAD+并利用生成的ADP-核糖部分合成ADP-核糖同聚物来响应DNA链断裂。使用苯甲酰胺衍生物等药物抑制酶功能会导致DNA链断裂积累，并增强一些DNA链断裂剂如博来霉素的杀肿瘤作用。聚（ADP-核糖）聚合酶还可以以引发直接导致细胞死亡的生化改变的方式影响吡啶核苷酸代谢。因此，合成聚（ADP-核糖）所用的NAD量取决于细胞中存在的DNA链断裂数量。DNA损伤可充分激活该酶，迅速消耗NAD，从而耗尽ATP水平，导致所有能量依赖性功能停止和细胞死亡。了解这条导致细胞死亡的生化途径为调节化疗提供了新的基础。例如，噻唑呋林和/或6-氨基烟酰胺等药物可分别用于改变吡啶核苷酸代谢、降低NAD池并增强其他主要靶点是诱导DNA损伤的化疗药物的细胞毒性作用。
