1-beta-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking.
1-beta-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking.
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发表时间：
1989-03
期刊：
影响因子：
11.2
通讯作者：
L. Swinnen;D. Barnes;S. Fisher;K. Albain;R. Fisher;L. Erickson
中科院分区：
文献类型：
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作者：
L. Swinnen;D. Barnes;S. Fisher;K. Albain;R. Fisher;L. Erickson
研究了1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）和羟基脲（HU）作为顺铂（DDP）诱导的DNA损伤修复的可能抑制剂。选择HU和ara-C是因为它们在UV照射后抑制DNA切除修复的已知能力。几个小组的工作表明，DDP诱导的DNA损伤的修复可能涉及切除修复机制。通过集落形成试验，在人结肠癌细胞系（HT-29）中研究了三种药物的剂量、暴露时间和顺序的细胞毒性作用。无论在DDP暴露之前还是之后给予HU + ara-C，都观察到显著的协同细胞毒性。在HU + ara-C本身之间也观察到细胞毒性协同作用。通过DNA碱性洗脱评估组合抗代谢物对DDP诱导的DNA链间交联的水平和持久性的影响。测量这些作为DDP-DNA加合物形成和去除的指标。当HU + ara-C暴露在DDP治疗之前或之后时，在较晚的时间点发现比单独DDP观察到的更高水平的链间交联，表明修复抑制。我们的结论是，HU，阿糖胞苷和DDP的组合显示协同细胞毒性，这种效果可能是由于部分抑制DDP诱导的DNA加合物修复。体外使用的药物浓度可在人体内实现。根据这些结果，已经启动了三种药物联合使用的I/II期临床试验。
1-beta-D-Arabinofuranosylcytosine (ara-C) and hydroxyurea (HU) were investigated as possible inhibitors for the repair of cis-diamminedichloroplatinum(II) (DDP)-induced DNA damage. HU and ara-C were chosen for their known ability to inhibit DNA excision repair following UV irradiation. Work by several groups has suggested that the repair of DDP-induced DNA damage may involve an excision-repair mechanism. The cytotoxic effects of dose, exposure duration, and sequence for the three drugs was studied in a human colon cancer cell line (HT-29) by colony formation assays. Significant synergistic cytotoxicity was seen whether HU + ara-C were given prior to, or following DDP exposure. Cytotoxic synergy was also seen between HU + ara-C themselves. The effect of the combined antimetabolites on the level and persistence of DDP-induced DNA interstrand cross-links was assessed by DNA alkaline elution. These were measured as an indicator of DDP-DNA adduct formation and removal. When HU + ara-C exposure preceded or followed DDP treatment, higher levels of interstrand cross-linking were found at late time points than were seen with DDP alone, suggesting repair inhibition. We conclude that the combination of HU, ara-C, and DDP shows synergistic cytotoxicity, and that this effect may be due in part to inhibition of DDP-induced DNA adduct repair. The concentrations of drugs used in vitro are achievable in humans. On the basis of these results, a Phase I/II clinical trial of the three agents in combination has been initiated.