Frühauf S, Zeller W J
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Cancer Res. 1991 Jun 1;51(11):2943-8.
DNA protein cross-links (DPC), DNA interstrand cross-links (ISCL), and DNA single strand breaks following treatment of experimental ovarian tumor cells (O-342) with five new metal complexes (three platinum, one titanium, one ruthenium compounds) were investigated at 6, 24, and 48 h after drug exposure and compared with their in vitro growth inhibitory potential. cis-Diamminedichloroplatinum(II) (cisplatin, DDP) served as reference drug. The following new compounds were tested: 18-crown-6-tetracarboxybis-diammineplatinum(II) (CTDP), cis-aminotrismethylenephosphonato-diammineplatinum(II) (AMDP), cis-diamminecyclohexano-aminotrismethylenephosphonato-platin um(II) (DAMP), diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) (budotitane), and trans-indazolium-tetrachlorobisindazole-ruthenate(III) (IndCR). At equimolar concentrations DNA cross-linking activity of the platinum agents decreased in the order cisplatin, CTDP, AMDP, DAMP; this was paralleled by growth inhibition in a cell proliferation assay. CTDP-induced interstrand cross-linking occurred more slowly compared to cisplatin (DDP) (6 h: CTDP, 73 +/- 15 versus DDP, 365 +/- 72 rad equivalents), but reached a peak similar to cisplatin 24 h after exposure (CTDP, 317 +/- 68 versus DDP, 392 +/- 116 rad equivalents). At this time point in contrast to DDP no DNA protein cross-links were observed for CTDP (total cross-links: CTDP 310 +/- 71, DDP 1987 +/- 436 rad equivalents). Thus, at 24 h, CTDP was found to be distinctly less reactive to proteins than DDP, and it is suggested that CTDP might be similar in its toxicity pattern to the structurally related compound carboplatin which was also reported to be less reactive to protein than DDP. By 48 h, CTDP- and DDP-induced interstrand cross-links were 65 +/- 21 and 180 +/- 33 rad equivalents, respectively. Although at a lower level, by 24 h, AMDP showed a ratio of ISCL to total cross-links (179 +/- 39 versus 213 +/- 31 rad equivalents), which was comparable to CTDP. The second biphosphonate complex DAMP was the least active platinum compound in terms of DNA damage, effecting only 16 +/- 7 rad equivalents ISCL and 63 +/- 28 rad equivalents total cross-links; similar to DDP, DAMP displayed a higher DPC fraction at 24 h. The titanium complex diethoxybis-(1-phenylbutane-1,3-dionato)-tita-++ +nium(IV) showed dose-dependent inhibition of cell proliferation, while no significant DNA damage could be detected with the alkaline elution technique. These results, together with observations from other authors, indicating that space-filling planar aromatic ring systems are important for its antitumor activity, suggest as possible mechanism of action of diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) intercalation into the DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
研究了用五种新型金属配合物（三种铂化合物、一种钛化合物、一种钌化合物）处理实验性卵巢肿瘤细胞（O - 342）后在6小时、24小时和48小时时的DNA - 蛋白质交联（DPC）、DNA链间交联（ISCL）以及DNA单链断裂情况，并将其与它们的体外生长抑制潜力进行比较。顺二氯二氨铂（II）（顺铂，DDP）作为参考药物。测试了以下新型化合物：18 - 冠 - 6 - 四羧基双二氨铂（II）（CTDP）、顺 - 氨基三亚甲基膦酸二氨铂（II）（AMDP）、顺 - 二氨环己烷氨基三亚甲基膦酸铂（II）（DAMP）、二乙氧基双 -（1 - 苯基丁烷 - 1,3 - 二酮）钛（IV）（布多替钛）和反式吲唑四氯双吲唑钌（III）（IndCR）。在等摩尔浓度下，铂类药物的DNA交联活性按顺铂、CTDP、AMDP、DAMP的顺序降低；这与细胞增殖试验中的生长抑制情况平行。与顺铂（DDP）相比，CTDP诱导的链间交联发生得更慢（6小时：CTDP为73± + 15，而DDP为365± + 72辐射当量），但在暴露后24小时达到与顺铂相似的峰值（CTDP为317± + 68，而DDP为392± + 116辐射当量）。在这个时间点，与DDP相反，未观察到CTDP的DNA - 蛋白质交联（总交联：CTDP为310± + 71，DDP为1987± + 436辐射当量）。因此，在24小时时，发现CTDP与蛋白质的反应性明显低于DDP，并且表明CTDP的毒性模式可能与结构相关的化合物卡铂相似（据报道卡铂与蛋白质的反应性也低于DDP）。到48小时时，CTDP和顺铂诱导的链间交联分别为65± + 21和180± + 33辐射当量。尽管水平较低，但到24小时时，AMDP显示出ISCL与总交联的比率（179± + 39与213± + 31辐射当量），与CTDP相当。就DNA损伤而言，第二种双膦酸盐配合物DAMP是活性最低的铂化合物，仅产生16± + 7辐射当量的ISCL和总交联63± + 28辐射当量；与DDP相似，DAMP在2小时时显示出更高的DPC分数。钛配合物二乙氧基双 -（1 - 苯基丁烷 - 1,3 - 二酮）钛（IV）表现出剂量依赖性的细胞增殖抑制作用，而用碱性洗脱技术未检测到明显的DNA损伤。这些结果，连同其他作者的观察结果，表明空间填充平面芳香环系统对其抗肿瘤活性很重要，提示二乙氧基双 -（1 - 苯基丁烷 - 1,3 - 二酮）钛（IV）插入DNA可能是其作用机制。（摘要截于400字）
