Zheng H, Fink D, Howell S B
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla, California 92093-0058, USA.
Clin Cancer Res. 1997 Jul;3(7):1157-65.
In pursuit of a strategy for increasing delivery of platinum drugs to tumors, we compared the cytotoxicity, extent of cellular uptake, and DNA platination of native cisplatin (DDP) and aquated cisplatin (aqDDP) in human head and neck carcinoma UMSCC10b cells. AqDDP was 1. 8-fold more toxic than DDP when tested against UMSCC10b cells in vitro. At high concentrations, aqDDP uptake was 3-fold more rapid than that of DDP; uptake of DDP and aqDDP was nonsaturable up to a concentration of 1600 micrometer. AqDDP produced 6.4-fold more platination of DNA than did DDP at the same concentration, suggesting that once inside the cell, aqDDP was 2-fold more effective at producing adducts in DNA than the native drug. Despite the paradox that aqDDP, which contains some charged species, entered the cell more rapidly than did neutral native DDP at high concentrations, studies on the effect of temperature, ATP depletion, and sulfhydryl group blockade did not provide evidence for uptake of aqDDP via a channel or transporter. AqDDP was more nephrotoxic to mice than DDP; however, s.c. administration of sodium thiosulfate protected against this toxicity and permitted a 7-fold escalation of aqDDP dose. These studies provide the preclinical basis for a novel therapeutic strategy based on the regional intraarterial or intracavitary administration of aqDDP in combination with a systemic neutralizing agent.
为了寻求提高铂类药物向肿瘤递送的策略，我们比较了天然顺铂（DDP）和水化顺铂（aqDDP）在人头颈癌UMSCC10b细胞中的细胞毒性、细胞摄取程度和DNA铂化作用。在体外对UMSCC10b细胞进行测试时，aqDDP的毒性比DDP高1.8倍。在高浓度下，aqDDP的摄取速度比DDP快3倍；在浓度达到1600微摩尔之前，DDP和aqDDP的摄取均不饱和。在相同浓度下，aqDDP使DNA的铂化程度比DDP高6.4倍，这表明一旦进入细胞内，aqDDP在DNA中产生加合物的效率比天然药物高2倍。尽管存在矛盾之处，即含有一些带电物种的aqDDP在高浓度下比中性的天然DDP进入细胞的速度更快，但关于温度、ATP耗竭和巯基阻断作用的研究并未提供aqDDP通过通道或转运体摄取的证据。aqDDP对小鼠的肾毒性比DDP更大；然而，皮下注射硫代硫酸钠可预防这种毒性，并使aqDDP剂量增加7倍。这些研究为基于区域动脉内或腔内给予aqDDP并联合全身中和剂的新型治疗策略提供了临床前依据。
