Department of Pharmacology, Tokyo Dental College, Chiba, Japan.
J Pharmacol Sci. 2010;112(3):361-8. doi: 10.1254/jphs.09323fp. Epub 2010 Mar 2.
We investigated the enhancing effect of two metal-chelating compounds, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), on the antitumor activity of cisplatin (CDDP). In the in vivo experiments, DMPS showed a clear synergistic effect and significantly enhanced the antitumor activity of CDDP in terms of survival and life span in mice transplanted with ascites sarcoma 180 cells (S180 cells) at a dose of <100 micromol/kg, s.c., but not at a dose of >500 micromol/kg. On the other hand, DMSA did not enhance the antitumor activity of CDDP. DMPS (50 micromol/kg, s.c.) combined with CDDP also potently suppressed [(3)H]thymidine uptake in S180 cells implanted in mice, whereas DMSA did not. In the in vitro experiments, DMPS (10(-6) to 10(-5) M) produced a time- and dose-dependent decrease in intracellular Ca(2+) concentrations (Ca(2+)) in S180 cells and, in combination with CDDP, yielded a significant increase in intracellular platinum accumulation compared to that in cells treated with CDDP alone. These results indicate that DMPS used in combination with CDDP may be of considerable benefit in enhancing the cytotoxicity of CDDP in tumor cells, especially at a low dose. The results also suggest that the enhancing effect of DMPS is closely related to a decrease in Ca(2+) and that the suitable dose and adequate administrational time of DMPS are important for its effective action.
我们研究了两种金属螯合剂，2,3-二巯基-1-丙磺酸（DMPS）和meso-2,3-二巯基琥珀酸（DMSA），对顺铂（CDDP）抗肿瘤活性的增强作用。在体内实验中，DMPS 在 100 微米ol/kg 以下剂量（sc）时表现出明显的协同作用，并显著提高了荷腹水肉瘤 180 细胞（S180 细胞）小鼠的生存时间和寿命，增强了 CDDP 的抗肿瘤活性，但在 500 微米ol/kg 以上剂量时没有增强作用。另一方面，DMSA 没有增强 CDDP 的抗肿瘤活性。DMPS（50 微米ol/kg，sc）联合 CDDP 也能强烈抑制植入小鼠的 S180 细胞中[(3)H]胸苷的摄取，而 DMSA 则不能。在体外实验中，DMPS（10（-6）至 10（-5）M）在时间和剂量上依赖于 S180 细胞内 Ca（2+）浓度[Ca（2+）]（i）的降低，并且与 CDDP 联合使用，与单独用 CDDP 处理的细胞相比，细胞内铂积累显著增加。这些结果表明，DMPS 与 CDDP 联合使用可能会显著增强 CDDP 在肿瘤细胞中的细胞毒性，特别是在低剂量时。结果还表明，DMPS 的增强作用与[Ca（2+）]（i）的降低密切相关，并且 DMPS 的合适剂量和足够的给药时间对于其有效作用非常重要。
