The effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the nephrotoxicity in the mouse during repeated cisplatin (CDDP) treatments
The effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the nephrotoxicity in the mouse during repeated cisplatin (CDDP) treatments
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2,3-二巯基-1-丙磺酸 (DMPS) 和内消旋 2,3-二巯基琥珀酸 (DMSA) 对顺铂 (CDDP) 重复治疗期间小鼠肾毒性的影响
DOI：
10.1016/j.jphs.2017.05.006
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发表时间：
2017
影响因子：
3.5
通讯作者：
Katakura A.
中科院分区：
文献类型：
--
作者：
Yajima Y;Kawaguchi M;Yoshikawa M;Okubo M;Tsukagoshi E;Sato K;Katakura A.
此前，我们报道了特定剂量的2，3-二硫代-1-丙磺酸钠(DMPS)作为重金属中毒的解毒剂，反向增强顺铂(CDDP)诱导的对S-180细胞的抗肿瘤活性。然而，只有中-2，3-二硫代琥珀酸(DMSA)的这种活性很弱。本研究探讨了小剂量DMPS或DMSA对顺铂肾毒性和动力学的影响。取雌性小鼠肾和血，连续4d分别给予顺铂加或不加DMPS或DMSA，测定血尿素氮(BUN)和转运蛋白(OCT2：有机阳离子转运体；MATE1：多药和毒素排出物)mRNA、CDDP来源的铂和肾小管上皮细胞的TUNEL染色。DMPs或DMSA能有效降低CDDP诱导的BUN，并引起肾脏铂的适度减少。此外，两种二巯基化合物均能恢复CDDP降低的转运蛋白(OCT2和MATE1mRNA)水平，并能明显抑制CDDP诱导的细胞凋亡。这些结果表明，在顺铂的大约17倍剂量(μ摩尔/公斤)时，DMPS和DMSA有足够的潜力逆转顺铂的肾毒性，同时考虑给药剂量和给药时机的DMPS在顺铂化疗过程中可能有助于预防肾毒性和增强抗肿瘤活性。
Previously, we reported that specific lower dose of sodium 2,3-dimercapto-1-propanesulfonic acid (DMPS) which is an antidote to heavy metal intoxication, inversely enhanced cisplatin (CDDP)-induced antitumor activity to S-180 cell-bearing mouse. This activity was only weak withmeso-2,3-dimercaptosuccinic acid (DMSA), however. This study investigated the effects of lower doses of DMPS or DMSA on the nephrotoxicity and kinetics of CDDP. Kidney and blood isolated from female mice which received CDDP with or without DMPS or DMSA once daily for 4 days were provided for measuring levels of blood urea nitrogen (BUN) and transporter proteins (OCT2: organic cation transporter; MATE1: multidrug and toxin extrusion) mRNA, and CDDP-originated platinum, and TUNEL staining of renal tubular cells. DMPS or DMSA reduced effectively CDDP-induced BUN, and caused a moderate reduction of platinum in kidney. Additionally, both dimercapto-compounds restored the CDDP-reduced mRNA levels of transporter proteins (OCT2 and MATE1), and apparently suppressed the CDDP-induced apoptosis. These results suggest that DMPS, as well as DMSA, at approximate 17-fold dose (μmol/kg) of CDDP, has an enough potential to reverse the CDDP nephrotoxicity, and concomitant use of DMPS considering both dose and timing for administration is potentially useful for preventing nephrotoxicity and enhancing antitumor activity during CDDP chemotherapy.