Yajima Yuka, Kawaguchi Mitsuru, Yoshikawa Masanobu, Okubo Migiwa, Tsukagoshi Eri, Sato Kazumichi, Katakura Akira
Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, 5-11-13 Sugano, Ichikawa, Chiba 272-8513, Japan.
Department of Pharmacology, Tokyo Dental College, 2-1-14 Misakicho, Chiyoda-ku, Tokyo 101-0061, Japan.
J Pharmacol Sci. 2017 Jun;134(2):108-115. doi: 10.1016/j.jphs.2017.05.006. Epub 2017 Jun 3.
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 with meso-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.
此前，我们报道过，特定低剂量的2,3-二巯基-1-丙磺酸钠（DMPS）作为重金属中毒的解毒剂，可反向增强顺铂（CDDP）对荷S-180细胞小鼠的抗肿瘤活性。然而，中-2,3-二巯基琥珀酸（DMSA）的这种活性较弱。本研究调查了较低剂量的DMPS或DMSA对CDDP肾毒性及动力学的影响。从雌性小鼠分离出肾脏和血液，这些小鼠连续4天每天接受一次含或不含DMPS或DMSA的CDDP，用于测量血尿素氮（BUN）水平、转运蛋白（OCT2：有机阳离子转运体；MATE1：多药和毒素外排）mRNA水平、CDDP来源的铂，以及肾小管细胞的TUNEL染色。DMPS或DMSA有效降低了CDDP诱导的BUN，并使肾脏中的铂含量适度降低。此外，两种二巯基化合物均恢复了CDDP降低的转运蛋白（OCT2和MATE1）mRNA水平，并明显抑制了CDDP诱导的细胞凋亡。这些结果表明，DMPS以及DMSA在约为CDDP剂量17倍（μmol/kg）时，有足够潜力逆转CDDP肾毒性，考虑到给药剂量和时间，同时使用DMPS对于预防肾毒性和增强CDDP化疗期间的抗肿瘤活性可能是有用的。
