Department of Epidemiology and Environmental Health, School of Public Health and Health Professions , The State University of New York , Buffalo , New York 14214 , United States.
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences , The State University of New York , Buffalo , New York 14214 , United States.
Chem Res Toxicol. 2019 Aug 19;32(8):1572-1582. doi: 10.1021/acs.chemrestox.9b00097. Epub 2019 Jul 9.
Cisplatin is a platinum-based chemotherapeutic drug widely used in the treatment of various cancers such as testicular, ovarian, lung, bladder, and cervical cancers. However, its use and the dosage range applied have been limited by severe side effects (e.g., nephrotoxicity and ototoxicity) and by the development of resistance to cisplatin in patients during treatment. Metal chelators have shown promising potential in overcoming these problems often associated with platinum drugs. Previously, a new chelating agent, sodium ()-2-(dithiocarboxylato((2,3,4,5)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC), was developed. In this study, we examined the effect of GMDTC in modifying cisplatin-induced toxicities following and exposures. GMDTC treatment dramatically reduced cisplatin-induced apoptosis and cytotoxicity in HK2 cells by decreasing the amount of intracellular platinum. In the 4T1 breast cancer mouse model, GMDTC reduced cisplatin-induced nephrotoxicity by reducing cisplatin deposition in the kidney. GMDTC attenuated cisplatin-induced elevations in blood urea nitrogen and plasma creatinine, ameliorated renal tubular dilation and vacuolation, and prevented necrosis of glomeruli and renal tubular cells. GMDTC also inhibited cisplatin-induced ototoxicity as shown by improved hearing loss which was assessed using the auditory brainstem response test. Furthermore, GMDTC attenuated cisplatin-induced hematotoxicity and hepatotoxicity. Importantly, co-treatment of cisplatin with GMDTC did not affect cisplatin antitumor efficacy. Tumor growth, size, and metastasis were all comparable between the cisplatin only and cisplatin-GMDTC co-treatment groups. In conclusion, the current study suggests that GMDTC reduces cisplatin-induced systemic toxicity by preventing the accumulation and assisting in the removal of intracellular cisplatin, without compromising cisplatin therapeutic activity. These results support the development of GMDTC as a chemotherapy protector and rescue agent to overcome the toxicity of and resistance to platinum-based antineoplastic drugs.
顺铂是一种基于铂的化疗药物，广泛用于治疗各种癌症，如睾丸癌、卵巢癌、肺癌、膀胱癌和宫颈癌。然而，由于其严重的副作用（如肾毒性和耳毒性）以及患者在治疗过程中对顺铂产生耐药性，其使用和应用剂量范围受到限制。金属螯合剂在克服与铂类药物相关的这些问题方面显示出了很大的潜力。以前，开发了一种新的螯合剂，即（）-2-（二硫代羧酸盐（（2,3,4,5）-2,3,4,5,6-五羟基己基）氨基）-4（甲硫基）丁酸盐（GMDTC）。在这项研究中，我们研究了 GMDTC 在修饰顺铂引起的毒性中的作用，分别在 和 暴露后。GMDTC 治疗通过减少细胞内铂的含量，显著降低了 HK2 细胞中顺铂诱导的细胞凋亡和细胞毒性。在 4T1 乳腺癌小鼠模型中，GMDTC 通过减少顺铂在肾脏中的沉积，减轻了顺铂引起的肾毒性。GMDTC 减轻了顺铂引起的血尿素氮和血浆肌酐升高，改善了肾小管扩张和空泡形成，并防止了肾小球和肾小管细胞的坏死。GMDTC 还抑制了顺铂引起的耳毒性，通过听觉脑干反应测试评估听力损失得到改善。此外，GMDTC 抑制了顺铂引起的血液毒性和肝毒性。重要的是，顺铂与 GMDTC 联合治疗并未影响顺铂的抗肿瘤疗效。单独使用顺铂和联合使用顺铂和 GMDTC 治疗的肿瘤生长、大小和转移均无差异。总之，本研究表明，GMDTC 通过防止细胞内顺铂的积累和协助其清除来减轻顺铂引起的全身毒性，而不影响顺铂的治疗活性。这些结果支持开发 GMDTC 作为化疗保护剂和救援剂，以克服铂类抗肿瘤药物的毒性和耐药性。
