Abstract 304: Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity

Abstract

Abstract Cisplatin is an anticancer drug widely used in the treatment of many cancers, including lung cancers. Although cisplatin causes various types of adverse events, the main dose-limiting toxicity of cisplatin is nephrotoxicity. Megalin is an endocytic receptor expressed at the apical membranes of proximal tubules. We previously demonstrated that cisplatin was reabsorbed through megalin and caused kidney injury. Cilastatin, an inhibitor of renal dehydropeptidase-I and used with imipenem, blocked the binding of cisplatin to megalin and reduced the nephrotoxicity induced by cisplatin. In the current study, we precisely evaluated the effect of cilastatin-mediated suppression of cisplatin nephrotoxicity to safely enhance the antitumor activity of cisplatin. BALB/c mice were administrated cisplatin with or without cilastatin. Tubular dilation or atrophy, brush border loss, tubular cell lysis and cast formation were observed in mice treated with cisplatin alone. However, these kidney injuries were decreased or disappeared in mice treated with cisplatin and cilastatin. Cilastatin also decreased the urinary levels of N-acetyl-β-D-glucosaminidase and neutrophil gelatinase-associated lipocalin, proximal tubular injury markers. Next, SCID mice were injected s.c. with A549, a human lung cancer cell line, and treated with cisplatin with or without cilastatin. Cilastatin did not affect the antitumor activity of cilastatin. Notably, A549 did not express megalin. Combined with cilastatin, the mice were successfully treated with 1.5 times dose of cisplatin with enhanced antitumor effects of cisplatin but without nephrotoxicity. In conclusion, cilastatin effectively suppressed nephrotoxicity of cisplatin by blocking the binding of cisplatin to megalin. These findings indicated that we could administer cisplatin into cancer patients without nephrotoxicity if we used cilastatin. Moreover, we might increase the dose of cisplatin and improve the outcome of cancer patients. Citation Format: Masashi Arita, Satoshi Watanabe, Nobumasa Aoki, Miho Takahashi, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Shoji Kuwahara, Junta Tanaka, Toshiyuki Koya, Akihiko Saito, Toshiaki Kikuchi. Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 304.