Ototoxicity of Cisplatin vs. Platinum Analogs CBDCA (JM-8) and CHIP (JM-9)

Abstract

Cis-diamminedichloroplatinum (cisplatin), a divalent platinum compound and cell-cycle nonspecific chemotherapeutic agent, produces a permanent high-frequency sensorineural hearing loss and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. Synthetic platinum analogs are presently being tested to identify an analog with greater antitumor activity, but less ototoxicity and nephrotoxicity than cisplatin. The objectives of this study were to analyze the potential cochlear and nephrotoxic effects of two synthetic platinum analogs presently in phases I and II of clinical trials, CBDCA [JM-8 or cis-diammine, 1,1-cyclobutane dicarboxylato (2)-0,0¹-platinum (NSC-241240)] and CHIP [JM-9 or cis-dichloro-trans-dihydroxybisisopropylamine platinum IV (NSC-256927)]. Cytocochleography, auditory brain-stem evoked response (ABR), double-blind light microscopy of renal tissues, and gamma emission analysis of ^195mpt localization in viscera and inner ear were employed in the evaluation of cisplatin and platinum analogs (JM-8 and JM-9) in adult guinea pigs. Final results indicate that the investigational chemotherapeutic analogs CBDCA (JM-8) and CHIP (JM-9) do not produce the ototoxicity and nephrotoxicity characteristic of cisplatin. Furthermore, these findings demonstrate ^195mpt localization in the vestibular labyrinth and confirm previous platinum distribution studies in the organ of Corti and stria vascularis tissues.