Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy

Cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is a widely used highly effective, oncolytic agent that has serious ototoxic side-effects. To rest the effectiveness of local delivery of L-methionine (L-Met) as nit otoprot ective agent against CDDP otoroxicity we used a rat model of a highly metas tatic breast cancer tumor i.e. Fisher 344 mts implanted with MTLn3 breast c ancer cells. Four experimental groups were evaluated - I: untreated; II: CD DP-treated (three dosages); III: systemically-delivered L-Met + CDDP-treate d; IV: locally delivered L-Met + CDDP-treated. The integrity of the outer h air cells (OHCs) was determined using scanning electron microscopy (SEM); h earing was assessed by recording auditory brainstem responses (ABRs) at mul tiple frequencies. The chemotherapeutic effectiveness of CDDP was quantifie d by measuring changes in tumor mass and the presence of tumor metastasis. L-Met provided otoprotection of the OHCs against CDDP toxicity in the cochl eae of rats following either systemic (III) or local (IV) administration. T he ABRs were unchanged in each of the L-Met protection Groups (III and IV) and in the untreated animals of Group I. Treatment with CDDP only (II) indu ced significant hearing losses at both 16 and Ig kHz when compared to ABRs of untreated mls(lj. CDDP was effective in controlling the MTLn3 initiated breast cancer tumors iii the CDDP-treated (II) and the local L-Met protecti on, CDDP-treated (IV) Groups. In contrast, the tumors in the systemic L-Met protection, CDDP-treated Group (III) were not controlled by the CDDP treat ment regime. This study demonstrates that local delivery of L-Met to the sc ala tympani of the cochlea via the round window membrane (Nj provides effec tive protection against CDDP ototoxicity without compromising its ability t o control a highly metastatic form of cancer: (C) 2001 Elsevier Science Inc . All rights reserved.