Li G, Frenz D A, Brahmblatt S, Feghali J G, Ruben R J, Berggren D, Arezzo J, Van De Water T R
Department of Otolaryngology, Albert Einstein College of Medicine, Bronx NY 10461, USA.
Neurotoxicology. 2001 Apr;22(2):163-76. doi: 10.1016/s0161-813x(00)00010-3.
Cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is a widely used, highly effective, oncolytic agent that has serious ototoxic side-effects. To test the effectiveness of local delivery, of L-methionine (L-Met) as an otoprotective agent against CDDP ototoxicity, we used a rat model of a highly metastatic breast cancer tumor, i.e. Fisher 344 rats implanted with MTLn3 breast cancer cells. Four experimental groups were evaluated--I: untreated; II: CDDP-treated (three dosages); III: systemically-delivered L-Met + CDDP-treated; IV: locally delivered L-Met + CDDP-treated. The integrity of the outer hair cells (OHCs) was determined using scanning electron microscopy (SEM); hearing was assessed by recording auditory brainstem responses (ABRs) at multiple frequencies. The chemotherapeutic effectiveness of CDDP was quantified by measuring changes in tumor mass and the presence of tumor metastasis. L-Met provided otoprotection of the OHCs against CDDP toxicity in the cochleae of rats following either systemic (III) or local (IV) administration. The 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) induced significant hearing losses at both 16 and 18 kHz when compared to ABRs of untreated rats(I). CDDP was effective in controlling the MTLn3 initiated breast cancer tumors in the CDDP-treated (II) and the local L-Met protection, CDDP-treated (IV) Groups. In contrast, the tumors in the systemic L-Met protection, CDDP-treated Group (III) were not controlled by the CDDP treatment regime. This study demonstrates that local delivery of L-Met to the scala tympani of the cochlea via the round window membrane (IV) provides effective protection against CDDP ototoxicity without compromising its ability to control a highly metastatic form of cancer.
顺铂（顺二氨二氯铂(II)，CDDP）是一种广泛使用的高效溶瘤剂，但具有严重的耳毒性副作用。为了测试局部递送L-蛋氨酸（L-Met）作为预防CDDP耳毒性的耳保护剂的有效性，我们使用了一种高转移性乳腺癌肿瘤的大鼠模型，即植入MTLn3乳腺癌细胞的Fisher 344大鼠。评估了四个实验组——I：未治疗；II：CDDP治疗（三种剂量）；III：全身递送L-Met + CDDP治疗；IV：局部递送L-Met + CDDP治疗。使用扫描电子显微镜（SEM）确定外毛细胞（OHC）的完整性；通过记录多个频率的听觉脑干反应（ABR）来评估听力。通过测量肿瘤质量的变化和肿瘤转移的存在来量化CDDP的化疗效果。在全身（III）或局部（IV）给药后，L-Met对大鼠耳蜗中的OHC提供了针对CDDP毒性的耳保护作用。在每个L-Met保护组（III和IV）以及I组的未治疗动物中，ABR均未改变。与未治疗大鼠（I）的ABR相比，仅用CDDP治疗（II）在16和18 kHz时均导致显著的听力损失。CDDP在CDDP治疗组（II）和局部L-Met保护、CDDP治疗组（IV）中有效地控制了MTLn3引发的乳腺癌肿瘤。相比之下，全身L-Met保护、CDDP治疗组（III）中的肿瘤未被CDDP治疗方案控制。这项研究表明，通过圆窗膜将L-Met局部递送至耳蜗鼓阶（IV）可有效预防CDDP耳毒性，而不会损害其控制高度转移性癌症形式的能力。
