Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
Chem Biol Interact. 2013 Oct 25;206(1):90-9. doi: 10.1016/j.cbi.2013.08.015. Epub 2013 Sep 6.
Cisplatin is an effective anticancer drug which has been used to treat a wide range of tumors for the last 30 years. However, its use is associated with nephrotoxicity. Protective strategies have been reported, but their impact on the antitumor activity of cisplatin has not been clarified. We have previously reported the protective potential of carvedilol against cisplatin nephrotoxicity in tumor-free rats. Therefore, in the present study we used a tumor-bearing model to investigate the impact of carvedilol on the antitumor activity of cisplatin. The renal damage induced by cisplatin and the protective effect of carvedilol were demonstrated by the levels of blood urea nitrogen and plasma creatinine as well as by renal histopathology and immunohistochemistry. The mechanism of protection was associated with significantly decreased (i) oxidative stress markers, (ii) Bax expression, (iii) caspase-3 activity and (iv) TUNEL labeling for apoptosis. More importantly, evaluation of tumor mass, tumor remission rate and the survival curve showed that carvedilol did not impair the antitumor action of cisplatin. These findings suggest that the mechanisms underlying the nephrotoxic and the antitumor activity of cisplatin might be different. This is the first study to report such findings. Compared to other reported potential cytoprotectors against cisplatin-induced nephrotoxicity, carvedilol stands out due to the fact that it is already clinically-employed and well tolerated by the patients. Based on these features and on the present findings, carvedilol is a very promising candidate for future clinical trials as nephroprotector in patients treated with cisplatin.
顺铂是一种有效的抗癌药物，在过去的 30 年中，已被用于治疗多种肿瘤。然而，其使用与肾毒性相关。已经报道了一些保护策略，但它们对顺铂的抗肿瘤活性的影响尚未阐明。我们之前曾报道过卡维地洛对无肿瘤大鼠顺铂肾毒性的保护潜力。因此，在本研究中，我们使用荷瘤模型来研究卡维地洛对顺铂抗肿瘤活性的影响。通过血液尿素氮和血浆肌酐水平以及肾脏组织病理学和免疫组织化学，证明了顺铂引起的肾损伤和卡维地洛的保护作用。保护机制与以下方面显著相关：（i）氧化应激标志物减少，（ii）Bax 表达减少，（iii）caspase-3 活性减少，（iv）细胞凋亡的 TUNEL 标记减少。更重要的是，对肿瘤质量、肿瘤缓解率和生存曲线的评估表明，卡维地洛并未损害顺铂的抗肿瘤作用。这些发现表明，顺铂的肾毒性和抗肿瘤活性的机制可能不同。这是首次报道此类发现的研究。与其他报道的针对顺铂诱导的肾毒性的潜在细胞保护剂相比，卡维地洛因其已经在临床上使用且患者耐受良好而脱颖而出。基于这些特点和本研究结果，卡维地洛作为顺铂治疗患者的肾保护剂，是未来临床试验的一个很有前途的候选药物。
