Cytochemical research concerning the protective effect of methylprednisolone against cisplatin-induced nephrotoxicity

顺铂是一种有效的抗肿瘤药物，但存在肾毒性的不良反应。本研究旨在探讨甲基强的松龙(MP)对顺铂肾毒性的预防作用及其机制。大鼠在不同时间静脉注射顺铂6.5 mg/kg，皮下注射不同剂量MP。顺铂注射前2小时或MP4处理组大鼠血尿素氮和血肌酐水平在第5天显著低于单纯顺铂组。为探讨MP对顺铂肾毒性保护作用的机制，我们观察了MP对顺铂体内给药后铂动力学的影响。在大鼠注射顺铂后，MP增加了尿铂排泄，同时伴随着血浆和肾脏铂浓度的下降。甲基强的松龙体内预处理对顺铂诱导的对氨基马尿酸(P-…)还原的影响用大鼠肾皮质切片检测更多的AH积聚和糖异生。大鼠肾切片经2 mM顺铂体外孵育后，PAH积聚明显减少，与对照组相当。然而，顺铂对脑片的抑制作用明显低于对照组。提示MP对顺铂肾毒性的保护作用可能是通过肾上皮细胞的糖异生作用实现的。为证实MP对顺铂肾毒性的保护作用，进行了临床研究。对14例尿路上皮肿瘤患者按MVAC方案进行顺铂注射治疗。在第一疗程化疗中不给予MP作为对照，但在第二疗程化疗期间在顺铂之前2-3小时给予2,000 mg/体剂量。甲基强的松龙不能显著抑制顺铂注射后尿酶排泄或血肌酐水平的升高。然而，在MP预处理期输注顺铂后，Ccr的下降幅度明显低于对照组。在这项前瞻性临床研究中，MP对顺铂肾毒性的保护作用也被证实。MP被认为是对抗顺铂肾毒性的有效药物。较少

cisplatin is an effective antitumor drug, but it is has an adverse effect of nephrotoxicity. In the present study, prophylatic effects of methyl-prednisolone (MP)on cisplatin-induced nephrotoxicity and its mechanism were studied. Rats were intravenously injected with 6.5 mg/kg of cisplatin combined with a subcutaneous MP in various doses at varous timing. BUN and serum creatinine levels in rats pretreated with MP4 or 2 hours prior to cisplatin injection were significantly lower than those in rats received cisplatin alone on day 5. To evaluate the mechanism responsible for the protective action of MP against cisplatin nephrotoxicity, the effects of MP on platinum kinetics following intraveenous administration of cisplatin in vivo were studied. MP increased urinary platinum excretion accompanied by a decrease in plasma and kidney platinum concentrations following cisplatin injections in rats. The effect of in vivo pretreatment with MP on cisplatin-induced reduction in p-aminohippurate (P … More AH) accumulation and gluconeogenesis was examined using renal cortical slices prepared from rats. The PAH accumulation in the kidney slices prepared rats were significantly reduced following in vitro incubation with 2mM cisplatin, to a degree equal to that observed in the slices prepared from control rats. However, the inhibitory effect of cisplatin on significantly less than that found in the slices from control rats. These findings suggest that MP may contribute to its protective effect against cisplatin nephrotoxicity via the process of gluconeogenesis in renal epithelial cells. The clinical study was conducted to confirm the protective effects of MP against the cisplatin nephrotoxicity. Fourteen patients with urothelial tumors werejinjected with cisplatin according to the MVAC therapy. MP was not administered during the first course of chemotherapy to provide a control, but was given in a dose of 2,000 mg/body 2-3 hours before cisplatin during the second course of chemotherapy in each patient. MP did not significantly inhibist the elevation in urinary enzyme excretion or serum creatinine levels following the cisplatin injection. However, the decrease in Ccr following cisplatin infusion in the MP-pretreated period were significantly lower than that observed in the control. The protective effects of MP against cisplatin nephrotoxicity were also indicated in this prospective clinical study. MP is considered to be a useful agent against cisplatin nephrotoxicity. Less