Basinger M A, Jones M M, Holscher M A
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Toxicol Appl Pharmacol. 1990 Mar 15;103(1):1-15. doi: 10.1016/0041-008x(90)90257-u.
L-Methionine administered simultaneously with cis-platinum (CDDP) iv results in a significant reduction of the nephrotoxicity normally associated with CDDP without any apparent effect on the antineoplastic activity for rats bearing the Walker 256 carcinosarcoma. CDDP given with L-methionine at a 1:20 mole ratio can be administered to rats at doses up to 35 mg/kg iv with the survival of all treated animals (3/3) and up to 56 mg/kg iv (bolus injection) with the survival of 3/6 animals, while CDDP administered alone at these levels is lethal. A reduced level of protection against the nephrotoxicity was also achieved at lower mole ratios of L-methionine to CDDP. Renal function was monitored using BUN and serum creatinine levels, and gastrointestinal toxicity by weight changes during the course of the experiments. A histopathological examination of the kidneys was also performed to evaluate the protection provided by L-methionine. Under the conditions used, the reaction between L-methionine and CDDP does not appear to proceed so rapidly as to interfere with the antitumor activity of the CDDP. The examination of structural analogs as agents for the control of CDDP-induced nephrotoxicity revealed that the C-S-C-group is the essential group for the protective action in these structures. Although L-methionine can provide renal protection in rats given high doses of CDDP, it does not prevent the accumulation of platinum in the kidney.
L-蛋氨酸与顺铂（CDDP）静脉注射同时给药，可显著降低通常与CDDP相关的肾毒性，而对携带Walker 256癌肉瘤的大鼠的抗肿瘤活性无明显影响。以1:20摩尔比将L-蛋氨酸与CDDP一起给药时，大鼠静脉注射剂量可达35 mg/kg，所有受试动物（3/3）存活；静脉注射剂量达56 mg/kg（推注）时，6只动物中有3只存活，而单独给予这些剂量的CDDP是致死的。在L-蛋氨酸与CDDP摩尔比更低时，对肾毒性的保护水平也有所降低。在实验过程中，通过监测血尿素氮（BUN）和血清肌酐水平来评估肾功能，通过体重变化评估胃肠道毒性。还对肾脏进行了组织病理学检查，以评估L-蛋氨酸提供的保护作用。在所使用的条件下，L-蛋氨酸与CDDP之间的反应似乎不会迅速进行到干扰CDDP的抗肿瘤活性的程度。对作为控制CDDP诱导的肾毒性药物的结构类似物的研究表明，C-S-C基团是这些结构中起保护作用的必需基团。虽然L-蛋氨酸可以为给予高剂量CDDP的大鼠提供肾脏保护，但它并不能阻止铂在肾脏中的蓄积。
