L-methionine antagonism of cis-platinum nephrotoxicity.
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.
Basinger
M A
MA
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Jones
M M
MM
Holscher
M A
MA
D000818:Animals; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D008715:Methionine; D005978:Glutathione; D002945:Cisplatin