Modulation of peroxidation in murine melanoma by dietary tyrosine-phenylalanine restriction, levodopa methylester chemotherapy, and sodium ascorbate supplementation.
Treatment with the drug combination of levodopa methylester and benserazide, supplemental ascorbate, and dietary deficiencies of tyrosine and phenylalanine more than doubled the median survival time of female (C57BL/6 X DBA/2)F1 mice bearing B16 melanoma tumors. The mechanism for this antitumor effect was not well defined. This study was designed to test the hypothesis that the antitumor activity of levodopa methylester and ascorbate against B16 melanoma is related to the generation of free radicals of oxygen, which peroxidize lipid constituents of cell membranes leading to cell death. As an indication of lipid peroxidation, the individual and combined effects of drug treatment and ascorbate supplementation on host and tumor malondialdehyde levels were examined in mice fed one of three test diets (commercial, purified, or deficient) containing decreasing amounts of tyrosine and phenylalanine. Malondialdehyde levels were increased in the livers of all untreated tumor-bearing mice, which suggests that the tumor alters host antioxidant defenses. Drug treatment and ascorbate supplementation alone and in combination increased hepatic malondialdehyde levels inversely to the amounts of tyrosine and phenylalanine in the diet, and the effects of drug and ascorbate on malondialdehyde levels were additive. Plasma levels remained unchanged by drug treatment, ascorbate supplementation, or tumors in mice fed the commercial or purified diets. Higher levels were observed only in tumor-bearing mice fed the deficient diet and given both drug treatment and ascorbate supplementation. Changes in tumor malondialdehyde levels generally correlated with the effects of the drug and ascorbate on survival time of mice bearing B16 melanoma. Tumors from mice fed the commercial diet accumulated little malondialdehyde, and therapy was relatively ineffective in this dietary group. In mice fed purified or deficient diets, drug treatment and ascorbate supplementation alone increased survival and tumor malondialdehyde levels, but the level of peroxidation in mice receiving the ascorbate supplementation was low compared to its greater antitumor effect on B16 melanoma. Although ascorbate enhanced the peroxidative activity of the drug on B16 melanoma tumors, the effects of the drug and ascorbate on malondialdehyde levels were not additive. Ascorbate enhanced survival of tumor-bearing mice that were fed the deficient diet and that were treated with drug, which indicated that ascorbate supplementation acted via other mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001205:Ascorbic Acid / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D004032:Diet; D005260:Female; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000032:analysis; D008315:Malondialdehyde / Q000032:analysis / Q000097:blood; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010649:Phenylalanine / Q000008:administration & dosage*; D014443:Tyrosine / Q000008:administration & dosage*
D008054:Lipid Peroxides; D014443:Tyrosine; D007980:Levodopa; D010649:Phenylalanine; D008315:Malondialdehyde; C035420:levodopa methyl ester; D001205:Ascorbic Acid