ascorbic-acid and levodopa-methyl-ester

Sodium ascorbate supplementation in drinking water inhibited subcutaneous tumor growth, enhanced levodopa methylester (LDME) chemotherapy, and increased survival of B16 melanoma-bearing mice. Antitumor activity was greatest in mice fed diets low in tyrosine and phenylalanine (restricted diet). Ascorbate partially protected against LDME-induced decrease in food intake. Primary tumor masses were smaller, more well defined, and less invasive in ascorbate-supplemented mice, and secondary tumor masses appeared encapsulated. Dehydroascorbate increased tumor growth and decreased survival. Ascorbate supplementation did not alter establishment of experimental B16-BL6 melanoma metastases but inhibited tumor outgrowth when combined with LDME chemotherapy and the restricted diet. Spontaneous metastasis was inhibited by ascorbate in mice fed the restricted diet. Ascorbate supplementation doubled plasma concentration in melanoma-bearing mice independent of diet and increased tumor concentration 3.7-fold (basal diet) and 5.6-fold (restricted diet) relative to unsupplemented mice. Tumor peroxidation also increased during ascorbate supplementation and LDME treatment.

Topics: Animals; Ascorbic Acid; Dehydroascorbic Acid; Female; Levodopa; Lung Neoplasms; Male; Malondialdehyde; Melanoma, Experimental; Mice; Neoplasm Transplantation

The single and combined effects of (a) dietary restriction of phenylalanine and tyrosine, (b) levodopa methylester chemotherapy, and (c) megadose sodium ascorbate supplementation on experimental metastasis was determined in B16-BL6 melanoma. Dietary restriction and levodopa methylester therapy inhibited tumor outgrowth, whereas ascorbate alone was inactive. In combination, however, the effect of dietary restriction and levodopa methylester chemotherapy was augmented by sodium ascorbate. Tumor cells surviving this combination therapy (treated population) were isolated from the lungs of treated mice, and proved to be tumorigenic when inoculated SC into the back of naive mice. The resulting tumors grew more slowly than those produced by inoculation of similarly isolated control cells (control population), irrespective of whether the diet was adequate or deficient in phenylalanine and tyrosine. Failure of the treated tumor cell population to exhibit reduced sensitivity to the combination chemotherapy or, unlike the control population, to exhibit variation in pigmentation levels, suggests that the restriction of phenylalanine and tyrosine during drug therapy alters the tumor response to reduce heterogeneity and perhaps interferes with the emergence of drug resistance.

Topics: Animals; Ascorbic Acid; Diet; Female; Levodopa; Lung Neoplasms; Melanoma; Mice; Mice, Inbred Strains; Phenylalanine; Tyrosine

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 supplemen

Topics: Animals; Ascorbic Acid; Diet; Female; Levodopa; Lipid Peroxides; Liver; Malondialdehyde; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Phenylalanine; Tyrosine

We report here the single and combined antitumor activity on B16 melanoma in female C57BL/6 X DBA/2F1 mice bearing s.c. tumors of sodium ascorbate, carbidopa-levodopa methyl ester, and dietary phenylalanine and tyrosine deficiency. Groups of 15 mice were fed continuously one of three test diets both with and without sodium ascorbate (30 mg/ml) in the drinking water beginning 2 weeks before inoculation of 10(6) melanoma cells. The test diets included the following amounts of tyrosine-phenylalanine: commercial, 1.09 and 0.64%; purified, 0.6 and 0.3%; and deficient, 0.08 and 0.04%. Drug-treated groups received daily injections of carbidopa (100 mg/kg) and levodopa methyl ester (1000 mg/kg) i.p. for 15 days beginning 1 day after tumor transplant. Tumor growth curves and median survival time were determined. Ascorbate stimulated tumor growth in the commercial diet group. In mice fed the purified diet, ascorbate inhibited growth in some tumors, while it had no effect on others. Ascorbate inhibited tumor growth in mice fed the deficient diet, which itself severely inhibited tumor growth, and in this group increased survival by 82%. Drug treatment had little effect on tumor growth and survival of mice fed the commercial diet, but it significantly decreased growth and moderately increased survival of mice fed the purified diet. The deficient diet enhanced drug activity and increased survival of tumor-bearing mice by 73%. Combined therapy had little effect in mice fed the commercial diet;l however, mice fed the purified diet and receiving drug and ascorbate had smaller tumors and lived 55% longer. In mice fed the deficient diet, the combination retarded tumor growth and increased survival dramatically by 123%. These data indicate that adding ascorbate and restricting tyrosine and phenylalanine in combination with levodopa methyl ester therapy may become an important strategy for treating malignant melanoma.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Carbidopa; Cell Line; Diet; Drug Synergism; Drug Therapy, Combination; Female; Injections, Intraperitoneal; Levodopa; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Phenylalanine; Tyrosine