Sodium ascorbate enhancement of carbidopa-levodopa methyl ester antitumor activity against pigmented B16 melanoma

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.