The present study was conducted to clarify the mechanism responsible for enhancement of the anti-
melanoma activity of
levodopa methylester by supplemental ascorbate in vivo.
5-Hydroxydopa, a known
cytotoxic agent and the major metabolite formed from
levodopa in the presence of ascorbate and mushroom
tyrosinase in vitro, was assessed for its antitumor activity against i.p. and s.c. inoculated
B16 melanoma,
P388 leukemia, and
L1210 leukemia in mice with and without supplemental ascorbate. Treatment with
5-hydroxydopa failed to significantly increase survival of mice bearing i.p. or s.c. pigmented and non-pigmented
B16 melanomas even though it inhibited local
tumor growth. Treatment increased survival of both P388 and L1210
leukemias, and this increase was more pronounced in mice bearing i.p.
tumors than in mice bearing s.c.
tumors. This treatment significantly decreased final
tumor weight of both
leukemias implanted s.c., and inhibited
ascites formation in mice inoculated with i.p.
tumors. Ascorbate supplementation decreased or abrogated the effect of
5-hydroxydopa on survival in mice bearing i.p. or s.c.
leukemia tumors and decreased survival relative to control mice bearing i.p. or s.c. pigmented and s.c. non-pigmented
tumors. It did not affect survival of treated mice bearing i.p. non-pigmented
melanoma tumors. Ascorbate supplementation did not modify the effect of
5-hydroxydopa treatment on primary s.c.
tumor growth in mice bearing
melanoma or
leukemia tumors nor did it affect
ascites formation in treated mice bearing i.p.
leukemia tumors. The lack of correlation between the observed inhibition of primary
tumor growth and the absence of an effect on survival in
5-hydroxydopa treated mice bearing i.p.
melanoma may relate to an inability of this
drug to interfere with
tumor metastasis. These data argue against a role for
5-hydroxydopa as a metabolically derived cytotoxic formed in situ during concurrent treatment with
levodopa methylester and supplemental ascorbate.