Advanced human
malignant melanoma continues to be an intractable
tumor unresponsive to most forms of
therapy. We have been engaged in the design of selective agents for the
chemotherapy of
malignant melanoma based on the unique biochemical features within this
tumor. Several analogues have been prepared with significant antitumor activity against
experimental melanoma models, and these include
levodopa,
dopamine, and the nonneurotoxic analogue
3,4-dihydroxybenzylamine. Pending the clinical availability of the improved analogues, we have investigated the effects of
levodopa and
dopamine on advanced human
malignant melanoma.
Dopamine has been shown to cause a significant biochemical inhibition of
tumor in 4 patients treated, but cardiovascular effects have precluded its repetitive use. The combination of
levodopa/
carbidopa has been used in an attempt to circumvent these toxicities as well as deliver
drug to the central nervous system (CNS). Of 12 patients treated to date, 8 are evaluable, and there have been 4 significant clinical responses. Importantly, the plasma levels achievable with
levodopa are in tumoricidal range as predicted by in vivo assays (10(-5) M). One patient had a complete resolution of a CNS lesion as measured by CAT scan and a corresponding improvement in symptoms. Pending the availability of improved analogues, further study of the use of
levodopa/
carbidopa as
therapy for
malignant melanoma in humans appears warranted, and different methods of delivery, either alone or in combination with conventional agents, will be explored.