The chemotherapy of malignant melanoma

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.