Anita Libert

Human melanoma targeting with alpha-MSH-melphalan conjugate.

A conjugate made of alpha-MSH as a drug carrier and melphalan has been designed in order to target human melanoma cells. Iodination of the alpha-MSH moiety led to a relatively stable tracer which could be easily separated and analysed by reverse phase high pressure liquid chromatography. The conjugate was found to be unstable at neutral pH and a serious denaturation can take place at concentrations exceeding 100 micrograms/ml, especially in plasma. Receptor-mediated cytotoxicity has been shown by the use of cultured alpha-MSH receptor positive/negative cells as well as in vivo B16 murine melanoma model. Body distribution and uptake of the labelled compound were unaltered as compared to those of labelled free hormone. alpha-MSH receptor recognition properties also remained unchanged with a better apparent affinity of the conjugate probably due to the alkylating activity of melphalan itself. Using human melanoma dendritic cells expressing more than 10,000 alpha-MSH binding sites per cell as an in vitro model, we were able to demonstrate higher cytotoxicities as compared to melphalan-treated cells. In contrast, melanoma cells with low receptivity did not show higher cytotoxicity. P388D1 mouse plasmocytoma cells lacking receptors were much more sensitive to melphalan than the conjugate. This phenomenon appeared to be related with the number of binding sites expressed at the time of the experiment as well as cell differentiation and the doubling time. Our findings strongly support the concept of a receptor-mediated cytotoxicity and may enable the in vivo melphalan delivery to target tissues to be increased, achieving an improvement of drug penetration inside melanoma cells.

Melanoma-associated antigens: Prospects for clinical use

Malignant melanomas, although less common than most malignancies, account for 1% of all cancers, and have been the subject of numerous new biological and clinical approaches reported in thousands of publications over the last 15 years. Their strong biological aggressiveness when they attain as little as 1.5 mm in thickness, and their persistent resistance to therapy when they spread - 80% failure to chemotherapy - make malignant melanomas one of the biggest challenges to therapy. A new approach could be the therapeutic use of the immunological reaction of the host. Attempts to demonstrate the existence of melanoma-associated antigens were made in the early seventies and were followed by specific immunotherapy trials, using vaccines prepared from melanoma cells. No definite evidence of melanoma immunogenicity was ever obtained. However, monoclonal antibodies definitely demonstrate the presence of melanoma-associated antigenic structures at the cell surface. In this commentary the following topics will be dealt with: antibodies to melanomas; melanoma antigens; and clinical applications of monoclonal antibodies.