Résumé : The alkylating peptide PSF shows very promising results in vitro on different cancer cells but its efficacy in animals has not been assessed. Here we evaluate the efficacy of PSF in human melanoma-bearing nude mice and examine the underlying mechanism. In melanoma-bearing nude mice, escalating doses of PSF showed dose-dependent responses and reached tumor regression with an optimal dose of 20 mg/kg for 1 month. A comparison of PSF with its free moiety m-sarcolysin and melphalan showed a highly significant advantage of PSF. Furthermore, dose fractionation yielded an even better control of tumor regrowth. In vitro studies unraveled an original delivery mechanism based on the rapid binding of PSF mainly due to red blood cells to form a pro-drug complex and the subsequent release of active metabolites by tumor-associated proteolytic enzymes. Blood kinetics showed one major metabolite partially released over time, while in the presence of melanoma cells three additional metabolites are generated. Interestingly, tumor-shed proteases also induce the production of these metabolites and varying combinations of enzyme inhibitors indicate the involvement of metallo- and other families of proteases in the delivery process. This particular transport and delivery of such an alkylating agent may have several benefits, mainly lowering the drug-free moiety in plasma and at the same time increasing its concentration in protease rich areas such as tumors.