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.