AN APPROACH TOWARDS MORE SELECTIVE ANTICANCER AGENTS

A promising approach towards better targeted anticancer drug therapy t akes advantage of enhanced expression of proteases associated with hum an malignancies. Especially plasminogen activator activity has been fo und to be substantially increased, leading to an enhanced activity of the serine protease plasmin. Bifunctional alkylating agents, such as N -(2-chloroethyl)-N-nitrosoureas, display broad spectrum anticancer act ivity, but also exhibit considerable systemic toxicity. We describe he re the synthesis of new N-nitrosourea-based prodrugs designed to becom e activated by tumor-associated proteases, to provide for enhanced ant itumor activity and reduced systemic toxicity. Tripeptides representin g substrates for plasmin were linked by an amide bond to N'-(2-aminoet hyl)-N-(2-chloroethyl)-N-nitrosourea and the corresponding N'-methyl d erivative. Synthesis and plasmin-triggered decomposition of these new tripeptide conjugates is described. Cancer cells expressing high plasm inogen activator activity are highly sensitive to the new prodrugs in the presence of plasminogen, but not in its absence.