Protease-activated “prodrugs” for cancer chemotherapy

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Abstract
Many types of malignant cells and human tumors display increased concentrations of the protease plasminogen activator that converts plasminogen to the highly active protease, plasmin. Because plasmin rapidly cleaves various low MW compounds coupled to appropriate peptide specifiers, coupling of such peptide specifiers to anticancer drugs might create prodrugs which would be locally activated by tumor-associated plasmin and consequently would be less toxic to normal cells. To provide an initial test of this concept peptidyl prodrugs of the structure D-Val-Leu-Lys-X were synthesized in which the peptidyl portion was designed to allow the prodrug to serve as an excellent plasmin substrate and X is an anticancer drug, the glutamine analog (.alpha.S,5S) .alpha.-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) or the alkylating agent N,N-bis(2-chloroethyl)-p-phenylenediamine (phenylenediamine mustard). Treatment of these prodrugs with plasmin generated the free peptide and the free drug, demonstrating that these prodrugs are plasmin substrates. The prodrugs and free drugs were tested in an in vitro system against normal chicken embryo fibroblasts, which display a low level of plasminogen activator, or their virally transformed [Rous sarcoma virus] counterparts, which produce high levels of plasminogen activator. In each case the peptidyl prodrugs displayed at least 5-fold increase in selectivity for the transformed cells compared to the free drug. The greater selectivity of action of the peptidyl prodrugs against transformed cell cultures suggests that these or similar prodrugs that are substrates for tumor-associated proteases may show increased therapeutic effectiveness in the treatment of tumors that produce sufficiently increased amounts of plasminogen activator.