ANTICANCER EFFICACY IN-VIVO AND IN-VITRO, SYNERGY WITH 5-FLUOROURACIL, AND SAFETY OF RECOMBINANT METHIONINASE

The elevated exogenous-methionine dependency of tumors for growth has been observed in all major cancer cell types. We have previously clone d a methioninase (rMETase) from Pseudomonas putida to deplete methioni ne. Growth inhibition followed by apoptotic cell death was induced by treatment of tumor cells with rMETase in vitro. A single i.p. injectio n of 300 units of rMETase can lower the serum methionine level in the mice from 70 mu M to less than 1 mu M within 2 h and maintain this dep leted level for 8 h, Repeated dosing of rMETase of tumor-bearing mice could be administered without acute immune-hypersensitivity. rMETase t reatment demonstrated growth inhibitory activity against human tumors in nude mice, including those which were multiple drug-resistant, No b ody weight loss or hematotoxicity, except a slight anemia, was found t hroughout the therapy. The combined treatment of the Lewis lung carcin oma with a fixed rMETase dose and increasing doses of 5-fluorouracil ( 5-FU) resulted in a dose-dependent enhanced antitumor efficacy for sur vival as well as tumor growth inhibition. Thus, methionine depletion b y rMETase potentiates the antitumor efficacy of 5-FU, The data present ed in this report thus indicate that rMETase is active alone, is syner gistic in combination with 5-FU, and has negligible toxicity suggestin g a novel clinical approach for effective cancer therapy.