Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase
Yoshioka, T.; Wada, T.; Uchida, N.; Maki, H.; Yoshida, H.; Ide, N.; Kasai, H.; Hojo, K.; Shono, K.; Maekawa, R.; Yagi, S.; Hoffman, R.M.; Sugita, K.
Cancer Research 58(12): 2583-2587
1998
ISSN/ISBN: 0008-5472 PMID: 9635582 Document Number: 491809
The elevated exogenous-methionine dependency of tumors for growth has been observed in all major cancer cell types. We have previously cloned a methioninase (rMETase) from Pseudomonas putida to deplete methionine. Growth inhibition followed by apoptotic cell death was induced by treatment of tumor cells with rMETase in vitro. A single i.p. injection of 300 units of rMETase can lower the serum methionine level in the mice from 70 microM to less than 1 microM within 2 h and maintain this depleted level for 8 h. Repeated dosing of rMETase of tumor-bearing mice could be administered without acute immune-hypersensitivity. rMETase treatment demonstrated growth inhibitory activity against human tumors in nude mice, including those which were multiple drug-resistant. No body weight loss or hematotoxicity, except a slight anemia, was found throughout the therapy. The combined treatment of the Lewis lung carcinoma with a fixed rMETase dose and increasing doses of 5-fluorouracil (5-FU) resulted in a dose-dependent enhanced antitumor efficacy for survival as well as tumor growth inhibition. Thus, methionine depletion by rMETase potentiates the antitumor efficacy of 5-FU. The data presented in this report thus indicate that rMETase is active alone, is synergistic in combination with 5-FU, and has negligible toxicity suggesting a novel clinical approach for effective cancer therapy.