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Discovery Research Laboratories II, Shionogi and Co., Ltd., Osaka 553, Japan [T. Y., T. W., N. Y., H. M., H. Y., N. I., H. K., K. H., K. S., R. M., S. Y., K. S.] and AntiCancer, Inc., San Diego, California 92111 [R. M. H.]
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 µM to less than 1 µM 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.
1 To whom requests for reprints should be addressed, at Discovery Research Labs II, Shionogi & Co., Ltd., 12-4, Sagisu, 5-chome, Fukushima-ku, Osaka 553-0002, Japan. Phone: 81-6-458-5861; Fax: 81-6-458-0987; E-mail: takayuki.yoshioka@shionogi.co.jp.
Received 2/ 5/98. Accepted 4/21/98.
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