Anticancer efficacy of methioninase in vivo.
Therapeutics that are selective for cancer would have a high potential for efficacy. We have previously shown that the metabolic defect of enhanced methionine dependence is a broad cancer-selective target. Methionine depletion can completely arrest the growth of methionine-dependent tumor cells in vivo with a reversible pre-mitosis cell-cycle block. Dietary methionine depletion can partially arrest the growth of methionine-dependent rodent tumors in vivo. This report demonstrates that methioninase isolated from Pseudomonas putida can arrest rodent and human tumors in nude mice with no apparent toxic side effects. Methioninase injected i.p. arrested the growth of the Yoshida sarcoma in nude mice and greatly slowed the growth of the H460 human non-small-cell-lung carcinoma in nude mice. The effectiveness of methioninase against H460 was in contrast to 5-fluorouracil and vincristine, which were inactive against this tumor. The activity of the administered methioninase did not cause weight loss for up to 10 days treatment at 40-120 units/day indicating the possibility of low toxicity. In contrast, vincristine was highly toxic despite its ineffectiveness. Methioninase also induced a tumor-specific late cell-cycle block. The tumor-selective late cell-cycle block induced by methioninase should be able to be exploited to enhance the tumor specificity of antimitotic drugs and other agents in future experiments. Thus methioninase is a highly effective antitumor agent with a new tumor-selective mode of action with minimal toxicity, demonstrating potential clinical effectiveness against solid tumors.
Tan
Y
Y
AntiCancer Inc., San Diego, CA 92111, USA.
Xu
M
M
Guo
H
H
Sun
X
X
Kubota
T
T
Hoffman
R M
RM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D013437:Carbon-Sulfur Lyases / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D012517:Sarcoma, Yoshida / Q000188:drug therapy
D000964:Antimetabolites, Antineoplastic; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase