Related Experiment Videos
Anticancer efficacy of methioninase in vivo
Abstract:
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.
Insights
Methioninase, an enzyme targeting methionine-dependent cancers, effectively arrests tumor growth in mice with minimal toxicity. This novel therapeutic approach shows promise for treating solid tumors.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Enhanced methionine dependence is a cancer-selective metabolic vulnerability.
- Methionine restriction halts cancer cell growth via cell-cycle arrest.
- Previous studies showed dietary methionine restriction partially arrests rodent tumors.
Purpose of the Study:
- To evaluate the efficacy and toxicity of methioninase from Pseudomonas putida against rodent and human tumors in vivo.
- To investigate methioninase's mechanism of action, specifically its effect on the cell cycle.
Main Methods:
- Administration of purified methioninase to nude mice bearing Yoshida sarcoma or H460 human non-small-cell lung carcinoma.
- Comparison of methioninase efficacy with 5-fluorouracil and vincristine.
- Assessment of tumor growth, animal weight, and cell-cycle progression.
Main Results:
- Methioninase arrested Yoshida sarcoma growth and significantly slowed H460 tumor growth.
- Methioninase demonstrated effectiveness where 5-fluorouracil and vincristine were inactive.
- Treatment with methioninase showed no weight loss in mice for up to 10 days, indicating low toxicity.
- Methioninase induced a tumor-specific late cell-cycle block.
Conclusions:
- Methioninase is a potent antitumor agent with a novel, tumor-selective mechanism.
- The enzyme exhibits minimal toxicity, suggesting potential for clinical application.
- Methioninase's ability to induce cell-cycle arrest can be leveraged to enhance other cancer therapies.