Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey.

Abstract

INTRODUCTION:

All tested cancer cell types are methionine dependent in that the cells arrest and eventually die when deprived of methionine, a condition that is generally nontoxic to normal cells. Methionine dependence is the only known general metabolic defect in cancer. Methionine-deprived cancer cells arrest at the S/G2 phase, an unusual position for cell cycle arrest. In order to exploit the cancer-specific metabolic defect of methionine dependence, methioninases were developed.

AREAS COVERED:

The present Expert Opinion describes the phenomena of methionine dependence and a methioninase cloned from Pseudomonas putida (chemical name: l-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer as well as in macaque monkeys and a pilot Phase I trial of human cancer patients. Efficacy of rMETase has been demonstrated against various cancer types in mouse models.

EXPERT OPINION:

The most promising application of rMETase therapy is in sequential combination therapy, whereby the cancer cells within a tumor are trapped in S/G2 by methioninase treatment and then treated with chemotherapeutic agents active against cells in S/G2.

• Authors: Robert M Hoffman
• Journal: Expert opinion on biological therapy (Expert Opin Biol Ther) Vol. 15 Issue 1 Pg. 21-31 (Jan 2015) ISSN: 1744-7682 [Electronic] England
• PMID: 25439528 (Publication Type: Journal Article, Review)

Chemical References

• Recombinant Proteins
• Methionine
• Carbon-Sulfur Lyases
• L-methionine gamma-lyase

Topics

• Animals
• Carbon-Sulfur Lyases (genetics, metabolism, therapeutic use)
• Clinical Trials, Phase I as Topic
• Cloning, Molecular
• Combined Modality Therapy
• Humans
• Macaca
• Methionine (metabolism)
• Mice
• Molecular Targeted Therapy
• Neoplasms (drug therapy, metabolism)
• Pseudomonas putida (enzymology, genetics)
• Recombinant Proteins (therapeutic use)