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.

Keywords:

• cancer
• combination chemotherapy
• Escherichia coli
• gene cloning
• methioninase
• recombinant rMETase
• methionine dependence
• PEGylation
• purification
• S/G₂
• selective cancer-cell-cycle arrest
• trap

Acknowledgement

This paper is dedicated to the memory of A.R. Moossa, M.D. The author is very grateful to Richard W. Erbe, M.D., who introduced and expertly mentored the author on methionine metabolism.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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