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

作者：Hoffman Robert M^*

来源：Expert Opinion on Biological Therapy, 2015, 15(1): 21-31.

DOI：10.1517/14712598.2015.963050

• cancer
• combination chemotherapy
• Escherichia coli
• gene cloning
• methioninase
• recombinant rMETase
• methionine dependence
• PEGylation
• purification
• S/G(2)
• selective cancer-cell-cycle arrest
• trap

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/G(2) 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 alpha-deamino-gamma-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/G(2) by methioninase treatment and then treated with chemotherapeutic agents active against cells in S/G(2).

• 出版日期2015-1