Physicochemical and pharmacokinetic characterization of highly potent recombinant L-methionine gamma-lyase conjugated with polyethylene glycol as an antitumor agent

Cancer Research
Tomoaki TakakuraN Esaki

Abstract

A highly potent recombinant L-methionine gamma-lyase (METase) conjugated with polyethylene glycol (PEG) was characterized physicochemically and pharmacokinetically in vivo and in vitro. Pegylated METase (PEG-METase), which contains pyridoxal 5'-phosphate (PLP) as a cofactor in the molecule, is a potent anticancer agent that can deplete L-methionine from plasma. Although pegylation decreased its specific activity, dithiothreitol (DTT) treatment increased it over three times with the detachment of one PEG moiety modified with a cysteine residue. We can produce DTT-treated PEG-METase on a large scale in sufficient quality for therapeutic use. The superiority of DTT-treated PEG-METase was confirmed by the enhancement of L-methionine depletion and amelioration of pharmacokinetics in mice. The holoenzyme of DTT-treated PEG-METase gave a several times larger area under the plasma concentration curve than that of DTT-untreated PEG-METase, not because of an increase of the half-life but because of high specific activity. Conversely, simultaneous PLP infusion led to a greatly increased half-life of the holoenzyme. DTT-treated PEG-METase administration with PLP infusion was the most useful combination for maximizing the potency of the enz...Continue Reading

References

May 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·R M Hoffman, R W Erbe
Jan 11, 1977·Biochemistry·H TanakaK Soda
Jul 1, 1991·Archives of Biochemistry and Biophysics·M L FondaU M Guempel
Dec 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·R M Hoffman, S J Jacobsen
Dec 16, 1983·Biochemical and Biophysical Research Communications·J O MechamR M Hoffman
Jan 1, 1994·Methods in Enzymology·L J KarrJ M Harris
Jan 1, 1997·British Journal of Cancer·D M KokkinakisS C Schold
Mar 14, 1998·Protein Expression and Purification·Y TanR M Hoffman
Mar 10, 2001·Journal of Chromatography. B, Biomedical Sciences and Applications·C L DeitrickL Burrus
Aug 21, 2001·Clinical Pharmacokinetics·J M HarrisM Modi
Jun 8, 2002·Advanced Drug Delivery Reviews·M J RobertsJ M Harris
Oct 9, 2002·Journal of Pharmaceutical and Biomedical Analysis·Goro KominamiMasahiro Ohno
Mar 4, 2003·Nature Reviews. Drug Discovery·J Milton Harris, Robert B Chess
May 1, 1959·Archives of Biochemistry and Biophysics·G L ELLMAN
Oct 31, 2003·Cancer Treatment Reviews·E CellarierP Chollet
Mar 26, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhijian YangRobert M Hoffman

❮ Previous
Next ❯

Citations

Sep 25, 2014·BioMed Research International·Bhupender SharmaShamsher S Kanwar
Feb 17, 2007·Expert Opinion on Investigational Drugs·Edwina N ScottAnne L Thomas
Sep 10, 2009·Bioconjugate Chemistry·Chien-Hsing ChangDavid M Goldenberg
Apr 12, 2021·International Journal of Biological Macromolecules·E MorozovaT Demidkina
Jan 18, 2008·Journal of Pharmaceutical Sciences·C Simone Fishburn
Oct 1, 2021·Proceedings of the National Academy of Sciences of the United States of America·Andrey A ParkhitkoNorbert Perrimon

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.