Amino acid degrading enzymes and their application in cancer therapy

Background: Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on the development and preclinical and clinical evaluation of amino acid degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, L-lysine α-oxidase. Further research into cancer cell metabolism may therefore define possible targets for controlling tumor growth. Objective: The purpose of this review was to summarize recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on Lasparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer. Methods: We carried out a structured search among literature regarding to amino acid degrading enzymes. The main aspects of search were in vitro and in vivo studies, clinical trials concerning application of these enzymes in oncology. Results: Most published research are on the subject of L-asparaginase properties and it’s use for cancer treatment. L-arginine deiminase has shown promising results in a phase II trial in advanced melanoma and hepatocellular carcinoma. Other enzymes, in particular Lmethionine γ-lyase and L-lysine α-oxidase, were effective in vitro and in vivo. Conclusion: The findings of this review revealed that therapy based on amino acid depletion may have the potential application for cancer treatment but further clinical investigations are required to provide the efficacy and safety of these agents. © 2019 Bentham Science Publishers

Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes

PK studies were carried out after a single i.v. administration of 500 and 1000 U/kg by measuring of MGL activity in plasma samples. L-methionine concentration was measured by mass spectrometry. After single i.v. injection of 500 U/kg the circulating T1/2 of enzymes in mice varies from 73 to 123 min. The AUC0-tinf values determined for MGL 500 U/kg from C. freundii, C. tetani and C. sporogenes are 8.21 ± 0.28, 9.04 ± 0.33 and 13.88 ± 0.39 U/(ml × h), respectively. Comparison of PK parameters of three MGL sources in the dose of 500 U/kg indicated the MGL C. sporogenes to have better PK parameters: clearance 0.83(95%CI: 0.779–0.871) – was lower than C. tetanii 1.27(95%CI: 1.18–1.36) and C. freundii 1.39(95%CI: 1.30–1.49). Mice plasma methionine decreased to undetectable level 10 min after MGL 1000 U/kg injection. After MGL C. sporogenes 500 U/kg injection plasma methionine level completely omitted after 10 min till 6 h, assuming the sustainability of negligible levels of methionine ( < 5 μM) in plasma of mice for about 6 h. The recovery of methionine concentration showed the advantageous efficiency of MGL from C. sporogenes: 95% 0.010–0.022 vs 0.023–0.061 for MGL C. freundii and 0.036–0.056 for MGL C. tetani. There are no significant differences between methionine cleavage after MGL C. tetani and MGL C. sporogenes i.v. injection at all doses. MGL from C. sporogenes may be considered as promising enzyme for further investigation as potential anticancer agent. © 2017 Elsevier Masson SA

Methionine gamma lyase from clostridium sporogenes increases the anticancer efficacy of doxorubicin on A549 cancer cells in vitro and human cancer xenografts

The anticancer efficacy of methionine γ-lyase (MGL) from Clostridium sporogenes (C. sporogenes) is described. MGL was active against cancer cells in vitro and in vivo. Doxorubicin (DOX) and MGL were more effective on A549 human lung-cancer growth inhibition than either agent alone in vitro and in vivo. © Springer Science+Business Media, LLC, part of Springer Nature 2019

Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes

PK studies were carried out after a single i.v. administration of 500 and 1000 U/kg by measuring of MGL activity in plasma samples. L-methionine concentration was measured by mass spectrometry. After single i.v. injection of 500 U/kg the circulating T1/2 of enzymes in mice varies from 73 to 123 min. The AUC0-tinf values determined for MGL 500 U/kg from C. freundii, C. tetani and C. sporogenes are 8.21 ± 0.28, 9.04 ± 0.33 and 13.88 ± 0.39 U/(ml × h), respectively. Comparison of PK parameters of three MGL sources in the dose of 500 U/kg indicated the MGL C. sporogenes to have better PK parameters: clearance 0.83(95%CI: 0.779–0.871) – was lower than C. tetanii 1.27(95%CI: 1.18–1.36) and C. freundii 1.39(95%CI: 1.30–1.49). Mice plasma methionine decreased to undetectable level 10 min after MGL 1000 U/kg injection. After MGL C. sporogenes 500 U/kg injection plasma methionine level completely omitted after 10 min till 6 h, assuming the sustainability of negligible levels of methionine ( < 5 μM) in plasma of mice for about 6 h. The recovery of methionine concentration showed the advantageous efficiency of MGL from C. sporogenes: 95% 0.010–0.022 vs 0.023–0.061 for MGL C. freundii and 0.036–0.056 for MGL C. tetani. There are no significant differences between methionine cleavage after MGL C. tetani and MGL C. sporogenes i.v. injection at all doses. MGL from C. sporogenes may be considered as promising enzyme for further investigation as potential anticancer agent. © 2017 Elsevier Masson SA