title: In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts.
abstract: Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.
authors.affiliation: aScott & White Cancer Research Institute, Baylor-Scott & White Health bDepartment of Medical Physiology, Texas A&M Health Science Center, Temple cDepartment of Chemical Engineering, University of Texas, Austin dDepartment of Internal Medicine University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Agrawal
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Woo
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Mauldin
authors.forename: Everett M
authors.initials: EM
authors.lastname: Stone
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Meininger
authors.forename: Chanhee
authors.initials: C
authors.lastname: Jo
authors.forename: Keri
authors.initials: K
authors.lastname: Kleypas
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Frenkel
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001119:Arginase / Q000627:therapeutic use*; D003035:Cobalt / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000627:therapeutic use; D019169:Jurkat Cells; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D003035:Cobalt; D011092:Polyethylene Glycols; D006867:Hydrolases; D001119:Arginase; C000600158:pegylated Co-arginase; C512527:ADI PEG20