In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts

Vaidehi Agrawal, Jung Hee Woo, Jeremy P. Mauldin, Everett M. Stone, Cynthia J. Meininger, Chanhee Jo, Keri Kleypas, Eugene P. Frenkel, Arthur E. Frankel

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)556-567
Number of pages12
JournalMelanoma Research
Volume24
Issue number6
DOIs
StatePublished - Dec 10 2014

Fingerprint

Arginase
Heterografts
Melanoma
Argininosuccinate Synthase
Citrulline
Neoplasms
Pharmaceutical Preparations
Therapeutics
Enzymes
Drug Delivery Systems
pegylated Co-arginase
Phosphorylation
Apoptosis
Amino Acids
Growth

Keywords

  • A375 cancer cell line
  • Amino acid depletion therapy
  • Arginase
  • Arginine depletion
  • Auxotrophy
  • Melanoma
  • Therapeutic

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Dermatology

Cite this

In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts. / Agrawal, Vaidehi; Woo, Jung Hee; Mauldin, Jeremy P.; Stone, Everett M.; Meininger, Cynthia J.; Jo, Chanhee; Kleypas, Keri; Frenkel, Eugene P.; Frankel, Arthur E.

In: Melanoma Research, Vol. 24, No. 6, 10.12.2014, p. 556-567.

Research output: Contribution to journalArticle

Agrawal, V, Woo, JH, Mauldin, JP, Stone, EM, Meininger, CJ, Jo, C, Kleypas, K, Frenkel, EP & Frankel, AE 2014, 'In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts', Melanoma Research, vol. 24, no. 6, pp. 556-567. https://doi.org/10.1097/CMR.0000000000000119
Agrawal V, Woo JH, Mauldin JP, Stone EM, Meininger CJ, Jo C et al. In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts. Melanoma Research. 2014 Dec 10;24(6):556-567. https://doi.org/10.1097/CMR.0000000000000119
Agrawal, Vaidehi ; Woo, Jung Hee ; Mauldin, Jeremy P. ; Stone, Everett M. ; Meininger, Cynthia J. ; Jo, Chanhee ; Kleypas, Keri ; Frenkel, Eugene P. ; Frankel, Arthur E. / In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts. In: Melanoma Research. 2014 ; Vol. 24, No. 6. pp. 556-567.
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