Recombinant human arginase Toxicity in mice is reduced by citrulline supplementation

Jeremy P. Mauldin, Ideen Zeinali, Keri Kleypas, Jung Hee Woo, Rebecca S. Blackwood, Chan Hee Jo, Everett M. Stone, George Georgiou, Arthur E. Frankel

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 (HuArg I [Co]-PEG5000) achieved potent in vitro depletion of arginine from tissue culture medium and cytotoxicity to many cancer cell lines. The recombinant enzyme also produced tumor growth inhibition of hepatocellular carcinoma and pancreatic carcinoma xenografts. Although these results were promising, the therapeutic index was narrow. Toxicities were seen in normal cells in tissue culture. In vivo normal tissue injury occurred at doses twice the effective dose. The current study was conducted to define, in greater detail, the maximum tolerated dose (MTD), pharmacodynamics, and doselimiting toxicities (DLTs) of twice-weekly intraperitoneal HuArg I [Co]-PEG5000 in Balb/c mice. Animal weight and survival were monitored, serum arginine levels measured, and complete blood cell counts, chemistries, necropsies, and histologies were performed. In addition, methods to ameliorate the HuArg I [Co]-PEG5000 adverse effects were tested. Supplemental L-citrulline was given concurrently with the arginase drug. The HuArg I [Co]-PEG5000 MTD in mice was 5 mg/kg twice weekly, and DLTs included weight loss and marrow necrosis. No other organ damage or changes in blood cell counts or chemistries were observed. Arginase reduced serum arginine levels from 60 μM to 4 to 6 μM. Supplemental L-citrulline given per os or daily subcutaneously reduced and delayed toxicities, and L-citrulline given twice daily subcutaneously completely prevented animal toxicities. On the basis of these results, we hypothesize that HuArg I [Co]-PEG5000, particularly with supplemental L-citrulline, may be an attractive therapeutic agent for argininosuccinate synthetase-deficient tumors.

Original languageEnglish (US)
Pages (from-to)26-31
Number of pages6
JournalTranslational Oncology
Volume5
Issue number1
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Recombinant human arginase Toxicity in mice is reduced by citrulline supplementation'. Together they form a unique fingerprint.

  • Cite this

    Mauldin, J. P., Zeinali, I., Kleypas, K., Woo, J. H., Blackwood, R. S., Jo, C. H., Stone, E. M., Georgiou, G., & Frankel, A. E. (2012). Recombinant human arginase Toxicity in mice is reduced by citrulline supplementation. Translational Oncology, 5(1), 26-31. https://doi.org/10.1593/tlo.11262