TY - JOUR
T1 - Recombinant human arginase Toxicity in mice is reduced by citrulline supplementation
AU - Mauldin, Jeremy P.
AU - Zeinali, Ideen
AU - Kleypas, Keri
AU - Woo, Jung Hee
AU - Blackwood, Rebecca S.
AU - Jo, Chan Hee
AU - Stone, Everett M.
AU - Georgiou, George
AU - Frankel, Arthur E.
N1 - Funding Information:
Address all correspondence to: Arthur E. Frankel, 5701 S Airport Rd, Temple, TX 76502. E-mail: afrankel@swmail.sw.org 1This study was supported by Love Cures Foundation Grant (A.E.F.), Sweetest Loop Grant (A.E.F.), Tula Lee Stone Endowed Chair of Cancer Research (A.E.F.), Cancer Prevention and Research Institute of Texas Grant RP100890 (G.G.), Scott & White Memorial Hospital Foundation (A.E.F.), TI3D/Welch Foundation grant HF0032 (G.G.), and National Institutes of Health grant 139059 (G.G.). Received 29 August 2011; Revised 29 August 2011; Accepted 23 September 2011 Copyright © 2012 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124/12 DOI 10.1593/tlo.11262
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
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U2 - 10.1593/tlo.11262
DO - 10.1593/tlo.11262
M3 - Article
C2 - 22348173
AN - SCOPUS:84856008075
SN - 1944-7124
VL - 5
SP - 26
EP - 31
JO - Translational Oncology
JF - Translational Oncology
IS - 1
ER -