期刊
TRANSLATIONAL ONCOLOGY
卷 4, 期 3, 页码 138-146出版社
ELSEVIER SCIENCE INC
DOI: 10.1593/tlo.10265
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资金
- National Institutes of Health [R01 CA139059]
- Welch Foundation [TI-3D]
- National Institutes of Health through MD Anderson's Cancer Center [CA016672]
- University of Texas MD Anderson Cancer Center [CA16672]
Hepatocellular carcinoma (HCC) and pancreatic carcinoma (PC) cells often have inherent urea cycle defects rendering them auxotrophic for the amino acid L-arginine (L-arg). Most HCC and PC require extracellular sources of L-arg and undergo cell cycle arrest and apoptosis when L-arg is restricted. Systemic, enzyme-mediated depletion of L-arg has been investigated in mouse models and human trials. Non-human enzymes elicit neutralizing antibodies, whereas human arginases display poor pharmacological properties in serum. Co2+ substitution of the Mn2+ metal cofactor in human arginase I (Co-hArgI) was shown to confer more than 10-fold higher catalytic activity (k(cat)/K-m) and 5-fold greater stability. We hypothesized that the Co-hArgI enzyme would decrease tumor burden by systemic elimination of L-arg in a murine model. Co-hArgI was conjugated to 5-kDa PEG (Co-hArgI-PEG) to enhance circulation persistence. It was used as monotherapy for HCC and PC in vitro and in vivo murine xenografts. The mechanism of cell death was also investigated. Weekly treatment of 8 mg/kg Co-hArgI-PEG effectively controlled human HepG2 (HCC) and Panc-1 (PC) tumor xenografts (P = .001 and P = .03, respectively). Both cell lines underwent apoptosis in vitro with significant increased expression of activated caspase-3 (P < .001). Furthermore, there was evidence of autophagy in vitro and in vivo. We have demonstrated that Co-hArgI-PEG is effective at controlling two types of L-arg-dependent carcinomas. Being a nonessential amino acid, arginine deprivation therapy through Co-hArgI-PEG holds promise as a new therapy in the treatment of HCC and PC. Translational Oncology (2011) 4, 138-146
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