Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer

Background: pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. several mechanisms of resistance have been described,though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. methods: we examined the ability of cellular arginine depletion through treatment with peg-adi to alter in vitro and in vivo cytotoxicity of gemcitabine. the effect on levels of key regulators of gemcitabine efficacy (e.g. rrm2,hent1,and dck) were examined. results: combination of peg-adi and gemcitabine substantially increases growth arrest,leading to increased tumor response in vivo. peg-adi is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit m2 (rrm2) levels both in vivo and in vitro,which is associated with gemcitabine resistance. this mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on e2f-1 function,a transcriptional repressor of rrm2. conclusion: the ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer. ©2014 daylami et al.