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World J Gastroenterol. Mar 7, 2014; 20(9): 2218-2223
Published online Mar 7, 2014. doi: 10.3748/wjg.v20.i9.2218
Opioid growth factor and the treatment of human pancreatic cancer: A review
Ian S Zagon, Patricia J McLaughlin
Ian S Zagon, Patricia J McLaughlin, Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
Author contributions: Zagon IS and McLaughlin PJ contributed equally to this review.
Supported by Grants from NIH in part, Philip Morris United States, and The Pennsylvania Department of Heath, as well as generous gifts from the Paul I and Anna E Shockey Family Foundation
Correspondence to: Patricia J McLaughlin, Professor, Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, MC-H109, 500 University Drive, Hershey, PA 17033, United States. pxm9@psu.edu
Telephone: +1-717-5316414 Fax: +1-717-5315003
Received: August 28, 2013
Revised: January 2, 2014
Accepted: January 19, 2014
Published online: March 7, 2014
Processing time: 189 Days and 15.9 Hours
Abstract

Opioid growth factor (OGF), chemically termed [Met5]-enkephalin, and its receptor, OGF receptor (OGFr), form a biological axis that tonically regulates cell proliferation by delaying the G1/S interface of the cell cycle under homeostatic conditions or in neoplasia. Modulation of the OGF-OGFr pathway mediates the course of pancreatic cancer, with exogenous OGF or upregulation of OGFr repressing growth of human pancreatic cancer cells in culture and in nude mice. OGF therapy alone or in combination with standard chemotherapies such as gemcitabine and 5-fluorouracil results in enhanced inhibition of DNA synthesis and tumor growth. Molecular manipulation of OGFr confirms that the receptor is specific for OGF’s inhibitory action. Preclinical studies have warranted Phase I and Phase II clinical trials using OGF infusions as a treatment for patients with advanced, unresectable pancreatic cancers. OGF, an endogenous neuropeptide, is a safe, non-toxic, and effective biotherapy that utilizes the OGF-OGFr axis to mediate pancreatic tumor progression.

Keywords: Enkephalins; DNA synthesis; Pancreatic adenocarcinoma; Opioids; Nude mice; Receptor transfection

Core tip: Opioid growth factor (OGF) biotherapy for human pancreatic cancer is based on inhibition of DNA synthesis by upregulation of cyclin-dependent inhibitory kinases. Preclinical studies using human pancreatic cancer cell lines have demonstrated that OGF interaction with its selective receptor OGF receptor (OGFr) is a physiological determinant of cell proliferation. Addition of OGF to standard chemotherapies enhances the efficacy of treatment. Studies in nude mice confirm that the OGF-OGFr axis regulates pancreatic cancer progression. Clinical trials using OGF for treatment of patients with unresectable pancreatic tumors reveal that OGF is a novel endogenous opioid that is safe, non-toxic, elicits negligible side effects and reduces pancreatic tumor size in persons who have failed other therapies.