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Research Articles: Therapeutics, Targets, and Development

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Departments of ¹ Medicine and ² Anesthesia and Critical Care, University of Chicago, Chicago, Illinois

Requests for reprints: Jonathan Moss, Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637. Phone: 773-702-3901; Fax: 312-896-9187. E-mail: jm47{at}midway.uchicago.edu

Abstract

Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the µ-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF)–induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC₅₀ of 100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC₅₀ of 5-FU from 5 µmol/L to 7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC₅₀ of bevacizumab on inhibition of EC migration from 25 to 6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary µ-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase µ activity, which was independent of µ-opioid receptor expression. Silencing receptor protein tyrosine phosphatase µ expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index. [Mol Cancer Ther 2008;7(6):1669–79]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J. Moss serves as a paid consultant to Progenics Pharmaceuticals, has a financial interest in MNTX as a patent holder through the University of Chicago, and receives stock options from Progenics.

Received 10/29/07; revised 3/27/08; accepted 4/15/08.