Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV

Ji Young Yoo, Jason Pradarelli, Amy Haseley, Jeffrey Wojton, Azeem Kaka, Anna Bratasz, Christopher A. Alvarez-Breckenridge, Jun Ge Yu, Kimerly Powell, Andrew P. Mazar, Theodoros N. Teknos, E. Antonio Chiocca, Joseph C. Glorioso, Matthew Old, Balveen Kaur*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Purpose: Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus-derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV. Experimental Design: Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated. Results: Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery. Conclusion: This study shows that combining ATN-224 withoHSVsignificantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy.

Original languageEnglish (US)
Pages (from-to)4931-4941
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number18
DOIs
StatePublished - Sep 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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