The potential of recombinant vesicular stomatitis virus-mediated virotherapy against metastatic colon cancer

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related mortality in the United States. The liver and lung are the most common sites of distant metastasis of CRC. The approval of newer chemotherapeutic agents such as oxaliplatin, irinotec...

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Published in:International journal of molecular medicine 2013-02, Vol.31 (2), p.299-306
Main Authors: YAMAKI, MINORU, SHINOZAKI, KATSUNORI, SAKAGUCHI, TAKEMASA, MESECK, MARCIA, EBERT, OLIVER, OHDAN, HIDEKI, WOO, SAVIO L.C
Format: Article
Language:English
Subjects:
Animals
Cancer therapies
Clinical trials
Colorectal cancer
Immunotherapy
Infections
Metastasis
metastatic colorectal cancer
Monoclonal antibodies
oncolytic vesicular stomatitis virus
Rodents
Targeted cancer therapy
Tumors
Veins & arteries
virotherapy
Viruses
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Summary:Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related mortality in the United States. The liver and lung are the most common sites of distant metastasis of CRC. The approval of newer chemotherapeutic agents such as oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab has significantly improved survival, yet the majority of patients still succumb to the disease in less than 2 years. Novel therapeutic agents that can provide significant clinical benefit for metastatic CRC patients are needed. Oncolytic vesicular stomatitis virus (VSV) is a promising tool as a cancer therapeutic agent. In this study, we examined the feasibility of repeated intravenous infusions of rVSV in multiple CRC lung metastases, compared with repeated hepatic arterial administration in multifocal CRC liver metastasis in immune competent rats. We established a multifocal liver metastases model or the multiple lung metastases model using a CRC cell line, RCN-H4, implanted into syngeneic F344/DuCrj rats. 4.0×106 plaque-forming units (pfu) of recombinant VSV vectors expressing mutant (L289A) Newcastle disease virus fusion protein [rVSV-NDV/F(L289A)] were administered 3 times for 3 consecutive days locally via the hepatic artery for liver metastases or systemically via the penial vein for lung metastases. In the liver metastasis model, significantly enhanced survival was observed with rVSV-NDV/F(L289A)-treated rats (P=0.0196). Median survival was 110 and 25 days, respectively. In addition, 4 out of 7 of the rVSV-NDV/F(L289A)-treated rats demonstrated long-term survival exceeding 100 days. The long-term surviving rats were sacrificed to evaluate for residual malignancy. Liver tumors were not detected. In the lung metastasis model, median survival was 10 [VSV-NDV/F(L289A)-treated rats] and 7 days (control). Although survival was significantly prolonged (P
ISSN:1107-3756
1791-244X
DOI:10.3892/ijmm.2012.1205