Tumor-Selective Gene Expression in a Hepatic Metastasis Model after Locoregional Delivery of a Replication-Competent Retrovirus Vector

• Published in: Clinical cancer research Vol. 12; no. 23; pp. 7108 - 7116
• Main Authors: HIRAOKA, Kei, KIMURA, Takahiro, LOGG, Christopher R, KASAHARA, Noriyuki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2006
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; Biological and medical sciences; Catheterization - methods; Cell Line, Tumor; colon cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - therapy; Colorectal Neoplasms - virology; Disease Models, Animal; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Infusions, Intralesional; liver metastasis; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - secondary; Liver Neoplasms, Experimental - therapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Nude; molecular imaging; oncolytic virotherapy; Pharmacology. Drug treatments; Predictive Value of Tests; retrovirus; Reverse Transcriptase Polymerase Chain Reaction - methods; Transfection; Transplantation, Heterologous; Tumors; Virus Replication; Xenograft Model Antitumor Assays; Retrovirus; Digestive diseases; Hepatic disease; Replication; Models; Malignant tumor; Gene expression; Vector; Liver metastasis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-1452

Purpose: Replication-competent retrovirus (RCR) vectors have been shown to achieve highly efficient and tumor-restricted replicative spread and gene transfer in vivo after direct intratumoral injection in a variety of primary cancer models. In this setting, the intrinsic inability of retroviruses to infect postmitotic normal cells, combined with their unique ability to persist through stable integration, allow further transduction of ectopic tumor foci as the infected cancer cells migrate. However, i.v. delivery of RCR vectors has never been tested previously, particularly in an immunocompetent tumor model. Experimental Design: We combined optical imaging, flow cytometry, and molecular analysis to monitor RCR vector spread after administration via locoregional infusion in a hepatic metastasis model of colorectal cancer. Results: Robust RCR replication was first confirmed in both human WiDr and murine CT26 colorectal cancer cells in vitro , with transduction levels reaching >90% in <12 days after virus inoculation at multiplicities of infection of 0.01 to 0.1. In vivo , infusion of RCR supernatant into the portal circulation resulted in progressive and significant transduction of multifocal intrahepatic CT26 tumors in syngeneic mice, averaging about 30% but with up to 60% transduction in some tumors within 4 weeks. However, immunohistochemistry and quantitative PCR analysis showed no evidence of RCR spread to adjacent normal liver or to any other normal tissues. Conclusions: Our results thus show that locoregional infusion of RCR vectors can be used to deliver therapeutic genes selectively to tumor cells in the liver while sparing normal hepatocytes and without dissemination to extrahepatic normal tissues.