Abstract
Species C human adenovirus serotype 5 (HAdV-C5) is widely used as a vector for cancer gene therapy, because it efficiently transduces target cells. A variety of HAdV-C5 vectors have been developed and tested in vitro and in vivo for cancer gene therapy. While clinical trials with HAdV-C5 vectors resulted in effective responses in many cancer patients, administration of HAdV-C5 vectors to solid tumors showed responses in a limited area. A biological barrier in tumor mass is considered to hinder viral spread of HAdV-C5 vectors from infected cells. Therefore, efficient virus-spread from an infected tumor cell to surrounding tumor cells is required for successful cancer gene therapy. In this study, we compared HAdV-C5 to sixteen other HAdV serotypes selected from species A to G for virus-spread ability in vitro. HAdV-D9 showed better virus-spread ability than other serotypes, and its viral progeny were efficiently released from infected cells during viral replication. Although the HAdV-D9 fiber protein contains a binding site for coxsackie B virus and adenovirus receptor (CAR), HAdV-D9 showed expanded tropism for infection due to human CAR (hCAR)-independent attachment to target cells. HAdV-D9 infection effectively killed hCAR-negative cancer cells as well as hCAR-positive cancer cells. These results suggest that HADV-D9, with its better virus-spread ability, could have improved therapeutic efficacy in solid tumors compared to HAdV-C5.
Highlights
Cancer is a major public health problem in the United States
12 kinds of oncolytic Human adenoviruses (HAdVs) tested in patients with a variety of cancers were well tolerated [12,15,16,17,18,19,20,21,22,23]
Most patients showed stable disease defined in Response Evaluation Criteria in Solid Tumor (RECIST) [12,15,16,17,18,19,20,21,22,23]
Summary
Cancer is a major public health problem in the United States. Approximately 1.64 million new cancer cases and approximately 580,000 deaths were predicted to occur in the United States in 2012 [1]. Primary tumors will often relapse and subsequently metastasize to other organs [2]. These considerations warrant the development of new treatment strategies for cancer. Virotherapy in particular represents a promising new direction for cancer gene therapy [4,5]. This approach utilizes viruses designed to kill tumor cells but not normal cells [6,7]. A number of strategies to kill tumor cells are based on the interacting molecular mechanisms between adenoviral biology and cellular signaling pathways associated with human cancers [5]. As a biological barrier in tumor mass hinders virus spread from infected cells [12,27,28], we need to develop more efficacious oncolytic HAdVs
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