Abstract
Oncolytic adenoviruses (Ads) have been shown to be safe and have great potential for the treatment of solid tumors. However, the therapeutic efficacy of Ads is antagonized by limited spread within solid tumors. To develop Ads with enhanced spread, viral particles of an E1-wildtype Ad5 dl309 was repeatedly treated with UV type C irradiation and selected for the efficient replication and release from cancer cells. After 72 cycles of treatment and cancer selection, AdUV was isolated. This vector has displayed many favorable characteristics for oncolytic therapy. AdUV was shown to lyse cancer cells more effectively than both E1-deleted and E1-wildtype Ads. This enhanced cancer cell lysis appeared to be related to increased AdUV replication in and release from infected cancer cells. AdUV-treated A549 cells displayed greater expression of the autophagy marker LC3-II during oncolysis and formed larger viral plaques upon cancer cell monolayers, indicating increased virus spread among cancer cells. This study indicates the potential of this approach of irradiation of entire viral particles for the development of oncolytic viruses with designated therapeutic properties.
Highlights
Human adenoviruses (Ads) have been modified for selective replication in cancer cells, causing lysis [1]
Induced greater cell rounding, consistent with cytopathic effects (CPE) relative to A549 cells treated with Adhz60, adenovirus serotype 5 (Ad5) (Figure 2C)
All clinical studies have shown that the efficacy of Ad virotherapy, dl1520/ONYX-015 and H101, has remained low [22,24,30,31,42,43,44,45]
Summary
Human adenoviruses (Ads) have been modified for selective replication in cancer cells, causing lysis [1]. Ads exhibit their favorable safety profile of oncolytic therapy because they only cause negligible flu-like symptoms and cannot integrate their genomes into the host cell chromosomes [2]. The therapeutic effects of oncolytic Ads are initiated from a small number of infected cancer cells from which the progeny viruses are released to further infect adjacent cancer cells within tumors [3,4]. Preclinical and clinical studies have suggested that Ad spread is restricted in large tumors, limiting their therapeutic efficacy.
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