Abstract
Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.
Highlights
Adenovirus is a non-enveloped virus with a double-stranded DNA genome
To assess the spatiotemporal biodistribution of OBP-301, we have developed an human telomerase reverse transcriptase (hTERT) promoter-driven oncolytic adenovirus, OBP-401 (TelomeScan), which induces the expression of the green fluorescent protein (GFP) in tumor cells [23]
We focus on the therapeutic potential of hTERT promoter-driven oncolytic adenoviruses for the treatment of bone and soft-tissue sarcomas
Summary
Adenovirus is a non-enveloped virus with a double-stranded DNA genome. There are multiple adenovirus serotypes [1], among which adenovirus serotype 5 (Ad5) is well characterized and has been genetically engineered to transduce transgenes in cancer gene therapy [2,3]. For the development of tumor-specific oncolytic virotherapy, we have generated three types of hTERT promoter-driven replication-competent oncolytic adenoviruses: OBP-301, OBP-401, and OBP-702 (Figure 1). These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT promoter to facilitate tumor-specific virus replication. To assess the spatiotemporal biodistribution of OBP-301, we have developed an hTERT promoter-driven oncolytic adenovirus, OBP-401 (TelomeScan), which induces the expression of the green fluorescent protein (GFP) in tumor cells [23]. To enhance the antitumor efficacy of OBP-301, we have developed an hTERT promoter-driven oncolytic adenovirus, OBP-702, which induces the expression of the tumor suppressor p53 gene in tumor cells [24]. The future directions of hTERT promoter-driven oncolytic virotherapy are discussed, especially for the treatment of metastatic bone and soft-tissue sarcomas
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