E1A, E1B double-restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer

Abstract

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 Â 10 7 PFU, plaque-forming unit) plus AxCEAprTK (2 Â 10 8 PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 Â 10 7 PFU)/GCV or AxCEAprTK (2 Â 10 9 PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

“…Promoters have been used previously to increase adenoviral replication or p53 expression, but the use of two promoters at same time is rare (6,10). In the present study, to enhance the oncolysis of CRAd on tumor cells, a P74-Tp-Gp53 plasmid, containing the p53 gene, the early region 1A (E1A) gene and two tumor-specific promoters hTERT and glial fibrillary acidic protein (GFAP), was constructed.…”

“…Oncolytic viruses have been developed by adding specific promoter elements and therapeutic genes, including the human telomerase reverse transcriptase (hTERT) gene to control gene expression essential for adenoviral replication, and the p53 gene to promote the dissolution of tumor cells (7,10). In addition, the release of viral progeny from infected tumor cells offers a potential to amplify the oncolytic effects of CRAds by lateral spread in a solid tumor (6,9).…”

Strategies and developments of immunotherapies in osteosarcoma

“…Moreover, AdDeltaΔ24-RGD OS treatment induced antitumor activity in vitro, which was additionally enhanced when combined with cisplatin treatment (106). In addition, E1A, E1B double-restricted replicating adenovirus significantly replicated in and led to oncolysis of tumors in vitro and in vivo, without marked toxicity to normal cells, suggesting a potential use of this combination therapy for the treatment of OS (107,108). Another method of introducing therapeutic genes into malignant cells in vivo may provide an effective treatment strategy for OS.…”

Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells

“…Tumor selective oncolytic adenoviruses have been developed by using tumor specific promoter elements, such as the human telomerase protein/enzyme (hTERT ) gene promoter, to control gene expression essential for adenoviral replication. [1][2][3] Since E1A and E1B have been identified to be important for adenoviral replication, many telomerase promoter-regulated adenoviral vectors retain both E1a and E1b genes. 4 This reduces the capacity of oncolytic adenoviruses to carry therapeutic genes.…”