Potent Antitumor Effect of Interleukin-24 Gene in the Survivin Promoter and Retinoblastoma Double-Regulated Oncolytic Adenovirus

Abstract

Interleukin (IL)-24 is an excellent therapeutic gene for cancer therapy. In this work, IL-24 was inserted into Ad.sp-E1A(Delta24), an oncolytic adenovirus with a 24-bp deletion in the E1A gene, which was driven by the survivin promoter to form Ad.sp-E1A(Delta24)-IL-24. Ad.sp-E1A(Delta24)-IL-24 has an excellent antitumor effect in vitro for human nasopharyngeal, liver, lung, and cervical carcinoma cell lines but does no or little damage to normal cell lines L-02 and WI38. Furthermore, it achieved nearly complete inhibition (although not elimination) of NCI-H460 lung carcinoma growth in nude mice. The antitumor efficacy of Ad.sp-E1A(Delta24)-IL-24 on NCI-H460 cells was clearly mediated by apoptosis, because it induced caspase-3 and poly(ADP-ribose) polymerase cleavage. This is the first report of Ad.sp-E1A(Delta24)-IL-24 with such an excellent, broad, and specific antitumor effect in vitro and nearly complete inhibition of lung tumor growth in vivo.

Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

“…Many members of our laboratory have shown the strong anti-tumor effect of the CTGVT strategy. 3,15,16 In this study, the tumor necrosis factor-related apoptosisinducing ligand (TRAIL) gene was incorporated into the oncolytic adenoviral vector AdÁAFPÁD55. TRAIL was first identified and cloned by Wiley et al in 1995.…”

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

“…The strategy combines the advantages of both gene therapy and virotherapy by using an oncolytic adenoviral vector (OA) harboring an anti-cancer gene. Currently, two main strategies are applied to construct the viral vector with oncolytic ability, which can specifically infect tumor cells but rarely infects normal cells [3] . The first strategy is to delete the adenoviral genes that are necessary for viral replication in normal cells but not in tumor cells.…”

“…The second strategy involves transcription targeting through the use of tumor-or tissue-selective promoters, which can control the expression of early viral genes such as E1A and/or E1B that are essential for replication. Our previous studies have shown that CTGVT exhibits greater antitumor effects than gene therapy or virotherapy alone [3,5,6] . The tumor suppressor in lung cancer-1 (TSLC1) was originally identified as a putative tumor suppressor for non-smallcell lung cancer (NSCLC) and was the first named tumor suppressor in lung cancer [7] .…”

“…Of significance, survivin has aberrantly high expression in cancer cells such as lung cancer but little expression in most normal tissues, making survivin an attractive anticancer target [22,23] . Recent studies have shown that a designed oncolytic adenovirus driven by the survivin promoter exhibited a tumor-selective antitumor effect in vitro and in vivo [3,24,25] , suggesting that the survivin promoter is a good candidate for cancer therapy. To improve the OA tumor-specificity, a 24 bp region within the E1A conserved region 2 (CR2), which is responsible for binding the retinoblastoma (Rb) protein, was deleted.…”

“…To improve the OA tumor-specificity, a 24 bp region within the E1A conserved region 2 (CR2), which is responsible for binding the retinoblastoma (Rb) protein, was deleted. This deletion restricts viral replication to dividing cells or Rb-inactive and arrested cells [3] . In this study, the dual-regulated Ad·sp-E1A (∆24) oncolytic virus contained the 24 bp deletion within E1A and was driven by the survivin promoter.…”