Potent Antitumor Activity of Oncolytic Adenovirus Expressing mda-7/IL-24 for Colorectal Cancer

Abstract

It has been demonstrated that interleukin 24 (IL-24, also called melanoma differentiation associated gene 7) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-24 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-24 (ZD55-IL-24) was constructed by insertion of an IL-24 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. ZD55-IL-24 could express substantially more IL-24 than Ad-IL-24 because of replication of the vector. It has been shown that ZD55-IL-24 exerted a strong cytopathic effect and significant apoptosis in tumor cells with p53 dysfunction. Moreover, no cytotoxic and apoptotic effects could be seen in normal cells infected with ZD55-IL-24. Expression of IL-24 did not interfere with viral replication induced by oncolytic adenovirus. Activation of caspase 3 and caspase 9, and induction of bax gene expression, were involved in tumor cell apoptosis induced by ZD55-IL-24. Treatment of established tumors with ZD55-IL-24 showed much stronger antitumor activity than that induced by ONYX-015 or Ad-IL- 24. These data indicated that oncolytic adenovirus expressing IL-24 could exert potential antitumor activity and offer a novel approach to cancer therapy.

Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil

“…We previously have reported that ZD55-delivering therapeutic genes (for example TRAIL and IL-24) suppresses tumor growth and induces tumor cell apoptosis. 28,29 We speculate that the potency of ZD55 could be similarly improved by the expression of synthetic lethal shRNAs against endogenous antiapoptotic genes instead of expressing proapoptotic transgenes.…”

Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells

“…This ability to augment cell killing by the combinatorial approach involves enhanced expression of MDA-7/IL-24 protein and concomitant alterations in the levels of BCL-family proteins in tumor cells. Achieving a threshold level of MDA-7/IL-24 protein appears critical for the induction of apoptosis by this novel cytokine, as recently emphasized using a conditionally replication-competent adenovirus to deliver MDA-7/IL-24 to human colorectal cancer xenografts in nude mice, which resulted in significant activity in curing animals of tumors and prolonging their survival (Zhao et al, 2005). The levels of expression of mda-7/IL-24 mRNA and protein resulting from delivery by the replicating virus greatly exceeded that of the non-replicating adenovirus in colorectal cancer cells, which demonstrated a less dramatic antitumor effect (Zhao et al, 2005).…”

“…Achieving a threshold level of MDA-7/IL-24 protein appears critical for the induction of apoptosis by this novel cytokine, as recently emphasized using a conditionally replication-competent adenovirus to deliver MDA-7/IL-24 to human colorectal cancer xenografts in nude mice, which resulted in significant activity in curing animals of tumors and prolonging their survival (Zhao et al, 2005). The levels of expression of mda-7/IL-24 mRNA and protein resulting from delivery by the replicating virus greatly exceeded that of the non-replicating adenovirus in colorectal cancer cells, which demonstrated a less dramatic antitumor effect (Zhao et al, 2005). In these contexts, approaches that augment the achievable level of MDA-7/IL-24 protein in cancer cells may prove beneficial in enhancing the antitumor activity of mda-7/IL-24.…”

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

“…The effect of ZD55-IL-24 on growth suppression and apoptosis induction was found to be more significant than that of Ad-IL-24 in vitro. 20 Similarly, the animal tumor model studies also showed that antitumor efficacy of ZD55-IL-24 was much better than that of Ad-IL-24.…”