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.

Following targeted gene virotherapy, the suppression of tumorigenicity 13 (ST13) gene was inserted into the doubleregulated oncolytic adenovirus SG500 to ensure more safety and potent antitumor activity against colorectal cancer in vitro and in vivo. We generated the ST13-expressing oncolytic adenovirus SG500-ST13, with which colorectal carcinoma cell lines SW620 and HCT116, and the lung fibroblast cell line WI38, were infected. Crystal violet staining was carried out to detect the cytopathic effect in cells, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used to assay cell viability. The effect of apoptosis induced by SG500-ST13 was confirmed by Hoechst staining and the TdT-mediated dUTP-biotin nick-end labeling method. To further identify the antitumor effects of SG500-ST13 on HCT116 xenografts in Balb/c nude mice, the induction of cell death was assessed by hematoxylin-eosin staining. Immunohistochemical study was also carried out. (Cancer Sci 2009; 100: 678-683) C olorectal cancer ranks second in both morbidity and mortality in developed countries. Nearly 945 000 new colorectal cancer cases are diagnosed worldwide each year and its mortality rate is approximately 492 000.(1) Despite advanced progress in technologies for diagnosis and therapy, around 50% of newly diagnosed colorectal cancer patients will die of this disease due to metastases.(2) Surgical resection or surgery coupled with systemic chemotherapy of liver metastasis is the treatment currently available for these patients.(3) These findings underscore the need for improved therapeutic approaches to more efficaciously control this aggressive type of cancer and reduce its metastatic spread.Conditional replicative adenoviruses appear to be attractive anticancer agents that are currently being evaluated in clinical trials.(4,5) CRAd exerts intrinsic anticancer activity through its selective replication in and lysis of cancer cells. In addition, release of CRAd progeny by infected tumor cells provides a potential to amplify the oncolytic effect and its lateral spread through solid tumors.One strategy to ensure tumor targeting is to place the virual essential genes under the control of tumor-specific promoters. Because the hTERT promoter is expected to be active in the majority (~90%) of human cancer cells with upregulated telomerase expression, (6) the hTERT promoter is used to control the essential gene E1A for adenovirus replication in a series of CRAd.(7-9) Hypoxia occurs in virtually all solid tumors as they outgrow their blood supply. Hypoxia augments cellular levels of HIF, a transcription factor that regulates target genes through the binding of HRE. Activation of the HIF pathway enables cancer cells to survive and proliferate in a hypoxic environment and contributes to a more aggressive phenotype.(10,11) Therefore, the HIF-HRE system of gene regulation under hypoxia, or as a result of genetic alterations during cell transformation, is particularly attractive to specifically target solid tumors. Therefore, HRE ha...