Potent and specific antitumor effect for colorectal cancer by CEA and Rb double regulated oncolytic adenovirus harboring ST13 gene.

Abstract

Cancer Targeting Gene-Viro-Therapy (CTGVT) is constructed by inserting an antitumor gene into an oncolytic virus (OV). It is actually an OV-gene therapy, which has much better antitumor effect than either gene therapy alone or virotherapy alone in our previously published papers. This study is a modification of CTGVT by inserting a colorectal cancer (CRC) specific suppressor gene, ST13, into a CRC specific oncolytic virus, the Ad·CEA·E1A(Δ24), to construct the Ad·(ST13)·CEA·E1A(Δ24) for increasing the targeting tropism to colorectal cancer and it was briefly named as CTGVT-CRC. Although many studies on CEA promoter and ST13 gene were reported but no construct has been performed to combine both of them as a new strategy for colorectal cancer (CRC) specific therapy. In addition to the CRC specificity, the antitumor effect of Ad·(ST13)·CEA·E1A(Δ24) was also excellent and got nearly complete inhibition (not eradication) of CRC xenograft since ST13 was an effective antitumor gene with less toxicity, and a Chinese patent (No. 201110319434.4) was available for this study. Ad·(ST13)·CEA·E1A(Δ24) caused cell apoptosis through P38 MAPK (i.e. P38) which upregulated CHOP and ATF2 expression. The mitochondrial medicated apoptosis pathway was activated by the increase of caspase 9 and caspase 3 expression.