Combination of Targeting Gene-ViroTherapy with 5-FU Enhances Antitumor Efficacy in Malignant Colorectal Carcinoma

Abstract

To improve the therapeutic effect of ONYX015, an E1B55kD-deleted replication-competent adenovirus, ZD55 was constructed and armed with the therapeutic gene hTRAIL to form ZD55-hTRAIL, which was used for cancer therapy and which we call Targeting Gene-ViroTherapy. In vitro experiments with SW620, HCT116, and HT29 colorectal carcinoma cell lines demonstrated that they were all sensitive to ZD55-hTRAIL, and especially sensitive to ZD55-hTRAIL plus 5-fluorouracil (5-FU) treatment. In the SW620 xenograft tumor model, various treatment groups showed marked differences at week 11, with the tumor volume for the phosphate-buffered saline (PBS) treatment group >1700 mm³, for 5-FU > 1300 mm³, for ONYX015 1051.3 mm³, for ZD55-hTRAIL 600.05 mm³, and for ZD55-hTRAIL plus 5-FU 230.2 mm³. At the end of week 14, tumor-bearing mice in the other groups almost all died, whereas all the mice in the combined treatment group were alive, with one mouse tumor free. By transmission electron microscopy (TEM) assay, most tumor cells treated with ONYX015 or with ZD55-hTRAIL singly or in combination with 5-FU were lysed due to viral propagation. RT-PCR analysis and immunohistochemistry examination revealed that hTRAIL was expressed in ZD55-hTRAIL-treated SW620 tumor tissue. Furthermore, no detectable hepatoxicity was found by serum enzyme level analysis. These results suggest that ZD55-hTRAIL alone or in combination with 5-FU may have potential clinical implications.