Abstract
BackgroundColorectal cancer (CRC) is the most common type of gastrointestinal cancer. CRC gene therapy mediated by adenovirus holds great promise for the treatment of malignancies. However, intravenous delivery of adenovirus exhibits limited anti-tumor activity in vivo when used alone.MethodsIn this study, the antitumor activity of the recombinant adenovirus KGHV500 was assessed with the MTT, TUNEL, Matrigel invasion and cell migration assays. To enhance the intravenous delivery of KGHV500 in vivo, cytokine-induced killer (CIK) cells were used as a second vector to carry KGHV500. We explored whether CIK cells could carry the recombinant adenovirus KGHV500 containing the anti-p21Ras single chain fragment variable antibody (scFv) gene into tumors and enhance antitumor potency.ResultsOur results showed that KGHV500 exhibited significant antitumor activity in vitro. In the nude mouse SW480 tumor xenograft model, the combination of CIK cells with KGHV500 could induce higher antitumor activity against colorectal cancer in vivo than that induced by either CIK or KGHV500 alone. After seven days of treatment, adenovirus and scFv were detected in tumor tissue but were not detected in normal tissues by immunohistochemistry. Therefore, KGHV500 replicates in tumors and successfully expresses anti-p21Ras scFv in a colorectal cancer xenograft model.ConclusionsOur study provides a novel strategy for the treatment of colorectal cancer by combining CIK cells with the recombinant adenovirus KGHV500 which carried anti-p21 Ras scFv.
Highlights
Colorectal cancer (CRC) is the most common type of gastrointestinal cancer
HEK293 cells and SW480 cells were grown in the 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Biological Industries, Israel,#64–001-1ACS) under atmospheric conditions of 5% CO2 at 37 °C
SW480 cell infection by recombinant adenovirus KGHV500 Since the CD46, receptor of the fiber node of KGHV500 was expressed on the cell membrane of SW480 cells (Fig. 1), KGHV500 could bind to SW480 cells
Summary
Colorectal cancer (CRC) is the most common type of gastrointestinal cancer. CRC gene therapy mediated by adenovirus holds great promise for the treatment of malignancies. As the most common cancer malignancy worldwide, CRC is the fourth leading cause of cancer related deaths [1]. Radiotherapy and chemotherapy are a “double-edged sword”, that kills cancer cells, and damages normal cells. Targeted therapy and gene therapy are necessary improvements for colorectal cancer. The Ras gene was the first oncogene to be discovered in human tumors and plays a significant role in the development of many tumor types [6]. Our previous studies revealed a high expression rate of wild-type p21Ras in CRC but no expression in normal colorectal epithelia, which together with other data, suggest that p21Ras is an important intracellular target K-Ras mutations occur in approximately 30–50% of CRC cases [7], and p21Ras is overexpressed in CRC [8, 9].
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