Combined Liposome-Mediated Cytosine Deaminase Gene Therapy with Radiation in Killing Rectal Cancer Cells and Xenografts in Athymic Mice

Abstract

Purpose: The aim of this study was to assess the antitumor efficacy of combination of cytosine deaminase (CD) suicide gene therapy with radiation and to grope for new therapeutic strategy for local recurrent rectal cancer. Experimental Design: HR-8348 cell line of human rectal cancer was used to assess efficiency of transfectionwithplasmidpEGFP-N1and PXJ41-CD.The cells were exposedto radiationfollowedby liposome-mediated transfection. Cellinhibitionassay was done with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Antitumor efficacy of combined liposome-mediated CD suicide gene therapy with radiation was determined by treatment of nude mice bearing HR-8348 cancer cell xenograft. Results:The efficiency of liposome-mediated CD gene transfection can be improved by radiation. With radiation at 2, 4, 6, and 8 Gy, the efficiency of liposome-mediated transfection increased from 21.3% to 62.2%, 78.0%, 83.2%, and 87.8%, respectively. CD expression was enhanced as well. Cancer cell inhibition experiment showed that combined liposome-mediated CD gene therapy with radiation had much stronger antitumor effect. With HR-8348 tumor xenograft model, suppression of tumor xenograft was observed. Compared with control group, tumor volume was inhibited by 81.5%, 48.5%, and 37.4%, respectively, in the combined CD/5-fluorocytosine with radiation group, CD/5-fluorocytosine group, and radiation group and the wet weight of tumor was decreased by 80%, 41.7%, and 37.7%, respectively. Conclusion:These findings suggested that combination of liposome-mediated CD gene therapy with radiation is a safer and efficient anticancer method. Its therapeutic efficacy may meet clinical treatment on local recurrent rectal cancer.

Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture

“…Direct intratumoral injection of engineered constructs containing the CD gene have been reported in human clinical trials treating prostate cancer and breast cancer, and in those studies, therapeutic CD gene expression was determined in vivo (7,12). Direct intratumoral injection of CD-expressing constructs has also been reported in experimental animal models of breast and bladder cancer (11,37 (8).…”

Application of liposomes in drug development – focus on gastroenterological targets

“…115 Liposome mediated gene therapy can be an independent treatment [116][117][118][119][120] or be used in combination with other treatments. 121,122 Liposome encapsulated endostatin gene suppressed tumor growth and prolonged survival time of human CRC carrying mice and displayed comparable tumor suppressive effects to bevacizumab. 116,117 To avoid the unpredictable side effects of viral vectors, plasmids were evaluated in the liposomal formulation.…”

“…116,117 To avoid the unpredictable side effects of viral vectors, plasmids were evaluated in the liposomal formulation. 118,119,121,122 Liposomal fms-related tyrosine kinase 3 ligand (pEGF-FL) induced cell death in Lovo cells 118 and a combination of FL and tumor necrosis factor (ligand) superfamily, member 10 (TRAIL) genes in cationic liposomes achieved superior anticancer effects than single gene therapy. 119 While overexpressing cancer inhibitors can suppress tumor progression, knockdown of oncogenes with liposomal shRNA would have the same effect.…”

“…120 Combined with radiation, liposomal cytosine deaminase gene and 5-fluorocytosine reduced tumor volune more than 80% when compared to control in mice bearing human rectal cancer. 121 Par-4 plasmid delivered by liposomes enhanced 5-fluorouracil induced cancer cell apoptosis, 122 indicating liposome mediated gene therapy combined with chemotherapeutics or radiation can be a safe and efficient treatment for CRC.…”

Radiation improves gene delivery by a novel transferrin-lipoplex nanoparticle selectively in cancer cells

“…19 In addition, liposome-mediated delivery of the cytosine deaminase gene has resulted in radiosensitization of rectal cancer. 20 However, the mechanism of radiation induction in liposome-mediated gene transfer is not well understood.…”