Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and canstatin gene suppression therapy on breast tumor xenograft growth in mice.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and canstatin gene therapy have been investigated extensively in human xenograft tumor models established in immunocompromised nude mice. However, combination antitumor activity of these two agents and the safety of such gene constructs driven by the human telomerase reverse transcriptase (hTERT) promoter in nude mice have not been well documented. We hypothesized that TRAIL and canstatin gene therapy driven by the hTERT promoter might overcome the problem of liver toxicity and still effectively induce apoptosis on tumor cells. In this study, we evaluated the antitumor effects of TRAIL in human breast cancer cell lines and the antiangiogenic effects of canstatin on ECV204 cells. We also analyzed the effects of combined gene therapy using both TRAIL and canstatin in a human breast cancer nude mouse model. Tumor growth, tumor inhibition rate of each group, and toxicity were evaluated after gene therapy. Our results demonstrate that treatment using the canstatin- or TRAIL-expressing vector alone significantly suppresses tumor growth, compared to PBS or a vector control. We also found that combining these two therapies had greater antitumor activity than either treatment alone in the mouse model. Moreover, induction of apoptosis was not detected in normal mouse tissues after intratumoral injection of vectors and liver toxicity did not occur with either treatment. Thus, the combination of TRAIL and canstatin appears to be a promising approach for the gene therapy of breast tumors.
Wang
Wen-Bo
WB
Prenatal Medical Diagnosis Center of Xiamen Maternal & Child Health Care Hospital, Xiamen, Fujian, PR China. bea.999@163.com
Zhou
Yu-Lin
YL
Heng
De-Feng
DF
Miao
Chuan-Hui
CH
Cao
Ying-Lin
YL
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism
C502624:Col4a2 protein, mouse; D024141:Collagen Type IV; D010446:Peptide Fragments; D053221:TNF-Related Apoptosis-Inducing Ligand; D019098:Telomerase