Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival.
Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore, novel and effective treatments are urgently needed. A current strategy is cancer-specific targeted gene therapy. Although many identified that cancer-specific promoters are highly specific, they tend to have low activity compared with the ubiquitous cytomegalovirus (CMV) promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly specific with strong activity. Our expression vector uses the survivin promoter, highly expressed in many cancers but not normal adult tissues. We enhanced the survivin promoter activity comparable to the CMV promoter in lung cancer cell lines using an established platform technology, whereas the survivin promoter remained weak in normal cells. In mouse models, the transgene was specifically expressed in the lung tumor tissue, compared with the CMV promoter that was expressed in both normal and tumor tissues. In addition, the therapeutic gene BikDD, a mutant form of pro-apoptotic Bcl2 interacting killer, induced cell killing in vitro, and inhibited cell growth and prolonged mouse survival in vivo. Importantly, there was virtually no toxicity when BikDD was expressed with our expression system. Thus, the current report provides a therapeutic efficacy and safe strategy worthy of development in clinical trials treating lung cancer.
Sher
Y-P
YP
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University & Hospital, Taichung, Taiwan.
Tzeng
T-F
TF
Kan
S-F
SF
Hsu
J
J
Xie
X
X
Han
Z
Z
Lin
W-C
WC
Li
L-Y
LY
Hung
M-C
MC
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D003587:Cytomegalovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000627:therapeutic use*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D050505:Mutant Proteins / Q000235:genetics* / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D021141:Nucleic Acid Amplification Techniques; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D000077022:Survivin; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D000077022:Survivin