Adenovirus-mediated FLT1-targeted proapoptotic gene therapy of human prostate cancer.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is of particular interest in the development of prostate carcinoma therapeutics as it preferentially induces apoptosis of tumor cells. To employ adenoviral vectors for highly efficient and specific TRAIL gene transfer into cancer cells could overcome some potential problems for recombinant TRAIL. The vascular endothelial growth factor receptor FLT-1 is involved in regulation of angiogenesis and tumor growth, invasion, and metastasis of prostate carcinoma. FLT-1 expression is observed in both tumor endothelial cells and prostate cancer cells. We developed an adenoviral vector encoding the TRAIL gene under control of the FLT1 promoter (AdFlt-TRAIL), which produced endothelial and prostate cancer cell death. The combination of ionizing radiation and adenovirus-driven TRAIL expression overcame human prostate cancer cell resistance to TRAIL. Furthermore, in vivo administration of AdFlt-TRAIL at the site of tumor growth in combination with radiation treatment produced significant suppression of the growth of DU145 human prostate tumor xenografts in athymic nude mice. Our results suggest that specific TRAIL delivery employing the FLT1 promoter can effectively inhibit tumor growth and demonstrate the advantage of combination radiotherapy and gene therapy for the treatment of prostate cancer.
Kaliberov
Sergey A
SA
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Kaliberova
Lyudmila N
LN
Stockard
Cecil R
CR
Grizzle
William E
WE
Buchsbaum
Donald J
DJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D016326:Extracellular Matrix Proteins; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011839:Radiation, Ionizing; D053221:TNF-Related Apoptosis-Inducing Ligand; D014183:Transplantation, Heterologous / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1
D051017:Apoptosis Regulatory Proteins; D016326:Extracellular Matrix Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains