Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer.
We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adbetagal, Adbetagal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.
Fujita
T
T
Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Timme
T L
TL
Tabata
K
K
Naruishi
K
K
Kusaka
N
N
Watanabe
M
M
Abdelfattah
E
E
Zhu
J X
JX
Ren
C
C
Ren
C
C
Yang
G
G
Goltsov
A
A
Wang
H
H
Vlachaki
M T
MT
Teh
B S
BS
Butler
E B
EB
Thompson
T C
TC
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000532:radiotherapy / Q000556:secondary* / Q000628:therapy; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011471:Prostatic Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12