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Combined ionizing radiation and sKDR gene delivery for treatment of prostate carcinomas
S A Kaliberov1, L N Kaliberova, D J Buchsbaum
1Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
Overexpression of vascular endothelial growth factor (VEGF) and its cognate receptor KDR has been linked to a more aggressive phenotype of human prostate carcinomas. The importance of signal transduction through the VEGF receptor 2 is illustrated by use of soluble KDR, which binds to VEGF and sequesters this ligand before its binding to cellular receptor. Treatment with recombinant adenovirus AdVEGF-sKDR, encoding sKDR under control of the human VEGF promoter, significantly inhibited the proliferation of human vascular endothelial cells and prostate cancer cells. AdVEGF-sKDR infection decreased migration of endothelial 1P-1B cells (61% reduction) and DU145 prostate carcinoma cells (47%) in comparison with AdCMV-Luc-infected control cells. Ionizing radiation upregulated VEGF promoter activity in prostate carcinoma and endothelial cells. AdVEGF-sKDR infection significantly reduced human vascular endothelial and prostate cancer cell proliferation and sensitized cancer cells to ionizing radiation. In vivo tumor therapy studies demonstrated significant inhibition of DU145 tumor growth in mice that received combined AdVEGF-sKDR infection and ionizing radiation versus AdVEGF-sKDR alone or radiation therapy alone. These results suggest that selective transcriptional targeting of sKDR gene expression employing a radiation inducible promoter can effectively inhibit tumor growth and demonstrate the advantage of combination radiotherapy and gene therapy for the treatment of prostate cancer.
Insights
Gene therapy using AdVEGF-sKDR inhibits prostate cancer growth by blocking vascular endothelial growth factor (VEGF). Combined with radiation, it significantly enhances tumor suppression, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Gene Therapy
- Vascular Biology
Background:
- Vascular Endothelial Growth Factor (VEGF) and its receptor KDR are overexpressed in aggressive prostate cancer.
- Soluble KDR (sKDR) can sequester VEGF, inhibiting its signaling pathway.
- Targeting VEGF signaling is a potential strategy for prostate cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of recombinant adenovirus AdVEGF-sKDR in inhibiting prostate cancer cell proliferation and migration.
- To investigate the radiosensitizing effect of AdVEGF-sKDR on prostate cancer cells.
- To assess the in vivo therapeutic potential of combined AdVEGF-sKDR gene therapy and ionizing radiation.
Main Methods:
- AdVEGF-sKDR, encoding sKDR under a VEGF promoter, was used to treat human vascular endothelial and prostate cancer cells.
- Cell proliferation and migration assays were performed.
- In vivo studies involved DU145 tumor xenografts in mice treated with AdVEGF-sKDR, ionizing radiation, or both.
Main Results:
- AdVEGF-sKDR significantly inhibited proliferation of endothelial and prostate cancer cells.
- AdVEGF-sKDR reduced endothelial cell migration by 61% and DU145 cell migration by 47%.
- Combined AdVEGF-sKDR and ionizing radiation significantly inhibited DU145 tumor growth in vivo compared to monotherapy.
Conclusions:
- Selective transcriptional targeting of sKDR via radiation-inducible promoters can inhibit tumor growth.
- Combination radiotherapy and gene therapy demonstrates significant advantage for prostate cancer treatment.
- This approach offers a novel strategy for enhancing the efficacy of radiation therapy in prostate cancer.
