A novel targeting modality for renal cell carcinoma: human osteocalcin promoter-mediated gene therapy synergistically induced by vitamin C and vitamin D3
✍ Scribed by Nicole A. Johnson; Bing-Hung Chen; Shian-Ying Sung; Chia-Hui Liao; Wan-Chi Hsiao; Leland W. K. Chung; Chia-Ling Hsieh
- Book ID
- 102891677
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 525 KB
- Volume
- 12
- Category
- Article
- ISSN
- 1099-498X
- DOI
- 10.1002/jgm.1516
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Background
Advanced renal cell carcinoma (RCC) frequently develops skeletal metastasis and is highly resistant to conventional therapies. We hypothesized that the osteocalcin (OC) promoter may be a promising gene delivery system for RCC targeted gene therapy because osteotropic tumors gain osteomimetic properties and thrive in the new environment by exhibiting a bone‐like gene expression profile. Human OC (hOC) expression is highly regulated by vitamins and hormone. In the present study, we tested the feasibility of vitamin‐regulatable hOC promoter for RCC‐specific transcriptional targeting, and examined the anti‐tumor effect of vitamins C and D~3~ with hOC‐based adenoviral vectors towards RCC.
Methods
Real‐time reverse transcriptase‐polymerase chain reaction measured OC expression induced by vitamins C and D~3~, either alone or in combination, in RCC and normal human renal epithelial cells (HRE). The RCC‐cytotoxic effects of concomitant vitamins and hOC promoter‐based adenoviral vectors, Ad‐hOC‐TK and Ad‐hOC‐E1, were evaluated in both cell culture and a xenograft murine model.
Results
We found that high doses of vitamin C induced H~2~O~2~‐dependent apoptosis in RCC but not HRE. Treatment of RCC cells with combined vitamins C and D~3~ treatment significantly increased OC promoter activity compared to single reagent treatment. Combined vitamin therapy reduced tumor size (85%) and complete tumor regression occurred in 38% of mice co‐administrated Ad‐hOC‐E1.
Conclusions
The results obtained in the present study demonstrate that vitamins C and D~3~ synergized with the anti‐tumor effects of therapeutic genes driven by hOC promoter through direct cytotoxicity as well as transcriptional targeting. This combined gene therapy provides a promising modality for advanced RCC targeted therapy. Copyright © 2010 John Wiley & Sons, Ltd.