A novel targeting modality for renal cell carcinoma: human osteocalcin promoter-mediated gene therapy synergistically induced by vitamin C and vitamin D-3

作者：Johnson Nicole A; Chen Bing Hung; Sung Shian Ying; Liao Chia Hui; Hsiao Wan Chi; Chung Leland W K; Hsieh Chia Ling^*

来源：Journal of Gene Medicine, 2010, 12(11): 892-903.

DOI：10.1002/jgm.1516

• adenoviral vectors
• gene therapy
• osteocalcin promoter
• renal cell carcinoma
• vitamin C
• vitamin D-3

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 H2O2-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.

• 出版日期2010-11
• 单位中国医科大学