Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas  

Oleh:

Nair, S. ; Curiel, D.T. ; Rajaratnam, V. ; Thota, C. ; Al-Hendy, A.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Human Reproduction vol. 28 no. 09 (Sep. 2013), page 2398-2406.
Topik: uterine leiomyomas ; gene therapy ; adenovirus vectors ; Ad-SSTR-RGD-TK

Ketersediaan

Perpustakaan FK Nomor Panggil: H07.K.2013.03 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

STUDY QUESTION Is targeted adenovirus vector, Ad-SSTR-RGD-TK (Adenovirus –human somatostatin receptor subtype 2- arginine, glycine and aspartate-thymidine kinase), given in combination with ganciclovir (GCV) against immortalized human leiomyoma cells (HuLM) a potential therapy for uterine fibroids? SUMMARY ANSWER Ad-SSTR-RGD-TK/GCV, a targeted adenovirus, effectively reduces cell growth in HuLM cells and to a significantly greater extent than in human uterine smooth muscle cells (UtSM). WHAT IS KNOWN ALREADY Uterine fibroids (leiomyomas), a major cause of morbidity and the most common indication for hysterectomy in premenopausal women, are well-defined tumors, making gene therapy a suitable and potentially effective non-surgical approach for treatment. Transduction of uterine fibroid cells with adenoviral vectors such as Ad-TK/GCV (herpes simplex virus thymidine kinase gene) decreases cell proliferation. STUDY DESIGN, SIZE, DURATION An in vitro cell culture method was set up to compare and test the efficacy of a modified adenovirus vector with different multiplicities of infection in two human immortalized cell lines for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS Immortalized human leiomyoma cells and human uterine smooth muscle cells were infected with different multiplicities of infection (MOI) (5–100 plaque-forming units (pfu)/cell) of a modified Ad-SSTR-RGD-TK vector and subsequently treated with GCV. For comparison, HuLM and UtSM cells were transfected with Ad-TK/GCV and Ad-LacZ/GCV. Cell proliferation was measured using the CyQuant assay in both cell types. Additionally, western blotting was used to assess the expression of proteins responsible for regulating proliferation and apoptosis in the cells. MAIN RESULTS AND THE ROLE OF CHANCE Transduction of HuLM cells with Ad-SSTR-RGD-TK/GCV at 5, 10, 50 and 100 pfu/cell decreased cell proliferation by 28, 33, 45, and 84%, respectively (P < 0.05) compared with untransfected cells, whereas cell proliferation in UtSM cells transfected with the same four MOIs of Ad-SSTR-RGD-TK/GCV compared with that of untransfected cells was decreased only by 8, 23, 25, and 28%, respectively (P < 0.01). Western blot analysis showed that, in comparison with the untargeted vector Ad-TK, Ad-SSTR-RGD-TK/GCV more effectively reduced expression of proteins that regulate the cell cycle (Cyclin D1) and proliferation (PCNA, Proliferating Cell Nuclear Antigen), and it induced expression of the apoptotic protein BAX, in HuLM cells. LIMITATIONS, REASONS FOR CAUTION Results from this study need to be replicated in an appropriate animal model before testing this adenoviral vector in a human trial. WIDER IMPLICATIONS OF THE FINDINGS Effective targeting of gene therapy to leiomyoma cells enhances its potential as a non-invasive treatment of uterine fibroids. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a grant from the National Institute of Child Health and Human Development, National Institutes of Health [R01 HD046228]. None of the authors has any conflict of interest to declare.

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