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Báo cáo hóa học: " Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành hóa học dành cho các bạn yêu hóa học tham khảo đề tài: Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences | Amit and Hochberg Journal of Translational Medicine 2010 8 134 http www.translational-medicine.eom content 8 1 134 TRANSLATIONAL MEDICINE RESEARCH Open Access Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences Doron Amit Abraham Hochberg Abstract Background The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers including bladder cancer while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment DTA under the control regulation of IGF2-P4 or H19 regulatory sequences IGF2-P4-DTA and H19-DTA were previously successfully used in cell lines animal models and recently in human patients with superficial cell carcinoma of the bladder treated with H19-DTA . However this targeted medicine approach could be limited as not all cancer patients express high levels of H19. Hence a double promoter DTA-expressing vector was created carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment DTA from two different regulatory sequences selected from the cancer-specific promoters H19 and IGF2-P4. Methods H19 and IGF2-P4 gene expression was tested in samples of Transitional Cell Carcinoma TCC of the bladder by in-situ hybridization ISH and by quantitative Real-Time PCR qRT-PCR . The therapeutic potential of the double promoter toxin vector H19-DTA-IGF2-P4-DTA was tested in TCC cell lines and in heterotopic and orthotopic animal models of bladder cancer. Results Nearly 100 of TCC patients highly expressed IGF2-P4 and H19 as determined by ISH and by qRT-PCR. The double promoter vector exhibited superior tumor growth inhibition activity compared to the single promoter expression vectors in cell lines and in heterotopic and orthotopic bladder tumors. Conclusions Our findings show that bladder tumors may be successfully .