Use of Transcriptional Regulatory Sequences of Telomerase (hTER and hTERT) for Selective Killing of Cancer Cells

• DOI: 10.1006/mthe.2000.0196
• Publication Date: 2002-09-18T15:46:43Z
• Authors: R. Abdul-Ghani; P. Ohana; I. Matouk; S. Ayesh; B. Ayesh; M. Laster; O. Bibi; H. Giladi; K. Molnar-Kimber; M.A. Sughayer; N. de Groot; A. Hochberg
• Keywords: Pharmacology; 0303 health sciences; Carcinoma, Hepatocellular; Base Sequence; Transcription, Genetic; Cell Survival; Reverse Transcriptase Polymerase Chain Reaction; Liver Neoplasms; DNA Methylation; Regulatory Sequences, Nucleic Acid; Peptide Fragments; 3. Good health; 03 medical and health sciences; Urinary Bladder Neoplasms; Drug Discovery; Genetics; Tumor Cells, Cultured; Molecular Medicine; Humans; Diphtheria Toxin; Promoter Regions, Genetic; Molecular Biology; Telomerase; DNA Primers

Telomerase (hTER and hTERT) plays a crucial role in cellular immortalization and carcinogenesis. Telomerase activity can be detected in about 85% of different malignant tumors, but is absent in most normal cells. In situ hybridization analysis showed that high levels of hTER and hTERT expression are present in bladder cancer, while no signal was detected in normal tissue. Therefore, in this work we propose to use hTER and hTERT transcriptional regulatory sequences to control the expression of a cytotoxic gene in bladder tumor cells, resulting in the selective destruction of this cell population. Expression vectors containing the diphtheria toxin A-chain (DT-A) gene were linked to hTER and hTERT transcriptional regulatory sequences, respectively. Inhibition of protein synthesis occurred in bladder and hepatocellular carcinoma cells transfected with the plasmids containing the DT-A gene under the control of the hTER or hTERT promoters in correlation with their activity. These studies support the feasibility of using hTER and hTERT transcriptional regulatory sequences for targeted patient-oriented gene therapy of human cancer.