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Development of a therapeutically important radiation induced promoter.

ABSTRACT: Radio-genetic therapy is a combination of radiation therapy and gene therapy that may solve some of the problems associated with conventional radiotherapy. A promoter responsive to radiation was obtained from a promoter library composed of DNA fragments created by linking the TATA box signal to randomly combined binding sequences of transcription factors that are reactive to radiation. Each promoter connected to the luciferase gene, was evaluated by luciferase expression enhancement in transfected cells after X-ray irradiation. The reactivity of the best promoter was improved by the random introduction of point mutations and the resultant promoter showed more than a 20-fold enhancement of the luciferase expression after X-ray irradiation at 10 Gy. The expression of downstream genes was also enhanced in stably transfected cells not only by X-rays but also by proton beam irradiation; and either enhancement was attenuated when an anti-oxidant was added, thus suggesting the involvement of oxidative stress in the promoter activation. Constructed promoters were also activated in tumors grown in mice. In addition, cell killing with the fcy::fur gene (a suicide gene converting 5-fluorocytosin to highly toxic 5-fluorouracil) increased dose-dependently with 5-fluorocytosin only after X-ray irradiation in vitro. These results suggest that promoters obtained through this method could be used for possible clinical applications.

SUBMITTER: Ogawa R

PROVIDER: S-EPMC3566020 | biostudies-literature | 2013 Jan-Feb

REPOSITORIES: biostudies-literature

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Development of a therapeutically important radiation induced promoter.

Ogawa Ryohei R Morii Akihiro A Watanabe Akihiko A Cui Zheng-Guo ZG Kagiya Go G Fukuda Shigekazu S Kume Kyo K Hasegawa Takashi T Hatashita Masanori M Izumi Hironori H Ishimoto Tetsuya T Feril Loreto B LB

Bioengineered 20120828 1

Radio-genetic therapy is a combination of radiation therapy and gene therapy that may solve some of the problems associated with conventional radiotherapy. A promoter responsive to radiation was obtained from a promoter library composed of DNA fragments created by linking the TATA box signal to randomly combined binding sequences of transcription factors that are reactive to radiation. Each promoter connected to the luciferase gene, was evaluated by luciferase expression enhancement in transfect ...[more]

PMID: 22929999

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Project description:Background and objectiveRadiation-induced cystitis (RIC) is an important consequence of pelvic radiotherapy that can cause high morbidity and, in extreme cases, mortality. The lack of a widely accepted classification system makes it difficult to compare treatment regimens. Our aim was to develop a new classification system covering the RIC spectrum to improve treatment comparisons and accurate incidence estimates for systematic use in clinical and research settings.MethodsA three-phase project was planned. Phase 1 involved a literature review and development of the Portuguese Navy Radiation-induced Cystitis (PNRC) scale. In phase 2 the scale was applied to 20 clinical cases. Phase 3 involved assessment of the applicability, relevance, inter-rater reliability, and usability of the scale using numerical and graphical methods to achieve consensus among international experts.Key findings and limitationsIn phase 1, the panel analysed 13 existing classification systems and developed the PNRC scale, a comprehensive system encompassing five clinical domains: haematuria, other lower urinary tract symptoms, functional impairment, endoscopic findings, and therapeutic interventions. In phase 2, 114 experts from 30 countries completed the first validation round. Consensus was reached for 85% of cases. In phase 3, consensus was reached among 61 experts on the relevance and appropriateness of each domain, and on the exhaustiveness, hierarchy, clarity, mutual exclusivity, and clinical utility of the PNRC scale. Study limitations are the inclusion of only Medline-indexed manuscripts in the review and minor dispersion of responses, indicating subjectivity in the analysis of clinical case scenarios.Conclusions and clinical implicationsThe PNRC scale showed reliability and face and construct validity in the stratification of RIC severity for clinical cases.Patient summaryRadiation-induced cystitis is a debilitating complication of pelvic radiotherapy. A uniform classification system is needed to assess the incidence of this disease and to compare the results for different treatment options. We developed the Portuguese Navy Radiation-induced Cystitis (PNRC) scale, which was validated by an independent group of experts from 30 different countries.

Dataset Information

Development of a therapeutically important radiation induced promoter.

Publications

Development of a therapeutically important radiation induced promoter.

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