Greco, O. and Marples, B. and Joiner, M.C. and Scott, S.D. (2003) How to overcome (and exploit) tumor hypoxia for targeted gene therapy. Journal of Cellular Physiology, 197 (3). pp. 312-325. ISSN 0021-9541.
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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating Cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.
|Divisions:||Faculties > Science Technology and Medical Studies > Medway School of Pharmacy|
|Depositing User:||Simon Scott|
|Date Deposited:||15 Sep 2008 12:31|
|Last Modified:||14 Jan 2010 14:36|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/9624 (The current URI for this page, for reference purposes)|
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