White, C. L., Menghistu, T., Twigger, K. R., Searle, P. F., Bhide, S. A., Vile, R. G., Melcher, A. A., Pandha, H. S., Harrington, K. J. (2008) Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo. GENE THERAPY, 15 (6). pp. 424-433. ISSN 0969-7128

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Abstract

Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC50=0.35 mu M) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR - CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiation-induced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4',6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gamma H2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

Item Type:	Article
Authors (ICR Faculty only):	Harrington, Kevin
All Authors:	White, C. L., Menghistu, T., Twigger, K. R., Searle, P. F., Bhide, S. A., Vile, R. G., Melcher, A. A., Pandha, H. S., Harrington, K. J.
Uncontrolled Keywords:	adenovirus; CB1954; nitroreductase; radiotherapy; VDEPT DIRECTED ENZYME PRODRUG; CYTOSINE DEAMINASE GENE; PROSTATE-CANCER; PHASE-I; 2,4-DINITRO-5-AZIRIDINYL BENZAMIDE; IONIZING-RADIATION; GLIOMA-CELLS; THERAPY; ADENOVIRUS; RADIOSENSITIZATION
Research teams:	Clinical Units > Head & Neck Cancer Unit ICR divisions > Cancer Biology > Targeted Therapy ICR divisions > Radiotherapy and Imaging > Targeted Therapy
Depositing User:	Users 10 not found.
Date Deposited:	22 Apr 2008 11:57
Last Modified:	10 Feb 2010 11:50
URI:	http://publications.icr.ac.uk/id/eprint/6008

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