Radioiodinated sugar-coupled 2-nitroimidazoles:

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" Radioiodinated sugar-coupled 2-nitroimidazoles: "
Rezaul Hasan Mannan

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	1112802
Doc. No	:	TLpq238132609
Main Entry	:	Rezaul Hasan Mannan
Title & Author	:	Radioiodinated sugar-coupled 2-nitroimidazoles:\ Rezaul Hasan Mannan
College	:	University of Alberta (Canada)
Date	:	1991
student score	:	1991
Degree	:	Ph.D.
Page No	:	247-247 p.
Abstract	:	A series of four, novel, (radio)iodinated, sugar-coupled 2-nitroimidazoles were evaluated as non-invasive markers of tumor hypoxia. The compounds investigated were IAZA (1- (5-iodo-5-deoxy-usd\betausd-D-arabinofuranosyl) -2-nitroimidazole), IAZG (1- (6-iodo-6-deoxy-usd\betausd-D-galactopyranosyl) -2-nitroimidazole), IAZP (1- (4-iodo-4-deoxy-usd\betausd-L-xylopyranosyl) -2-nitroimidazole) and FIAZP (1- (2-fluoro-2-deoxy-4-iodo-4-deoxy-usd\betausd-L-xylopyranosyl) -2-nitroimidazole). The compounds were selectively cytotoxic to hypoxic EMT-6 cells in vitro. The cytotoxic effect of IAZA was higher than the others in the series; and was at least 10 times higher than misonidazole. The radiosensitizing effectiveness of these compounds was determined by gamma irradiation of EMT-6 cell cultures under hypoxic conditions with various concentrations of test substrate. IAZG was the best radiosensitizer in the series with an SER value of 1.8 at 0.5 mM. The other compounds showed similar though reduced SER values and all compounds were superior to misonidazole. The radioiodinated compounds were shown to undergo selective binding with hypoxic EMT-6 cells in culture, at a rate 7-30 times higher than with aerobic cells. IAZG had the highest binding rate (1100 pmol/10 cells/h) at 100 muM, followed by IAZA and IAZP. All compounds had higher binding rates than the reference compound misonidazole. Binding studies were performed at several oxygen concentrations and indicated a strong oxygen dependency below a concentration of 0.3%. In vivo biodistribution of the four compounds as their I analogs was performed in Balb/c mice bearing subcutaneous EMT-6 tumors. The maximum tumor to blood ratios for the test compounds were; IAZA, 8.7 at 8 h; IAZG, 1.6 at 4 h; IAZP, 13.9 at 24 h; FIAZP, 5.9 at 24 h. All four compounds showed a rapid excretion (>97% in 24 h) with moderate tissue levels, which in general declined as a function of blood clearance. Whole-body scintigraphic studies in the Balb/c: EMT-6 mouse tumor model, delineated tumor tissue with I labelled IAZA and IAZG at 8 h and 4 h post injection, respectively. These favourable results make these radioiodinated sugar-coupled analogs of 2-nitroimidazole potential markers of hypoxic tumor tissue.
Subject	:	Health and environmental sciences
	:	nitroimidazoles
	:	Oncology
	:	Pharmacology
	:	Pure sciences
	:	radioiodination