Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study

Parliament, M.B.; Chapman, J. D.; Urtasun, R C; McEwan, A. J. B.; Golberg, L.; Mercer, JR; Mannan, Rezaul H.; Wiebe, L. I.

doi:10.1038/bjc.1992.17

Cited by 133 publications

(37 citation statements)

References 20 publications

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“…SPECT hypoxia ligands would therefore be desirable. Iodinated derivatives labeled with 123 I, such as IAZA, 27,28,[57][58][59] and perhaps also 99m Tc-BMS-181321, 24,35 appear promising. On the other hand, the increasingly wider availability of PET in general hospitals for oncology diagnosis may have unexpected implications for hypoxia imaging in stroke.…”

Section: Discussionmentioning

confidence: 99%

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Takasawa

Moustafa

Baron

2008

Stroke

107

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Background and Purpose-Nitroimidazole imaging is a promising contender for noninvasive in vivo mapping of brain hypoxia after stroke. However, there is a dearth of knowledge about the behavior of these compounds in the various pathophysiologic situations encountered in ischemic stroke. In this article we report the findings from a systematic review of the literature on the use of the nitroimidazoles to map hypoxia after stroke. Summary of Review-We describe the characteristics of nitroimidazoles as imaging tracers, their pharmacology, and results of both animal and clinical studies during and after focal cerebral ischemia. Findings in brain tumors are also presented to the extent that they enlighten results in stroke. Early results from application of kinetic modeling for quantitative measurement of tracer binding are briefly discussed. Conclusions-Based on this literature review, nitroimidazole hypoxia imaging agents are of considerable interest in stroke because they appear, both in animal models and in humans, to specifically detect the severely hypoxic viable tissue, but not the reperfused nor the necrotic tissue. To fully realize this potential in stroke, however, formal validation by concurrent measurement of tissue oxygen tension, together with development of novel ligands with faster distribution kinetics, faster clearance from normal tissue, and well-defined trapping mechanisms, are important goals for future investigations.

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Section: Discussionmentioning

confidence: 99%

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Takasawa

Moustafa

Baron

2008

Stroke

107

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“…In hypoxic tissues bioreduction of 2-nitroimidazoles occurs, forming one or more reactive metabolites which bind to macromolecules. Identification of these adducts in vivo has been performed using positron emission tomography (Rasey et al, 1989), magnetic resonance spectroscopy , and single photon emission computed tomography (Parliament et al, 1992). The exact nature of the reactive metabolites which form these adducts, and the enzymes responsible for such nitroreduction, remain to be identified with certainty (Rauth, 1984;Franko, 1986).…”

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confidence: 99%

Nitroimidazole adducts as markers for tissue hypoxia: mechanistic studies in aerobic normal tissues and tumour cells

Parliament¹,

Wiebe²,

Franko³

1992

Br J Cancer

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Summary Two aspects of the aerobic metabolism of nitroimidazole markers for hypoxia were investigated. Several normal murine tissues which are likely to be well oxygenated bind misonidazole at rates comparable to those of hypoxic regions in tumours. The possibility that this aerobic activation occurs via an oxygen independent process such as an initial two electron reduction was studied. Binding to the oesophageal mucosa of mice which occurred under hypoxia in vitro was inhibited by at least 95% in the presence of 10% oxygen. Dicoumarol, an inhibitor of DT-diaphorase, was shown to cause only small reductions in misonidazole binding to oesophageal epithelium and smooth muscle in vitro and to EMT6 tumours, liver, oesophageal and tracheal epithelium, parotid gland and smooth muscle in vivo. Thus an oxygen-insensitive process is not a major cause of the high binding rate in oesophageal mucosa, and may not contribute significantly to the observed binding in other normal tissues. It has been suggested that metabolism of nitroimidazoles by aerobic cells in tumours might be sufficient to minimise access of these compounds to hypoxic regions, particularly at the micromolar concentrations currently in use clinically. The uptake of '251-iodoazomycin arabinoside by RIF-1 and EMT6 tumours was found to be directly proportional to injected dose over concentrations between 0.5 and 501M. Labelling of hypoxic regions in EMT6 tumours by high specific activity 3H-misonidazole at

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“…The study is part of a program to develop topoisomerase II-targeted agents capable of activation, from N-oxide prodrug forms, in cells with elevated bioreductive potential. Capacity for bioreductive activation is associated with tumor hypoxia, which is generally accepted to be a feature of certain human cancers (3,22,23). Indeed, a previous study has shown that in the absence of air, AQ4NO can be reduced in vitro with a significant increase in cytotoxic potency (26).…”

Section: Discussionmentioning

confidence: 97%

“…An aliphatic tertiary amine N-oxide of a cytotoxic anthraquinone is essentially a deactivated DNA-binding agent capable of tumor selectivity by bioreductive conversion and subsequent targeting of topoisomerase IIa. Such bioactivation could take place within the hypoxic regions of tumors (22,23,3). The involvement of NAD(P)Hdependent cytochrome P450's and other haemoproteins under hypoxia in mediating two-electron reduction of a wide range of structurally dissimilar N-oxides to their respective tertiary amines has been described (26).…”

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confidence: 98%

Flow cytometric analysis and confocal imaging of anticancer alkylaminoanthraquinones and their n-oxides in intact human cells using 647-nm krypton laser excitation

et al. 1997

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Flow cytometry and laser‐scanning confocal fluorescence microscopy have been used in the study of the pharmacodynamics, in single intact cells, of two novel alkylaminoanthraquinones (AQ4 and AQ6), structurally based upon the mid‐red excitable but very weakly fluorescent anticancer agent mitoxantrone, together with their respective N‐oxide derivatives (AQ4NO and AQ6NO). The drug design rationale was that N‐oxide modifications generates prodrug forms suitable for selective bioreductive‐activation in hypoxic tumor cells. DNA‐binding ranked in the order of mitoxantrone > AQ6 > AQ4 > AQ6NO >> AQ4NO. Using both cytometric methods a similar ranking was found for whole cell and nuclear location in human transformed fibroblasts. However, AQ6 showed enhanced nuclear uptake compared with mitoxantrone, in keeping with its greater capacity to inhibit DNA synthesis. Partial charge neutralisation by N‐oxide derivatization resulted in loss of DNA synthesis inhibition but retention of the ability to accumulate in the cytosol, an important property for prodrug development. We conclude that both flow cytometry and confocal imaging revealed biologically significant differences between analogues for subcellular distribution and retention properties. The study demonstrates the potential for these complementary 647‐nm krypton laser line‐based fluorometric methods to provide relevant structure‐activity information in anthraquinone drug‐design programmes. Cytometry 27:43–53, 1997. © 1997 Wiley‐Liss, Inc.

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Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study

Cited by 133 publications

References 20 publications

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Nitroimidazole adducts as markers for tissue hypoxia: mechanistic studies in aerobic normal tissues and tumour cells

Flow cytometric analysis and confocal imaging of anticancer alkylaminoanthraquinones and their n-oxides in intact human cells using 647-nm krypton laser excitation

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