A dual hypoxic marker technique for measuring oxygenation change within individual tumors

Abstract

Summary Rodent tumour models have been the 'workhorse' for tumour oxygenation research and for investigating radiobiological hypoxic fraction. Because of the intertumour heterogeneity of blood flow and related parameters, most studies have pooled information derived from several different tumours to establish the statistical significance of specific measurements. But it is the oxygenation status of and its modulation in individual tumours that has important prognostic significance. In that regard, the bioreducible hypoxic marker technique was tested for its potential to quantify oxygenation changes within individual tumours. f-D-lodinated azomycin galactoside (IAZG) and P-Diodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with lodine-125 and iodine-131 for measurements of animal tumour oxygenation. The tumour-blood (T/B) ratio of marker radioactivity in mice after the renal excretion of unbound marker (at 3 h and longer times) had been shown to be proportional to radiobiological hypoxic fraction. When markers labelled with both radioisotopes were administered simultaneously to EMT-6 tumour-bearing scid mice, T/B ratios were found to vary by up to 300% between different tumours, with an average intratumour variation of only -4%. When the markers were administered 2.5-3.0 h apart, changes in T/B ratios of 8-25% were observed in 10 out of 28 (36%) tumours. Changes to both higher and lower hypoxic fraction were observed, suggestive of acute or cycling hypoxia. When 0.8 mg g-1 nicotinamide plus carbogen was administered to increase tumour oxygenation, reductions in T/B ratios (mean AT/B -38%) were observed in all tumours. Similar results were obtained with Dunning rat prostate carcinomas growing in Fischer X Copenhagen rats whose T/B ratios of IAZG and radiobiological hypoxic fractions are significantly lower. These studies suggest that fluctuating hypoxia can account for at least 25% of the total hypoxic fraction in some tumours and that correlations between bioreducible marker avidity and related tumour properties will be optimal when the independent assays are performed over the same time period. This dual hypoxic marker technique should prove useful for investigating both spontaneous and induced oxygenation changes within individual rodent tumours.

Molecular imaging of hypoxia with radiolabelled agents

“…Newer agents based on the azomycin-nucleoside structure such as IAZG [ 109 , 110 ], iodoazomycin pyranoside (IAZP) [ 111 ], IAZGP [ 112 , 113 ] and iodoazomycin xylopyranoside (IAZXP) [ 109 ] have been developed and evaluated. Iyer et al demonstrated that microelectrode measurements in R3327-AT tumour-bearing rats did not correlate with [ 125 I]IAZGP uptake [ 112 ].…”

Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers

“…In contrast, at an injection interval of 2.5 to 3 h, a mismatch that was larger than 8% was found in 8 of 18 tumors. This was interpreted as evidence for significant amounts of transient hypoxia (190). With this assay, significant changes in labeling between the first and second marker were found upon treatment with carbogen and nicotinamide.…”

“…It inspired development of double hypoxia marker assays with consecutive injections of two different 2-nitroimidazoles for analysis of changes in hypoxia in individual experimental tumors (153,154,164,(189)(190)(191)(192). Since each tumor serves as its own control, these assays eliminate the effect of in- tertumor heterogeneities in hypoxic fractions within the same tumor line and histology.…”

Tumor Hypoxia Imaging

“…The radiopharmacokinetics and the radiation dosimetry of 123 I-IAZA concluded that 123 I-IAZA can be used in clinical hypoxia tissue imaging [90,91]. Because a major drawback of 123 I-IAZA is that it has inconsistent uptake into various tumors, efforts have been made to modify iodinated azomycin arabinosides [92]. IAZA, iodoazomycin pyranoside (IAZP), beta-Diodinated azomycin galactopyranoside (IAZGP), and iodoazomycin xylopyranoside (IAZXP) have been developed and evaluated as newer agents based on the azomycin-nucleoside structure [93].…”