Iyer R V, Kim E, Schneider R F, Chapman J D
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Br J Cancer. 1998 Jul;78(2):163-9. doi: 10.1038/bjc.1998.459.
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. Beta-D-iodinated azomycin galactoside (IAZG) and beta-D-iodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with Iodine-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 approximately 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 deltaT/B approximately 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.
啮齿动物肿瘤模型一直是肿瘤氧合研究和放射生物学缺氧分数研究的“主力军”。由于肿瘤间血流及相关参数的异质性，大多数研究汇总了来自几种不同肿瘤的信息，以确定特定测量结果的统计学意义。但个体肿瘤内的氧合状态及其调节具有重要的预后意义。在这方面，对生物可还原缺氧标记技术量化个体肿瘤内氧合变化的潜力进行了测试。β-D-碘化偶氮霉素半乳糖苷（IAZG）和β-D-碘化偶氮霉素木糖吡喃糖苷（IAZXP）分别用碘-125和碘-131进行放射性标记，用于测量动物肿瘤氧合。在未结合标记物经肾脏排泄后（3小时及更长时间），小鼠体内标记物放射性的肿瘤-血液（T/B）比值已被证明与放射生物学缺氧分数成正比。当同时给荷EMT-6肿瘤的scid小鼠注射两种放射性同位素标记的标记物时，发现不同肿瘤之间的T/B比值变化高达300%，肿瘤内平均变化仅约4%。当标记物间隔2.5 - 3.0小时给药时，28个肿瘤中有10个（36%）观察到T/B比值变化8 - 25%。观察到缺氧分数升高和降低的变化，提示急性或周期性缺氧。当给予0.8 mg g(-1)烟酰胺加碳合气以增加肿瘤氧合时，所有肿瘤的T/B比值均降低（平均ΔT/B约38%）。在Fischer×哥本哈根大鼠体内生长的邓宁大鼠前列腺癌中也获得了类似结果，其IAZG的T/B比值和放射生物学缺氧分数显著较低。这些研究表明，波动缺氧至少可占某些肿瘤总缺氧分数的25%，并且当在同一时间段内进行独立检测时，生物可还原标记物亲和力与相关肿瘤特性之间的相关性将达到最佳。这种双重缺氧标记技术对于研究个体啮齿动物肿瘤内的自发和诱导性氧合变化应该是有用的。
