Analysis of tumor reoxygenation using ^<31>P-MRS and hypoxic cell imaging

肿瘤缺氧状态不仅引起放射抵抗，而且引起肿瘤转移、组织浸润等恶性进展。肿瘤缺氧的无创测量可用于建立癌症治疗的个体化。(1)采用极谱氧电极（^31P-MRS）和新合成的缺氧标记物β-D-IAZGP测定鼠肿瘤中缺氧组分的含量。我们还研究了肿瘤的放射敏感性与这3种方法预测的低氧分数之间的关系。采用体内/体外克隆测定法测定肿瘤的放射敏感性。用极谱氧电极直接测量肿瘤氧合状态，用^<31>P-MRS间接估计肿瘤氧合状态。在给药24小时后，肿瘤组织中I-β-D-IAZGP的积累高于正常组织。对于^<125>I-β-D-IAGP的生物分布，肿瘤/血比差异较大，但与肿瘤重量相关。随着肿瘤体积的增大，p_O_2值和β-ATP/Pi、PCr/Pi比值显著降低。随着肿瘤体积的增大，肿瘤细胞对辐射的抵抗力增强。肿瘤体积的增大与平均p_O_2的升高、β atp /Pi或PCr/Pi比值的降低、β-D-IAZGP摄取的增加和再耐药显著相关。由于β-D-IAZGP的摄取可以通过核医学技术无创地测量，因此它可以在临床上用于监测人类肿瘤中的缺氧。(2)为了阐明肿瘤缺氧与恶性进展之间的关系，我们检测了HIF-1在III期宫颈癌肿瘤中的表达。HIF-1阳性组5年无病生存率为41.2%，阴性组为75.6%，差异有统计学意义。由于HIF-1阳性组和阴性组在远处转移方面有很强的相关性，因此HIF-1的表达表明肿瘤在子宫颈的恶性进展。少

Tumor hypoxic status causes not only radioresistance but also malignant progression such as metastasis,tissue invasion of the tumor. Non-invasive measurement of tumor hypoxia is available for establishing individualization of the cancer treatment.(1) The amount of hypoxic fraction in a rodent tumor was evaluated by polarographic oxygen electrode, ^31P-MRS, and a newly synthesized hypoxic marker, β-D-IAZGP. We also investigated the relationship between the radiosensrtivity of the tumor and the hypoxic fraction predicted by these 3 methods. Radiosensitivity of the tumor was measured by in vivo/in vitro clonogenic assay. Tumor oxygenation status was also measured directly by polarographic oxygen electrodes and indirectly estimated by ^<31>P-MRS. Higher accumulaion of ^<123>I-β-D-IAZGP was observed in the tumors than that in normal tissues at 24hr after administration. As to biodistribution of ^<125>I-β-D-IAGP,the tumor/blood ratio varted widely, but it was correlated with tumor weight. Me … More an p_O_2 values and β-ATP/Pi, PCr/Pi ratios decreased significantly with the increase in tumor volume. As tumor volume increased, tumor cells became more resistant to radiation. The increase in tumor volume was significantly ccirelated with the recbction in mean p_O_2, decrease in ratios ofβATP/Pi or PCr/Pi, increase in uptake of β-D-IAZGP and redioresistance. Because the uptake of β-D-IAZGP can be measured non-invasively by nuclear medicine techniques, it could be clinically useful for monitoring hypoxia in human tumors.(2) To clarify a correlation between tumor hypoxia and malignant progression, we examined an expression of HIF-1 in the tumor of the stage III uterine cervix cancer. Five-year disease free survival rates were 41.2 % in HIF-1 positive group and 75.6% in HIF-1 negative group with statistical significance. Because strong correlation in distant metastasis was found between HIF-1 positive and negative group, the expression of HIF-1 showed malignant progression of the tumor in the uterine cervix. Less