Kaanders Johannes H A M, Wijffels Karien I E M, Marres Henri A M, Ljungkvist Anna S E, Pop Lucas A M, van den Hoogen Franciscus J A, de Wilde Peter C M, Bussink Johan, Raleigh James A, van der Kogel Albert J
Department of Radiation Oncology, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands.
Cancer Res. 2002 Dec 1;62(23):7066-74.
Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation treatment. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. This study correlated the exogenous 2-nitroimidazole hypoxia marker 1-[(2-hydroxy-3-piperidinyl)propyl]-2-nitroimidazole hydrochloride (pimonidazole) with the endogenous hypoxia-related marker carbonic anhydrase 9 (CA9) and with vascular parameters using immunohistochemical techniques and a computerized image analysis system. Tumor biopsies were obtained from patients with head and neck carcinomas that were potential candidates for a Phase II trial with accelerated radiotherapy combined with carbogen and nicotinamide (ARCON). If, after completion of the diagnostic workup, the eligibility criteria were met and informed consent was obtained, patients were treated with ARCON. Those patients that were not eligible or refused ARCON were treated with radiotherapy, surgery, or a combined modality. Forty-three biopsies were analyzed, and the results were related with treatment outcome. The distribution patterns of pimonidazole and CA9 were similar, although the CA9 signal was generally observed already at shorter distances from blood vessels. There was a weak but significant correlation between the relative tumor areas positive for pimonidazole binding and areas with CA9 expression. Locoregional tumor control was significantly lower for patients who had hypoxic tumors or tumors with low vascular density. The 2-year control rates were 48 versus 87% for tumors with high and low pimonidazole binding levels (stratified by median, P = 0.01) and 48 and 88% for tumors with low and high vascular density (stratified by median, P = 0.01). These associations disappeared in the subgroup of patients treated with ARCON. There was no relationship between the level of CA9 expression and treatment outcome. It is concluded that pimonidazole binding and vascular density can predict treatment outcome in head and neck cancer and may be useful as selection tools for hypoxia-modifying treatments. Pimonidazole and CA9 demonstrate concordant staining patterns, but the latter is a less specific marker for hypoxia.
缺氧与肿瘤侵袭性相关，是放疗抵抗的重要原因。肿瘤缺氧检测可为缺氧修饰治疗提供选择工具。本研究采用免疫组化技术和计算机图像分析系统，将外源性2-硝基咪唑类缺氧标志物1-[(2-羟基-3-哌啶基)丙基]-2-硝基咪唑盐酸盐（匹莫硝唑）与内源性缺氧相关标志物碳酸酐酶9（CA9）以及血管参数进行关联分析。从头颈癌患者获取肿瘤活检组织，这些患者是加速放疗联合卡波金和烟酰胺（ARCON）的II期试验的潜在候选者。如果在完成诊断检查后符合入选标准并获得知情同意，患者接受ARCON治疗。那些不符合入选标准或拒绝ARCON治疗的患者接受放疗、手术或综合治疗。对43份活检组织进行分析，并将结果与治疗结果相关联。匹莫硝唑和CA9的分布模式相似，尽管通常在距血管较短距离处就已观察到CA9信号。匹莫硝唑结合阳性的相对肿瘤面积与CA9表达区域之间存在微弱但显著的相关性。对于有缺氧肿瘤或血管密度低的肿瘤患者，局部区域肿瘤控制率显著较低。匹莫硝唑结合水平高和低的肿瘤的2年控制率分别为48%和87%（按中位数分层，P = 0.01），血管密度低和高的肿瘤的2年控制率分别为48%和88%（按中位数分层，P = 0.01）。在接受ARCON治疗的患者亚组中，这些关联消失。CA9表达水平与治疗结果之间无相关性。结论是，匹莫硝唑结合和血管密度可预测头颈癌的治疗结果，可能作为缺氧修饰治疗的选择工具。匹莫硝唑和CA9显示出一致的染色模式，但后者作为缺氧标志物的特异性较低。
