Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy
Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy
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DOI：
10.1158/1078-0432.ccr-04-1306
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发表时间：
2004-12-01
影响因子：
11.5
通讯作者：
Rustum, YM
中科院分区：
文献类型：
--
作者：
Bhattacharya, A;T贸th, K;Rustum, YM
目的：伊立替康（CPT-11, 50 mg/kg/周X 4静脉滴注）联合化疗，24小时后再加5-氟尿嘧啶（50 mg/kg/周X 4静脉滴注），移植人头颈部鳞状细胞癌动物的治愈率为10%和100%；分别是A253和FaDu。A253由30%的高分化无血管区和70%的低分化区组成，微血管密度低（10/X400），而FaDu均匀低分化，微血管密度高（19/X400）。研究确定了A253的高分化区和无血管区在耐药中的作用，并利用无创功能磁共振（fMR）成像检测这些区域。实验设计：第3次给药后立即采集肿瘤进行组织病理学评估和免疫组化（CD31、CD34；分化标志物：天青蛋白；缺氧标志物：碳酸酐酶IX、吡莫硝唑；血管内皮因子（VEGF）和Ki67）。给药2小时后用高效液相色谱法测定7-乙基-10-羟基喜树碱瘤内药物浓度，并用c -14标记的CPT-11进行放射成像。结果：尽管A253异种移植物中7-乙基-10-羟基喜树碱的浓度增加了3倍，但FaDu对治疗的反应更强。治疗后，A253肿瘤主要由（接近80%）缺乏微血管的高分化区（花青素阳性）和缺氧边缘（碳酸酐酶IX和吡咪唑阳性）组成，其中含有少量增殖（Ki67阳性）低分化细胞。放射自显像显示，I分化的A253肿瘤区c -14标记的CPT-11浓度比低分化区低5倍（P < 0.001）。依靠血氧水平的fMR成像能够无创地区分肿瘤内的缺氧区和血管充血区。结论：鳞状细胞癌的无血管分化区为一些缺氧但存活的肿瘤细胞（碳酸酐酶IX和Ki67阳性）提供了避难所，这些细胞由于药物输送有限而逃避治疗。该研究提供了直接证据，表明由于特定的组织学结构，肿瘤中的无血管、分化良好的缺氧区表现出低药物摄取，并代表了一种独特的耐药形式。
Purpose: Combination chemotherapy with irinotecan (CPT-11; 50 mglkg/week X 4 intravenously), followed 24 hour later by 5-fluorouracil (50 mg/kg/week X 4 intravenously), results in 10 and 100% cure rates of animals bearing human head and neck squamous cell carcinoma xenografts; A253 and FaDu, respectively. A253 consists of 30% well-differentiated and avascular and 70% poorly differentiated regions with low microvessel density (10/X400), whereas FaDu is uniformly poorly differentiated with higher microvessel density (19/X400). Studies were carried out for determining the role of well-differentiated and avascular regions in drug resistance in A253 and detection of such regions with noninvasive functional magnetic resonance (fMR) imaging.Experimental Design: Tumors were harvested for histopathologic evaluation and immunohistochemistry (CD31, CD34; differentiation marker: involucrin; hypoxia markers: carbonic anhydrase IX, pimonidazole; vascular endothelial factor (VEGF) and Ki67) immediately after 17MR imaging following the 3rd dose of chemotherapy. High-performance liquid chromatography determination of intratumoral drug concentration of 7-ethyl-10-hydroxyl-camptothecin and antoradiography with C-14-labeled CPT-11 was done 2 hours after CPT-11 administration.Results: Although A253 xenografts showed three times higher concentration of 7-ethyl-10-hydroxyl-camptothecin, FaDu was more responsive to therapy. After therapy, A253 tumor consisted mostly (similar to80%) of well-differentiated regions (positive for involucrin) lacking microvessels with a hypoxic rim (positive for carbonic anhydrase IX and pimonidazole) containing few proliferating (Ki67 positive) poorly differentiated cells. Autoradiography revealed that we] I -differentiated A253 tumor regions showed 5-fold lower C-14-labeled CPT-11 concentrations compared with poorly differentiated areas (P < 0.001). Blood oxygen level dependant fMR imaging was able to noninvasively distinguish the hypoxic and well-vascularized regions within the tumors.Conclusion: Avascular-differentiated regions in squamous cell carcinoma offer sanctuary to some hypoxic but viable tumor cells (carbonic anhydrase IX and Ki67 positive) that escape therapy because of limited drug delivery. This study provides direct evidence that because of a specific histologic structure, avascular, well-differentiated hypoxic regions in tumors exhibit low drug uptake and represent a unique form of drug resistance.