Department of Urology, Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
BJU Int. 2011 Jan;107(1):118-25. doi: 10.1111/j.1464-410X.2010.09314.x.
To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC.
Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 µg (125) I-cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250.
While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible.
Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed.
研究三种不同的酪氨酸激酶抑制剂（TKIs）对识别碳酸酐酶 IX（CAIX）的嵌合单克隆抗体（mAb）cG250 生物分布的影响，在荷人肾细胞癌（RCC）异种移植瘤的裸鼠中。TKIs 是转移性肾细胞癌（mRCC）的最佳治疗方法，但仍不理想，联合治疗或序贯治疗可能有益。CAIX 在 RCC 中过度表达，临床试验表明 cG250 在肿瘤中有丰富且特异性的积累。将 TKI 与参与不同效应机制的 mAb cG250 联合使用，可能会导致 mRCC 患者的肿瘤反应和生存得到改善。
荷人 RCC 异种移植瘤的裸鼠每天口服 0.75mg 舒尼替尼、1mg 凡德他尼、1mg 索拉非尼或载体对照 7 或 14 天。在第 7 天，小鼠静脉注射 185kBq/5μg（125）I-cG250。在预定的天数处死小鼠，测定 cG250 的生物分布。通过免疫组织化学分析肿瘤中内皮细胞、层粘连蛋白、平滑肌肌动蛋白、CAIX 表达和 mAb cG250 的摄取。
在 TKI 治疗期间，cG250 的肿瘤摄取量显著下降，肿瘤生长受到轻微抑制，血管密度也因各种标志物的变化而明显下降。当在第 7 天停止治疗时，出现了强烈的新生血管形成，主要发生在肿瘤边缘。因此，cG250 的摄取也恢复了，尽管 cG250 的摄取似乎仅限于可见活跃新生血管的肿瘤边缘。
同时给予 TKI 和 mAb cG250 严重影响 mAb 的积累。然而，在 TKI 治疗停止后不久，mAb 的积累就恢复了。TKI 和 mAb 的联合治疗策略应谨慎设计。
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