Anticancer drug response and expression of molecular marker in early-passage xenotransplanted colon carcinomas
Anticancer drug response and expression of molecular marker in early-passage xenotransplanted colon carcinomas
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DOI：
10.1016/j.ejca.2003.10.011
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发表时间：
2004-01-01
影响因子：
8.4
通讯作者：
Bibby, M
中科院分区：
文献类型：
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作者：
Fichtner, I;Slisow, W;Bibby, M
尽管结直肠癌的治疗取得了一些成功，但针对特定癌症相关分子的新型合理疗法仍在开发中，迫切需要。这些方法需要在密切反映临床情况的模型中进行仔细的临床前评估。因此，我们建立了一个由15个直接来自新鲜外科材料的异种移植肿瘤组成的小组。我们发现，在裸鼠传代过程中，组织学和肿瘤相关标志物（上皮细胞粘附分子（EpCAM）、E-cadherin、癌胚抗原（CEA））的表达都可以维持。异种移植肿瘤以化学敏感性为特征，5-氟尿嘧啶（5-FU）的有效率为5/15(33%)，伊立替康的有效率为15/15(100%)，奥沙利铂的有效率为8/14（57%）。15例患者中有5例因同步转移而接受细胞抑制剂治疗。这些患者对化疗的反应与单个异种移植物的反应非常接近。所有异种移植物在蛋白水平上表达增殖标志物Ki67和核酶拓扑异构酶iα (Topo iα)。大多数异种移植物在蛋白水平上也表达肿瘤抑制因子p53（9/14）和核酶拓扑异构酶α (Topo i α)（13/14）。有趣的是，密码子12（5115异种移植物）中K-ras突变的存在与奥沙利铂的低应答率相吻合。这一观察结果需要用更多的肿瘤进一步证实。总之，我们能够建立适合于模拟临床情况的可移植异种移植物。这些表征良好的模型是临床前开发新治疗方法和研究转化研究方面的有用工具。(C) 2003 Elsevier Ltd.版权所有。
Despite some success in the treatment of colorectal carcinomas, novel rational therapies targeting specific cancer-related molecules are under development and urgently needed. These approaches need careful preclinical evaluation in models that closely mirror the clinical situation. Therefore, we established a panel of 15 xenotransplantable tumours directly from fresh surgical material. We showed that both the histology and expression of tumour-associated markers (Epithelial Cell Adhesion molecule (EpCAM), E-cadherin, carcinoembryonic antigen (CEA)) could be maintained during passaging in nude mice. Xenotransplanted tumours were characterised for chemosensitivity and revealed a response rate of 5/15 (33%) for 5-fluorouracil (5-FU), 15/15 (100%) for irinotecan and 8/14 (57%) for oxaliplatin. 5 patients out of 15 were treated with cytostatics because of synchronous metastases. The response to chemotherapy in these patients coincided very closely with the response of the individual xenografts. All of the xenografts expressed the proliferation marker Ki67 and the nuclear enzyme, Topoisomerase IIalpha (Topo IIalpha) at the protein level. Most of the xenografts also expressed the tumour suppressor, p53 (9/14) and the nuclear enzyme Topoisomerase Ialpha (Topo Ialpha) (13/14) at the protein level. Interestingly, the presence of a K-ras mutation in codon 12 (5115 xenografts) coincided with a low response rate towards oxaliplatin. This observation needs further confirmation using a larger number of tumours. In conclusion, we were able to establish transplantable xenografts suitable to mimic the clinical situation. These well characterised models are useful tools for the preclinical development of novel therapeutic approaches and for investigating translational research aspects. (C) 2003 Elsevier Ltd. All rights reserved.