Yeung Sai-Ching J, She Miaorong, Yang Huiling, Pan Jingxuan, Sun Lily, Chaplin David
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA.
J Clin Endocrinol Metab. 2007 Aug;92(8):2902-9. doi: 10.1210/jc.2007-0027. Epub 2007 Jun 5.
Anaplastic thyroid cancer (ATC) is extremely aggressive, and no effective treatment is available. Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, has limited activity against ATC in a clinical trial, and so does paclitaxel.
We hypothesized that a triple-drug combination including CA4P and paclitaxel would improve efficacy against ATC. Therefore, we evaluated two such combinations in vivo.
We used a nude mouse xenograft model with ARO and KAT-4 cells.
The first combination consisted of CA4P, paclitaxel, and manumycin A (a farnesyltransferase inhibitor), and the second, CA4P, paclitaxel, and carboplatin.
Main outcome measures included tumor growth curves and tumor weights.
Tumor growth curve analysis (linear mixed models, P < 0.05) and xenograft weight analysis (Kruskal-Wallis one-way ANOVA on ranks, post hoc pairwise comparison, Dunn's test, P < 0.05) demonstrated that both triple-drug combinations were significantly better than placebo for both cell lines. Anti-bromodeoxyuridine immunostaining of xenograft sections from animals injected with bromodeoxyuridine before being killed showed that CA4P alone did not inhibit DNA synthesis, but manumycin A and paclitaxel did. CA4P decreased the depth of the viable outer rim of tumor cells on xenograft sections. Using electron microscopy, we found blebbing/budding of endothelial cells into capillary lumens and autophagy of tumor cells in CA4P-treated xenografts.
Both triple-drug combinations demonstrated excellent antineoplastic activity against ATC. The correlative findings in xenografts were consistent with vascular disruption but not direct inhibition of cell proliferation as the primary antineoplastic mechanism contributed by CA4P. These regimens warrant further investigation in clinical trials for ATC.
间变性甲状腺癌（ATC）极具侵袭性，目前尚无有效的治疗方法。血管破坏剂磷酸考布他汀A4（CA4P）在一项临床试验中对ATC的活性有限，紫杉醇的情况也是如此。
我们假设包含CA4P和紫杉醇的三联药物组合能提高对ATC的疗效。因此，我们在体内评估了两种这样的组合。
我们使用了带有ARO和KAT - 4细胞的裸鼠异种移植模型。
第一种组合由CA4P、紫杉醇和马尼霉素A（一种法尼基转移酶抑制剂）组成，第二种组合由CA4P、紫杉醇和顺铂组成。
主要观察指标包括肿瘤生长曲线和肿瘤重量。
肿瘤生长曲线分析（线性混合模型，P < 0.05）和异种移植瘤重量分析（Kruskal - Wallis秩和单向方差分析，事后两两比较，Dunn检验，P < 0.05）表明，两种三联药物组合对两种细胞系均显著优于安慰剂。对处死前注射了溴脱氧尿苷的动物的异种移植瘤切片进行抗溴脱氧尿苷免疫染色显示，单独使用CA4P不抑制DNA合成，但马尼霉素A和紫杉醇能抑制。CA4P降低了异种移植瘤切片上肿瘤细胞存活外缘的深度。通过电子显微镜，我们在CA4P处理的异种移植瘤中发现内皮细胞向毛细血管腔的泡状/芽状突起以及肿瘤细胞的自噬。
两种三联药物组合均显示出对ATC优异的抗肿瘤活性。异种移植瘤中的相关发现与血管破坏一致，但与CA4P作为主要抗肿瘤机制的直接细胞增殖抑制不一致。这些方案值得在ATC的临床试验中进一步研究。
