Xu G, Pan J, Martin C, Yeung S C
Section of Endocrine Neoplasia and Hormonal Disorders, Department of Internal Medicine Specialties, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Clin Endocrinol Metab. 2001 Apr;86(4):1769-77. doi: 10.1210/jcem.86.4.7374.
Our laboratory has investigated the anticancer effects of combined manumycin (a farnesyltransferase inhibitor) and paclitaxel (a microtubule inhibitor) against anaplastic thyroid carcinoma (ATC). In this study we reported the in vivo efficacy of this combination against ATC cells and the lack of toxicity of this treatment in mice. We observed that manumycin-treated tumors looked paler than both control and paclitaxel-treated tumors. We hypothesized that angiogenesis inhibition mediated part of the in vivo effect of manumycin. This hypothesis was supported by the findings that manumycin significantly inhibited angiogenesis (as directly demonstrated by measurement of hemoglobin content and vascular area) in Matrigel implanted into mice, that manumycin decreased the vascular endothelial growth factor in hypoxic ATC cells, and that both manumycin and paclitaxel inhibited endothelial cell proliferation. Interestingly, inhibition of endothelial tubule formation in Matrigel was enhanced by combining manumycin and paclitaxel. As angiogenesis and tumor growth are continuous processes, we investigated the effect of sustained delivery of manumycin and found that paclitaxel plus slow release manumycin (13.25 mg/kg x week) inhibited ATC xenografts more than paclitaxel plus intermittent manumycin (15 mg/kg x week). In conclusion, manumycin plus paclitaxel is an effective combination against ATC, and inhibition of angiogenesis plays a role in the antineoplastic effect of this combination.
我们实验室研究了联合使用马尼霉素（一种法尼基转移酶抑制剂）和紫杉醇（一种微管抑制剂）对间变性甲状腺癌（ATC）的抗癌作用。在本研究中，我们报告了该联合用药对ATC细胞的体内疗效以及该治疗方法在小鼠体内的无毒性。我们观察到，经马尼霉素处理的肿瘤比对照和经紫杉醇处理的肿瘤颜色更浅。我们推测血管生成抑制介导了马尼霉素的部分体内效应。这一假设得到了以下研究结果的支持：马尼霉素显著抑制植入小鼠体内的基质胶中的血管生成（通过测量血红蛋白含量和血管面积直接证明），马尼霉素降低缺氧ATC细胞中的血管内皮生长因子，以及马尼霉素和紫杉醇均抑制内皮细胞增殖。有趣的是，联合使用马尼霉素和紫杉醇可增强对基质胶中内皮小管形成的抑制作用。由于血管生成和肿瘤生长是连续的过程，我们研究了持续递送马尼霉素的效果，发现紫杉醇加缓释马尼霉素（13.25毫克/千克×周）比紫杉醇加间歇马尼霉素（15毫克/千克×周）更能抑制ATC异种移植瘤。总之，马尼霉素加紫杉醇是一种有效的抗ATC联合用药，血管生成抑制在该联合用药的抗肿瘤作用中发挥作用。
