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Angiogenesis Inhibition in the in Vivo Antineoplastic Effect of Manumycin and Paclitaxel against Anaplastic Thyroid Carcinoma¹

Section of Endocrine Neoplasia and Hormonal Disorders, Department of Internal Medicine Specialties (G.X., J.P., S.-C.J.Y.), and Section of General Internal Medicine, Department of Internal Medicine Specialties (C.M., S.-C.J.Y.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: S. Jim Yeung, M.D., Ph.D., University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 40, Houston, Texas 77030. E-mail: syeung{at}notes.mdacc.tmc.edu

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·week) inhibited ATC xenografts more than paclitaxel plus intermittent manumycin (15 mg/kg·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.

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