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Combination Chemotherapy Including Combretastatin A4 Phosphate and Paclitaxel Is Effective against Anaplastic Thyroid Cancer in a Nude Mouse Xenograft Model

Departments of Endocrine Neoplasia and Hormonal Disorders (S.-C.J.Y.) and General Internal Medicine, Ambulatory Treatment, and Emergency Care (L.S., S.-C.J.Y.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Hematology (M.S.), Guangdong Provincial People’s Hospital, Guangzhou, 510089 People’s Republic of China; Department of Pathophysiology (H.Y., J.P.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510089 People’s Republic of China; and Oxigene, Inc. (D.C.), Waltham, Massachusetts 02451

Address all correspondence and requests for reprints to: Sai-Ching Jim Yeung, M.D., Ph.D., The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030. E-mail: syeung{at}mdanderson.org.

Context: 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.

Objective: We hypothesized that a triple-drug combination including CA4P and paclitaxel would improve efficacy against ATC. Therefore, we evaluated two such combinations in vivo.

Setting: We used a nude mouse xenograft model with ARO and KAT-4 cells.

Interventions: The first combination consisted of CA4P, paclitaxel, and manumycin A (a farnesyltransferase inhibitor), and the second, CA4P, paclitaxel, and carboplatin.

Main Outcome Measures: Main outcome measures included tumor growth curves and tumor weights.

Results: 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.

Conclusions: 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.