Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model.
BACKGROUND
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.


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


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


METHODS
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.
Yeung
Sai-Ching J
SC
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. syeung@mdanderson.org
She
Miaorong
M
Yang
Huiling
H
Pan
Jingxuan
J
Sun
Lily
L
Chaplin
David
D
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D016190:Carboplatin / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D048430:Cell Shape; D042783:Endothelial Cells / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage; D011090:Polyenes / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use; D013267:Stilbenes / Q000008:administration & dosage; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D013267:Stilbenes; D016190:Carboplatin; D001973:Bromodeoxyuridine; C058728:fosbretabulin; C054474:manumycin; D017239:Paclitaxel