Combretastatin A4 Phosphate Has Primary Antineoplastic Activity Against Human Anaplastic Thyroid Carcinoma Cell Lines and Xenograft Tumors

Abstract

Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas

“…However, the t 1/2 of the slow clearance phase in this study was similar to the t 1/2 reported for 131 I-A5B7 in the original single agent phase I study (9). Another consideration is that CA4P, in common with other microtubule-binding agents, has independent direct cytotoxic activity (27)(28)(29) that may be additive or synergistic with radiation in inducing marrow toxicity. In a phase I trial in which CA4P was given 60 minutes after carboplatin, dose-limiting thrombocytopenia was reported for carboplatin AUC 5 mg min/mL with CA4P at a relatively low dose of 36 mg/m 2 (30).…”

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

“…Combretastatin A4 phosphate (CA4P) is a tubulin-binding agent that inhibits tumor blood flow at doses less than 10% of the maximum tolerated dose (10); its rapid, selective, and extensive inhibition of tumor blood flow makes it a promising novel anticancer drug (11). CA4P has antineoplastic activity against ATC cell lines and xenografts (12). In a phase I trial, CA4P, given iv every 3 wk, induced remission of ATC for 30 months in one patient (13).…”

Anaplastic thyroid cancer and primary thyroid lymphoma: A review of these rare thyroid malignancies

“…Further experimental treatment options being explored include combretastatin A4-phosphate (CA4P) and bone morphogenetic protein (BMP-7). Combretastatin is an effective antitumor vascular targeting agent currently in phase I trials [58,59]. Bone morphogenetic protein (BMP-7) significantly inhibits tumor growth in four of six human ATC cell lines [60].…”