Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma

Our laboratory has investigated the anticancer effects of combined manumyci n (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 tox icity of this treatment in mice. We observed that manumycin-treated tumors looked paler than both control and paclitaxel-treated tumors. We hypothesiz ed that angiogenesis inhibition mediated part of the in vivo effect of manu mycin. This hypothesis was supported by the findings that manumycin signifi cantly inhibited angiogenesis las directly demonstrated by measurement of h emoglobin content and vascular area) in Matrigel implanted into mice, that manumycin decreased the vascular endothelial growth factor in hypoxic ATC c ells, and that both manumycin and paclitaxel inhibited endothelial cell pro liferation. Interestingly, inhibition of endothelial tubule formation in Ma trigel was enhanced by combining manumycin and paclitaxel. As angiogenesis and tumor growth are continuous processes, we investigated the effect of su stained delivery of manumycin and found that paclitaxel plus slow release m anumycin (13.25(.)mg/kg week) inhibited ATC xenografts more than paclitaxel plus intermittent manumycin (15 mg/kg(.)week). In conclusion, manumycin pl us paclitaxel is an effective combination against ATC, and inhibition of an giogenesis plays a role in the antineoplastic effect of this combination.