Docetaxel Versus Paclitaxel for Antiangiogenesis

Abstract

Cytoskeleton-toxic chemotherapeuticals, such as vinblastine and paclitaxel, display antiangiogenic activity. This study was designed to compare paclitaxel to its analog docetaxel and assess their doses still antiangiogenic in vitro and in vivo. Human endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, morphogenesis, and secretion of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) were studied in vitro upon exposure to docetaxel and paclitaxel, whereas their effect on angiogenesis was studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. Proliferation of mouse embryo fibroblasts and human Kaposi's sarcoma, breast and endometrial carcinoma, and lymphoid tumor cells was also studied. In vitro, 0.5, 0.75, and 1 nM docetaxel and 2, 3, and 4 nM paclitaxel, i.e., non-cytotoxic doses, impacted all endothelial cell functions, but not protease secretion, in a dose-dependent fashion, whereas they did not affect the proliferation of other cells, except those of Kaposi's sarcoma. No apoptosis was induced by 0.5 nM docetaxel and 2 nM paclitaxel, and moderate apoptosis was induced by 1 nM docetaxel and 4 nM paclitaxel. The antiangiogenic effect rapidly disappeared on drug suspension and was accompanied ultrastructurally by thin lesions of cytoskeleton in the form of slight and equally reversible depolymerization and accumulation of microfilaments. Massive endothelial cell apoptosis with evident cytotoxicity and irreversibility were associated with 2 nM docetaxel and 5 nM paclitaxel, although these higher doses were ineffective on other cells except Kaposi's sarcoma cells. In vivo, 1, 2, and 3 nM docetaxel and 4, 8, and 12 nM paclitaxel displayed a dose-dependent antiangiogenic activity. We suggest that very low docetaxel and paclitaxel doses selectively cause organic and functional damage of endothelial cells and that docetaxel is four times stronger. Their antiangiogenic activity could be applied to treat Kaposi's sarcoma and cancers.

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton

“…The taxane family of anticancer agents has been reported to possess antiangiogenic potential. When compared with paclitaxel, docetaxel inhibits angiogenesis more potently (4,6,27), but drug concentrations used in the experiments often inhibited endothelial cell proliferation as well. Hotchkiss et al (5) have been the first to highlight the potential of nontoxic docetaxel concentrations in angiogenesis inhibition.…”

Variation of Breast Vascular Maps on Dynamic Contrast-Enhanced MRI After Primary Chemotherapy of Locally Advanced Breast Cancer

“…Tumor angiogenesis and tumor vascular supply are key steps in tumor growth and the development of metastases; neoangiogenic peptides and the migration and proliferation of endothelial cells represent components critically involved in neoangiogenesis [27]. Taxanes are cytotoxic drugs capable of inhibiting cell mitosis and proliferation [28,29]. Preclinical studies have assessed that taxanes have strong antiangiogenic activity [8,9].…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…Interactions between these components determine the proliferation, migration and survival of plasma cells, as well as their acquisition of drug resistance and the development of diseases (Damiano et al, 1999;Hazlehurst et al, 2000Hazlehurst et al, , 2003. Receptors expressed by plasma cells, such as a V b3 integrin, are crucial for their relationships with each other (homotypic interrelationships) and with ECM proteins (Vacca et al, 2001). Very late activating antigen-4 (VLA-4), leukocyte function-associated antigen (LFA-1), mucin-1 antigen expressed by plasma cells, and vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expressed by BMSC mediate their heterotypic and homotypic interactions.…”