The Preclinical Bases of the Rational Combination of Paclitaxel and Antiangiogenic Drugs
Antonello Di Paolo, Guido Bocci and Romano Danesi
Affiliation: Department of Clinical and Exprimental Medicine, Via Roma 55, 56126 Pisa – Italy.
Keywords: Angiogenesis, angiopoietin-1, antiangiogenic drugs, bevacizumab, cediranib, celecoxib, cetuximab, gefitinib, lapatinib,
matrix metalloproteinases, monoclonal antibodies, paclitaxel, preclinical studies, receptor tyrosine-kinases, sorafenib,
thrombospondin-1, TNP-470, trastuzumab, vandetanib, vascular endothelial growth factor.
In the present review we report the preclinical development of paclitaxel-based combination treatment with
antiangiogenic drugs and their translation into clinical practice. A particular attention is paid to the mechanisms by which
an interaction between paclitaxel and antiangiogenic drugs may be advocated. In mid ‘90s, the discovery of the antiangiogenic
properties of paclitaxel has widened the possible uses of the drug for the treatment of solid tumors. In fact, paclitaxel
is able to negatively modulate vascular endothelial growth factor (VEGF) and angiopoietin-1 expression, whereas
the drug may induce an increased expression of the antiangiogenic endogenous modulator thrombospondin-1. On the basis
of these discoveries, several promising antiangiogenic treatments have been identified in preclinical models, in which
paclitaxel has been administered together with direct antiangiogenic drugs (i.e., bevacizumab and vandetanib). In other
cases, the paclitaxel-based combination included inhibitors of those mediators whose activity is associated with and supports
neovessel formation, such as matrix metalloproteinases, cyclooxygenase-2 and endothelin-1. The synergistic cytotoxic
effect of combined treatments may depend on the capability of paclitaxel to inhibit both tissue invasion by tumors
(i.e., antagonizing matrix metallo-proteinase activity) and secretion of pro-angiogenic mediators (i.e., VEGF) through an
antagonistic effect of the taxane against endothelin-1/endothelin A receptor. Some of these combination treatments have
not yet (or will not) reach clinical studies and the therapeutic armamentarium, despite the promising results achieved in
preclinical models. However, they may play a role as proof-of-concept in the growing knowledge and interest in the
mechanism by which we can modulate or halt angiogenic processes driven by tumors.
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