Comparison of antiangiogenic activities using paclitaxel (taxol) and docetaxel (taxotere).
Tumor growth requires a competent vascular supply and angiogenesis has been considered as a potential target for the treatment of several cancers. The two clinically approved taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials. Both taxanes have demonstrated significant activity against many solid tumors, but little is known about the effect of paclitaxel and docetaxel on endothelial cell function and angiogenic processes. The purpose of our study was to examine and compare the effects of these drugs on angiogenic processes in vitro and in vivo. These processes include: proliferation, migration and differentiation of cultured human umbilical vein endothelial cells (HUVEC) (in vitro), capillary sprouting of rat aortic ring explants (ex vivo) and HT1080 tumor growth in vivo. Our results demonstrate that endothelial cells are 10-100-fold more sensitive to these drugs than tumor cells. Additionally, comparison of the taxanes demonstrated that angiogenesis is blocked by both drugs primarily via inhibition of proliferation and differentiation (tube assay) and induction of cell death. Docetaxel, however, appears to be more potent at inhibiting angiogenesis, with an IC(50) concentration 10x less than that of paclitaxel. We conclude that these important findings should be taken in account in clinical trials where tumor angiogenesis is being targeted.
Grant
Derrick S
DS
Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5097, USA.
Williams
Torian L
TL
Zahaczewsky
Michael
M
Dicker
Adam P
AP
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000648:ultrastructure; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation; D014471:Umbilical Veins / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel