Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a "humanized" SCID mouse model.
Paclitaxel is an alkaloid that inhibits endothelial cell proliferation, motility, and tube formation at nanomolar concentrations. Cationic liposome preparations have been shown to target blood vessels. We wished to explore the possibility that paclitaxel encapsulated in cationic liposomes carries paclitaxel to blood vessels and thereby provides an antiangiogenic effect. We used a humanized SCID mouse melanoma model, which allowed us to analyze tumor growth and tumor angiogenesis in an orthotopic tumor model. Here, human melanoma cells grow on human dermis and are in part nourished by human vessels. We show that paclitaxel encapsulated in liposomes prevents melanoma growth and invasiveness and improves survival of mice. Moreover, liposome-encapsulated paclitaxel reduces vessel density at the interface between the tumor and the human dermis and reduces endothelial cell mitosis to background levels. In contrast, equimolar concentrations of paclitaxel solubilized in Cremophor EL(R) had only insignificant effects on tumor growth and did not reduce the mitotic index of endothelium in vivo, although the antiproliferative effect of solubilized paclitaxel in Cremophor EL(R)in vitro was identical to that seen with liposome-coupled paclitaxel. In conclusion, we present a model of how to exploit cytotoxic effects of compounds to prevent tumor growth by using cationic liposomes for targeting an antiproliferative drug to blood vessels.
Kunstfeld
Rainer
R
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, Austria.
Wickenhauser
Georg
G
Michaelis
Uwe
U
Teifel
Michael
M
Umek
Wolfgang
W
Naujoks
Kurt
K
Wolff
Klaus
K
Petzelbauer
Peter
P
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002214:Capsules; D002412:Cations / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008940:Mitotic Index; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000098:blood supply* / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000473:pathology
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D002214:Capsules; D002412:Cations; D008081:Liposomes; D017239:Paclitaxel