Kunstfeld Rainer, Wickenhauser Georg, Michaelis Uwe, Teifel Michael, Umek Wolfgang, Naujoks Kurt, Wolff Klaus, Petzelbauer Peter
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, Austria.
J Invest Dermatol. 2003 Mar;120(3):476-82. doi: 10.1046/j.1523-1747.2003.12057.x.
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.
紫杉醇是一种生物碱，在纳摩尔浓度下可抑制内皮细胞增殖、运动及血管生成。阳离子脂质体制剂已被证明可靶向血管。我们希望探究包裹在阳离子脂质体中的紫杉醇是否能将其携带至血管，从而产生抗血管生成作用。我们使用了人源化SCID小鼠黑色素瘤模型，该模型使我们能够在原位肿瘤模型中分析肿瘤生长和肿瘤血管生成。在此模型中，人黑色素瘤细胞在人真皮上生长，部分由人体血管提供营养。我们发现，包裹在脂质体中的紫杉醇可抑制黑色素瘤生长和侵袭，并提高小鼠存活率。此外，脂质体包裹的紫杉醇可降低肿瘤与人真皮界面处的血管密度，并将内皮细胞有丝分裂减少至背景水平。相比之下，等摩尔浓度的溶解在聚氧乙烯蓖麻油中的紫杉醇对肿瘤生长的影响微不足道，且在体内并未降低内皮细胞的有丝分裂指数，尽管溶解在聚氧乙烯蓖麻油中的紫杉醇在体外的抗增殖作用与脂质体偶联的紫杉醇相同。总之，我们展示了一种利用化合物的细胞毒性作用来预防肿瘤生长的模型，即通过使用阳离子脂质体将抗增殖药物靶向血管。
