Mechanism of paclitaxel activity in Kaposi's sarcoma

Kaposi's sarcoma (KS) is an angioproliferative disease characterized by pro liferation of spindle-shaped cells predominantly of endothelial cell origin , neoangiogenesis, inflammatory cell infiltration, and edema. At least in e arly stage, KS behaves as a reactive lesion sustained by the action of infl ammatory cytokines and growth factors, has a polyclonal nature, and can reg ress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increas ed expression of antiapoptotic oncogenes, We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spin dle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabiliz ing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly eff ective in the treatment of certain neoplasms, has recently been found to be active also in patients with advanced HIV-associated KS. Zn this report we investigated the mechanism(s) of paclitaxel activity in KS, By using a mod el of experimental KS induced by the inoculation of KS-derived spindle cell s in nude mice and primary cultures of KS spindle cells, we found that pacl itaxel promotes regression of RS lesions in vivo and that it blocks the gro wth, migration, and invasion of KS cells in vitro. Furthermore, paclitaxel treatment promoted apoptosis and down-regulated Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. Our results suggest that paclitaxel interferes with KS by down-regulating Bcl-2 antiapoptotic effec t.