Taxane-based
therapies appear to have a significant efficacy in clinical trials on
hormone-refractory prostate
carcinoma. In the present study, we investigated the cellular response of
androgen-independent prostate
carcinoma cell lines to the novel
taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new
paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by
oral administration. Upon treatment, DU145 and PC3 prostate
carcinoma cell lines underwent a transient mitotic arrest. This was followed by G1 arrest and rapid occurrence of apoptosis in DU145 cells, whereas in PC3 cells, which are defective for the postmitotic checkpoint, a slow cell death was preceded by
DNA endoreduplication. At the biochemical level, such events were associated with
tubulin polymerization, activation of the
mitosis-promoting factor, and phosphorylation of Bcl-X(L)/Bcl-2/Raf-1. In addition,
IDN 5109 shared with PTX the ability to down-regulate the expression of the two potent angiogenic factors
vascular endothelial growth factor and
basic fibroblast growth factor. These findings indicated that
IDN 5109 affected the same pathways involved in the cellular response to PTX and suggested that an antiangiogenic effect mediated by inhibition of paracrine stimulation of endothelial cells might contribute to the antitumor effect of both drugs. In in vivo experiments, the new
taxane displayed a superior and more persistent effect compared with PTX against DU145
tumor xenografts. Such an effect was associated with pronounced reduction of the
tumor microvessel density, superior to that achieved by PTX. These results support a potential therapeutic advantage of
IDN 5109 over PTX against
hormone-refractory prostate
carcinoma.