title: Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, Preclinical Chemotherapy and Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20139 Milan, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Diletta
authors.initials: D
authors.lastname: Laccabue
authors.forename: Giuditta
authors.initials: G
authors.lastname: Cuccuru
authors.forename: Ezio
authors.initials: E
authors.lastname: Bombardelli
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D016200:Maturation-Promoting Factor / Q000378:metabolism; D008938:Mitosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013347:Subcellular Fractions; D043823:Taxoids; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001952:Bridged-Ring Compounds; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D014404:Tubulin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; C404743:IDN 5109; D019908:Proto-Oncogene Proteins c-raf; D016203:CDC2 Protein Kinase; D016200:Maturation-Promoting Factor; D017239:Paclitaxel