Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer

Giuliana Cassinelli, Cinzia Lanzi, Rosanna Supino, Graziella Pratesi, Valentina Zuco, Diletta Laccabue, Giuditta Cuccuru, Ezio Bombardelli, Franco Zunino

Research output: Contribution to journalArticle

35 Citations (Scopus)

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-XL/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.

Original languageEnglish
Pages (from-to)2647-2654
Number of pages8
JournalClinical Cancer Research
Volume8
Issue number8
Publication statusPublished - 2002

Fingerprint

Paclitaxel
Prostatic Neoplasms
Hormones
Prostate
Carcinoma
Maturation-Promoting Factor
Endoreduplication
Cell Line
Angiogenesis Inducing Agents
Multiple Drug Resistance
Fibroblast Growth Factor 2
Tubulin
Microvessels
Heterografts
Polymerization
Vascular Endothelial Growth Factor A
Androgens
Oral Administration
IDN 5109
taxane

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cassinelli, G., Lanzi, C., Supino, R., Pratesi, G., Zuco, V., Laccabue, D., ... Zunino, F. (2002). Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer. Clinical Cancer Research, 8(8), 2647-2654.

Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer. / Cassinelli, Giuliana; Lanzi, Cinzia; Supino, Rosanna; Pratesi, Graziella; Zuco, Valentina; Laccabue, Diletta; Cuccuru, Giuditta; Bombardelli, Ezio; Zunino, Franco.

In: Clinical Cancer Research, Vol. 8, No. 8, 2002, p. 2647-2654.

Research output: Contribution to journalArticle

Cassinelli, G, Lanzi, C, Supino, R, Pratesi, G, Zuco, V, Laccabue, D, Cuccuru, G, Bombardelli, E & Zunino, F 2002, 'Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer', Clinical Cancer Research, vol. 8, no. 8, pp. 2647-2654.
Cassinelli, Giuliana ; Lanzi, Cinzia ; Supino, Rosanna ; Pratesi, Graziella ; Zuco, Valentina ; Laccabue, Diletta ; Cuccuru, Giuditta ; Bombardelli, Ezio ; Zunino, Franco. / Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 8. pp. 2647-2654.
@article{63d82152551f49548c13768fc4c00b0a,
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-XL/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.",
author = "Giuliana Cassinelli and Cinzia Lanzi and Rosanna Supino and Graziella Pratesi and Valentina Zuco and Diletta Laccabue and Giuditta Cuccuru and Ezio Bombardelli and Franco Zunino",
year = "2002",
language = "English",
volume = "8",
pages = "2647--2654",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer

AU - Cassinelli, Giuliana

AU - Lanzi, Cinzia

AU - Supino, Rosanna

AU - Pratesi, Graziella

AU - Zuco, Valentina

AU - Laccabue, Diletta

AU - Cuccuru, Giuditta

AU - Bombardelli, Ezio

AU - Zunino, Franco

PY - 2002

Y1 - 2002

N2 - 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-XL/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.

AB - 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-XL/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.

UR - http://www.scopus.com/inward/record.url?scp=0036023432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036023432&partnerID=8YFLogxK

M3 - Article

VL - 8

SP - 2647

EP - 2654

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 8

ER -