Abstract | PURPOSE: EXPERIMENTAL DESIGN: RESULTS: PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival. CONCLUSIONS: Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.
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Authors | Josep Domingo-Domenech, Cristina Oliva, Ana Rovira, Jordi Codony-Servat, Marta Bosch, Xavier Filella, Clara Montagut, Marian Tapia, Clara Campás, Lenny Dang, Mark Rolfe, Jeffrey S Ross, Pere Gascon, Joan Albanell, Begoña Mellado |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 18
Pg. 5578-86
(Sep 15 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 17000695
(Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Heterocyclic Compounds, 3-Ring
- Interleukin-6
- NF-kappa B
- PS1145
- Pyridines
- Taxoids
- Docetaxel
- Prostate-Specific Antigen
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Topics |
- Aged
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Bone Neoplasms
(drug therapy)
- Cell Survival
- Disease Progression
- Docetaxel
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
- Drug Resistance, Neoplasm
(physiology)
- Drug Synergism
- Heterocyclic Compounds, 3-Ring
(pharmacology, therapeutic use)
- Humans
- Interleukin-6
(biosynthesis, blood, physiology)
- Lymph Nodes
- Male
- Middle Aged
- NF-kappa B
(antagonists & inhibitors, metabolism)
- Neoplasm Metastasis
(drug therapy)
- Prognosis
- Prostate-Specific Antigen
(analysis)
- Prostatic Neoplasms
(drug therapy, mortality, secondary)
- Pyridines
(pharmacology, therapeutic use)
- Statistics as Topic
- Survival Analysis
- Taxoids
(therapeutic use)
- Tumor Cells, Cultured
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