Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/77991
Title:
Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer.
Authors:
Montague, Richard J; Hart, Claire A; George, Nicholas J; Ramani, Vijay A C; Brown, Michael D; Clarke, Noel W ( 0000-0001-7776-8059 )
Abstract:
OBJECTIVES: To determine the mode of action of Zoledronic acid in the inhibition of metastasis in prostate cancer and the reduction of prostate cancer bone metastases. METHODS: Benign and malignant primary prostatic epithelial cells (PEC) and the PC-3 prostate cancer cell line were studied in co-culture using human bone marrow stroma in the presence of escalating doses of EDTA, Clodronate, Pamidronate and Zoledronic acid. PEC binding and colony growth in bone marrow stroma was measured using standardised quantitative techniques. PEC cellular invasion through Matrigel and an endothelial monolayer was measured either in invasion chambers or by the measurement of endothelial monolayer permeability to fluorescent dextran. Co-culture supernatants were assayed for specific cytokine levels. Bone marrow cellular toxicity was assessed using a standard Mix assay. RESULTS: Treatment of PEC with up to 100 microM bisphosphonate did not affect their ability to bind to bone marrow endothelium or stroma. Bone marrow endothelial permeability was reduced by 100 microM Zoledronic acid by 3.8% (p = 0.03856). Both Pamidronate (40% at 100 microM, p < or = 0.05) and Zoledronic acid inhibited PEC invasion, with Zoledronic acid being the most potent (40% at 10 microM, p < or = 0.05 rising to 91% at 100 microM, p < or = 0.001). Zoledronic acid inhibits malignant PEC proliferation in bone marrow stroma co-culture (26.5% at 10 microM rising to 66.5% at 40 microM). This was accompanied by changes within the cytokine milieu with a >800% rise in TIMP-2. CONCLUSION: Zoledronic acid is a potent inhibitor of PEC invasion across bone marrow endothelium and colony formation with the bone marrow stroma, affecting the MMP: TIMP-2 balance to favour MMP inhibition.
Affiliation:
Genito-Urinary Cancer Research Group, Kay Kendall Laboratory, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK.
Citation:
Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer. 2004, 46 (3):389-401; discussion 401-2 Eur. Urol.
Journal:
European Urology
Issue Date:
Sep-2004
URI:
http://hdl.handle.net/10541/77991
DOI:
10.1016/j.eururo.2004.04.022
PubMed ID:
15306113
Type:
Article
Language:
en
ISSN:
0302-2838
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMontague, Richard J-
dc.contributor.authorHart, Claire A-
dc.contributor.authorGeorge, Nicholas J-
dc.contributor.authorRamani, Vijay A C-
dc.contributor.authorBrown, Michael D-
dc.contributor.authorClarke, Noel W-
dc.date.accessioned2009-08-20T10:59:23Z-
dc.date.available2009-08-20T10:59:23Z-
dc.date.issued2004-09-
dc.identifier.citationDifferential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer. 2004, 46 (3):389-401; discussion 401-2 Eur. Urol.en
dc.identifier.issn0302-2838-
dc.identifier.pmid15306113-
dc.identifier.doi10.1016/j.eururo.2004.04.022-
dc.identifier.urihttp://hdl.handle.net/10541/77991-
dc.description.abstractOBJECTIVES: To determine the mode of action of Zoledronic acid in the inhibition of metastasis in prostate cancer and the reduction of prostate cancer bone metastases. METHODS: Benign and malignant primary prostatic epithelial cells (PEC) and the PC-3 prostate cancer cell line were studied in co-culture using human bone marrow stroma in the presence of escalating doses of EDTA, Clodronate, Pamidronate and Zoledronic acid. PEC binding and colony growth in bone marrow stroma was measured using standardised quantitative techniques. PEC cellular invasion through Matrigel and an endothelial monolayer was measured either in invasion chambers or by the measurement of endothelial monolayer permeability to fluorescent dextran. Co-culture supernatants were assayed for specific cytokine levels. Bone marrow cellular toxicity was assessed using a standard Mix assay. RESULTS: Treatment of PEC with up to 100 microM bisphosphonate did not affect their ability to bind to bone marrow endothelium or stroma. Bone marrow endothelial permeability was reduced by 100 microM Zoledronic acid by 3.8% (p = 0.03856). Both Pamidronate (40% at 100 microM, p < or = 0.05) and Zoledronic acid inhibited PEC invasion, with Zoledronic acid being the most potent (40% at 10 microM, p < or = 0.05 rising to 91% at 100 microM, p < or = 0.001). Zoledronic acid inhibits malignant PEC proliferation in bone marrow stroma co-culture (26.5% at 10 microM rising to 66.5% at 40 microM). This was accompanied by changes within the cytokine milieu with a >800% rise in TIMP-2. CONCLUSION: Zoledronic acid is a potent inhibitor of PEC invasion across bone marrow endothelium and colony formation with the bone marrow stroma, affecting the MMP: TIMP-2 balance to favour MMP inhibition.en
dc.language.isoenen
dc.subjectBone Canceren
dc.subjectCell Line Tumouren
dc.subjectCancer Invasivenessen
dc.subjectCancer Metastasisen
dc.subjectProstatic Canceren
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBone Neoplasms-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDiphosphonates-
dc.subject.meshEpithelial Cells-
dc.subject.meshHumans-
dc.subject.meshImidazoles-
dc.subject.meshMale-
dc.subject.meshMatrix Metalloproteinases-
dc.subject.meshNeoplasm Invasiveness-
dc.subject.meshNeoplasm Metastasis-
dc.subject.meshProstatic Neoplasms-
dc.titleDifferential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer.en
dc.typeArticleen
dc.contributor.departmentGenito-Urinary Cancer Research Group, Kay Kendall Laboratory, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK.en
dc.identifier.journalEuropean Urologyen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.