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Clin Cancer Res. 2014 Jun 1;20(11):2922-32. doi: 10.1158/1078-0432.CCR-13-1246. Epub 2014 Mar 31.

Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo.

Author information

1
Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia P.D.Ottewell@sheffield.ac.uk.
2
Authors' Affiliations: Academic Unit of Clinical Oncology, Department of Oncology, Academic Unit of Bone Biology, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom; and Musculoskeletal Medicine Division, Garvan Institute of Medical Research, Sidney, New South Wales, Australia.

Abstract

PURPOSE:

Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings.

EXPERIMENTAL DESIGN:

Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy.

RESULTS:

OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups.

CONCLUSIONS:

This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. ©2014 AACR.

PMID:
24687923
PMCID:
PMC4040234
DOI:
10.1158/1078-0432.CCR-13-1246
[Indexed for MEDLINE]
Free PMC Article

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