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The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice

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Abstract

The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.

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Abbreviations

BLI:

bioluminescent imaging

IP:

intraperitoneal

Luc:

luciferase

OPG:

osteoprotegerin

PTHrP:

parathyroid hormone-related protein

SCC:

squamous cell carcinoma

SQ:

subcutaneous

TAB:

tumor-associated bone

TRAcP:

tartrate-resistant acid phosphatase

YFP:

yellow-fluorescent protein

ZOL:

zoledronic acid

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Acknowledgements

We would like to acknowledge Jeff Pan and Soledad Fernandez for statistical assistance, Tim Vojt for preparation of figures, Ann Saulsbery and Alan Flechtner for histotechnology support, University laboratory animal resources staff for animal care assistance, and Guangchun He and Drs. Gwendolyn Lorch, Ramiro Toribio, Alex Luchin, Nanda Thudi, Xiyun Deng, Jun Liu for laboratory support. Dr. Toribio also assisted with the statistical analysis. This work was supported by the National Institutes of Health, National Cancer Institute (K08 CA83766 for STG and R01 CA77911 for TJR) and the National Center for Research Resources (K26 RR00168 and S10 RR17841 for TJR).

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Authors and Affiliations

  1. Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Evansville, IN, USA

    S. H. Tannehill-Gregg

  2. Department of Veterinary Biosciences, The Ohio State University, 307 Goss Laboratory, 1925 Coffey Road, Columbus, OH, USA

    A. L. Levine, M. V. P. Nadella & T. J. Rosol

  3. Shikoku Cancer Center, Matsuyama, Japan

    H. Iguchi

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  1. S. H. Tannehill-Gregg
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  2. A. L. Levine
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  3. M. V. P. Nadella
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  4. H. Iguchi
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  5. T. J. Rosol
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Correspondence to T. J. Rosol.

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Tannehill-Gregg, S.H., Levine, A.L., Nadella, M.V.P. et al. The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice. Clin Exp Metastasis 23, 19–31 (2006). https://doi.org/10.1007/s10585-006-9008-z

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  • DOI: https://doi.org/10.1007/s10585-006-9008-z

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