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Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: A randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial†

  1. Rosemary A Hannon1,
  2. Glen Clack2,
  3. Martin Rimmer2,
  4. Alan Swaisland2,
  5. J Andrew Lockton2,
  6. Richard D Finkelman3,
  7. Richard Eastell1,*

Article first published online: 18 MAR 2010

DOI: 10.1359/jbmr.090830

Issue

Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Volume 25, Issue 3, pages 463–471, March 2010

Additional Information

How to Cite

Hannon, R. A., Clack, G., Rimmer, M., Swaisland, A., Lockton, J. A., Finkelman, R. D. and Eastell, R. (2010), Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: A randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J Bone Miner Res, 25: 463–471. doi: 10.1359/jbmr.090830

Author Information

  1. 1

    Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK

  2. 2

    AstraZeneca, Alderley Park, Macclesfield, UK

  3. 3

    AstraZeneca, Wilmington, Delaware

*Centre for Biomedical Research, Northern General Hospital, Sheffield, South Yorkshire S5 7AU, UK.

  1. †

    The data presented in this article were presented previously as an oral and poster presentations at the European Calcified Tissues and International Bone and Mineral Society Joint Meeting, Geneva, Switzerland, 25–29 June 2005; The Bone and Tooth Society Annual Meeting, Birmingham, UK, 4–5 July 2005; and the American Society of Bone and Mineral Research Annual Meeting, Nashville, TN, 23–27 September 2005.

Publication History

  1. Issue published online: 18 MAR 2010
  2. Article first published online: 18 MAR 2010
  3. Accepted manuscript online: 27 JAN 2010 12:00AM EST
  4. Manuscript Accepted: 27 AUG 2010
  5. Manuscript Revised: 7 JUL 2009
  6. Manuscript Received: 24 FEB 2009
Corrected by:

Errata: Erratum: Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: A randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial

Vol. 27, Issue 6, 1435, Article first published online: 17 MAY 2012

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References

  • 1
    Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003; 22: 337–358.
  • 2
    Horne WC, Sanjay A, Bruzzaniti A, et al. The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev. 2005; 208: 106–125.
    Direct Link:
  • 3
    Sanjay A, Houghton A, Neff L, et al. Cbl associates with Pyk2 and Src to regulate Src kinase activity, α(v)β(3) integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol. 2001; 152: 181–195.
  • 4
    Xing L, Venegas AM, Chen A, et al. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 2001; 15: 241–253.
  • 5
    Soriano P, Montgomery C, Geske R, et al. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991; 64: 693–702.
  • 6
    Boyce BF, Yoneda T, Lowe C, et al. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest. 1992; 90: 1622–1627.
  • 7
    Marzia M, Sims NA, Voit S, et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol. 2000; 151: 311–320.
  • 8
    Green TP, Fennell M, Whittaker R, et al. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol. 2009; 3: 248–261.
  • 9
    Li B, Boast S, de los Santos K, et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet. 2000; 24: 304–308.
  • 10
    de Vries TJ, Mullender MG, van Duin MA, et al. The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts. Mol Cancer Res. 2009; 7: 476–488.
  • 11
    Eastell R, Hannon RA, Gallagher N, et al. The effect of AZD0530, a highly selective, orally available Src/Abl kinase inhibitor, on biomarkers of bone resorption in healthy males [Abstract 3041]. J Clin Oncol. 2005; 23.
  • 12
    Lockton JA, Smethurst D, Macpherson M, et al. Phase I ascending single and multiple dose studies to assess the safety, tolerability and pharmacokinetics of AZD0530, a highly selective, dual-specific Src-Abl inhibitor [Abstract 3125]. Proc Am Soc Clin Oncol. 2005; 24.
  • 13
    Missbach M, Jeschke M, Feyen J, et al. A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo. Bone. 1999; 24: 437–449.
  • 14
    Rucci N, Recchia I, Angelucci A, et al. Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther. 2006; 318: 161–172.
  • 15
    Destaing O, Sanjay A, Itzstein C, et al. The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts. Mol Biol Cell. 2008; 19: 394–404.
  • 16
    Alatalo SL, Ivaska KK, Waguespack SG, et al. Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem. 2004; 50: 883–890.
  • 17
    Recchia I, Rucci N, Funari A, et al. Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-D]-pyrimidines induces osteoclast apoptosis in vivo and in vitro: involvement of ERK1/2 pathway. Bone. 2004; 34: 65–79.
  • 18
    Braga de Castro Machado A, Hannon R, Eastell R. Monitoring alendronate therapy for osteoporosis. J Bone Miner Res. 1999; 14: 602–608.
    Direct Link:
  • 19
    Schaller S, Henriksen K, Sveigaard C, et al. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res. 2004; 19: 1144–1153.
    Direct Link:
  • 20
    Karsdal MA, Neutzsky-Wulff AV, Dziegiel MH, et al. Osteoclasts secrete non-bone derived signals that induce bone formation. Biochem Biophys Res Commun. 2008; 366: 483–488.
  • 21
    Greenspan SL, Rosen HN, Parker RA. Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women. J Clin Endocrinol Metab. 2000; 85: 3537–3540.
  • 22
    Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003; 18: 1051–1056.
    Direct Link:
  • 23
    Boyce BF, Xing L, Shakespeare W, et al. Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases. Kidney Int. 2003; 85: S2–S5.
  • 24
    Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000; 19: 5636–5642.
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