TUHH Open Research
Help
  • Log In
    New user? Click here to register.Have you forgotten your password?
  • English
  • Deutsch
  • Communities & Collections
  • Publications
  • Research Data
  • People
  • Institutions
  • Projects
  • Statistics
  1. Home
  2. TUHH
  3. Publication References
  4. Pharmacologically inactive bisphosphonates as an alternative strategy for targeting osteoclasts: in vivo assessment of 5-fluorodeoxyuridine-alendronate in a preclinical model of breast cancer bone metastases
 
Options

Pharmacologically inactive bisphosphonates as an alternative strategy for targeting osteoclasts: in vivo assessment of 5-fluorodeoxyuridine-alendronate in a preclinical model of breast cancer bone metastases

Publikationstyp
Journal Article
Date Issued
2016-10-07
Author(s)
Schem, Christian  
Tower, Robert J.  
Kneissl, Philipp  
Rambow, Anna C.  
Campbell, Graeme Michael  
Desel, Christine  
Damm, Timo  
Heilmann, Thorsten  
Fuchs, Sabine  
Zuhayra, Maaz  
Trauzold, Anna  
Glüer, Claus Christian  
Schott, Sarah  
Tiwari, Sanjay  
Institut
Biomechanik M-3  
TORE-URI
http://hdl.handle.net/11420/4734
Journal
Journal of bone and mineral research  
Volume
32
Issue
3
Start Page
536
End Page
548
Citation
Journal of Bone and Mineral Research 3 (32): 536-548 (2017-03-01)
Publisher DOI
10.1002/jbmr.3012
Scopus ID
2-s2.0-84997719853
Publisher
Wiley
American Society for Bone and Mineral Research Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro–computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research.
Subjects
5-FDU-ALE
ANTIRESORPTIVES
BISPHOSPHONATES
BONE DISEASES
DDC Class
610: Medizin
More Funding Information
Financial support was provided by the Deutsche Forschungsgemeinschaft (DFG) through the Forschergruppe 1586 SKELMET and by the research grant from the state of Schleswig-Holstein and the European Union ERDF-European Regional Development Fund (MOIN CC, Zukunftsprogramm Wirtschaft) and by the medical faculty UK-SH, Campus Kiel (ST, F355922).
TUHH
Weiterführende Links
  • Contact
  • Send Feedback
  • Cookie settings
  • Privacy policy
  • Impress
DSpace Software

Built with DSpace-CRIS software - Extension maintained and optimized by 4Science
Design by effective webwork GmbH

  • Deutsche NationalbibliothekDeutsche Nationalbibliothek
  • ORCiD Member OrganizationORCiD Member Organization
  • DataCiteDataCite
  • Re3DataRe3Data
  • OpenDOAROpenDOAR
  • OpenAireOpenAire
  • BASE Bielefeld Academic Search EngineBASE Bielefeld Academic Search Engine
Feedback