Addition of receptor tyrosine kinase inhibitor to radiation increases tumour control in an orthotopic murine model of breast cancer metastasis in bone

Pawel Zwolak, Piotr Jasinski, Kaoru Terai, Nathan J. Gallus, Marna E. Ericson, Denis R. Clohisy, Arkadiusz Z. Dudek

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The receptor tyrosine kinase inhibitor, SU11248, was added to localised radiation to evaluate the response of bone metastases and to define the basic mechanism of radiosensitisation. Treatment with SU11248 and radiation was assessed in vitro using cultured 4T1 breast cancer cells and in vivo using an orthotopic 4T1 murine mammary tumour model of breast cancer bone metastasis. Cultured 4T1 cells treated with SU11248 (1 μM) and radiation (10 Gy) showed an almost 7.5-fold increase in caspase-mediated apoptosis after 24 h of incubation, compared to either treatment alone. Mice treated with SU11248 (40 mg/kg/daily) and radiation (15 Gy/single-dose) had a relatively greater reduction in tumour growth, bone osteolysis, osteoclast maturation and microvessel density. Combined modality treatment resulted in improvements in behavioural pain assessment scores and normalisation of neurochemical changes in the spinal cord receiving primary afferent innervation from tumour-bearing femora. Our study demonstrates that SU11248 enhances the radiation control of metastatic breast tumours in bone and tumour-induced pain.

Original languageEnglish (US)
Pages (from-to)2506-2517
Number of pages12
JournalEuropean Journal of Cancer
Volume44
Issue number16
DOIs
StatePublished - Nov 2008

Bibliographical note

Funding Information:
The authors would like to thank Michael Franklin for editorial support. We would like to acknowledge the use of confocal microscope made available through an NCRR Shared Instrumentation Grant (No. 1 S10 RR16851).

Keywords

  • Bone cancer pain
  • Metastatic bone cancer
  • Radiation
  • Ras inhibition
  • SU11248

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