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Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma

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Abstract

Feline vaccine-associated sarcoma (VAS) is a biologically aggressive soft-tissue sarcoma that can develop at sites where inactivated feline vaccines have been administered. We showed that platelet-derived growth factor (PDGF) and its receptor (PDGFR) play a role in the growth of VAS cells. The presence of PDGFR-β was confirmed in each of five VAS cell lines evaluated, one non-vaccine-associated feline fibrosarcoma (FSA) cell line and a feline fibroblast-derived cell line. The PDGF/PDGFR signaling pathway was inhibited in the VAS cell lines and the FSA cell line using the tyrosine kinase inhibitor imatinib mesylate (formerly called STI-571). Imatinib inhibited PDGF-BB-induced autophosphorylation of PDGFR in VAS cells and feline FSA cells in vitro in a dose-dependent manner. Imatinib also significantly inhibited growth of feline VAS tumors in a murine xenograft model. Imatinib reversed the protective effect of PDGF-BB on growth inhibition by doxorubicin and carboplatin. PDGF-BB protected VAS cells from serum starvation and doxorubicin-induced apoptosis but not carboplatin-induced apoptosis, and imatinib eliminated this protection. These observations suggest that imatinib inhibits PDGFR tyrosine kinase activity in feline soft tissue sarcomas in vitro and inhibits tumor growth in a xenograft model.

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Abbreviations

C/10:

Complete minimal essential medium supplemented with 10% FBS

CPT:

Carboplatin

DOX:

Doxorubicin

EGF:

Epidermal growth factor

FBS:

Fetal bovine serum

FSA:

Fibrosarcoma

HGF:

Hepatocyte growth factor

IGF-1:

Insulin-like growth factor-1

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

PI:

Propidium iodide

VAS:

Vaccine-associated sarcoma

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Authors and Affiliations

  1. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive West, Madison, WI 53706, USA

    Rieko Katayama, Michael K. Huelsmeyer, Amanda K. Marr, Ilene D. Kurzman, Douglas H. Thamm & David M. Vail

  2. The Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA

    Ilene D. Kurzman, Douglas H. Thamm & David M. Vail

Authors
  1. Rieko Katayama
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  2. Michael K. Huelsmeyer
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  3. Amanda K. Marr
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  4. Ilene D. Kurzman
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  5. Douglas H. Thamm
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  6. David M. Vail
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Corresponding author

Correspondence to David M. Vail.

Additional information

This work was supported in part by the American Veterinary Medical Association Feline Sarcoma Task Force. Imatinib mesylate was provided by Novartis Pharmaceuticals, Inc.

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Katayama, R., Huelsmeyer, M.K., Marr, A.K. et al. Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. Cancer Chemother Pharmacol 54, 25–33 (2004). https://doi.org/10.1007/s00280-004-0780-7

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