Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571.

Abstract

PURPOSE:

Osteosarcoma is an aggressive primary bone cancer characterized by expression of platelet-derived growth factor (PDGF) and its cognate receptor. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. It has been reported previously that STI571 has specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Osteosarcomas express low levels of c-Kit but abundant levels of PDGF receptor (PDGFR).

EXPERIMENTAL DESIGN:

To investigate the potential of STI571 as therapy for osteosarcoma, we studied its effects on PDGF-mediated cell growth in vitro and in an in vivo mouse model.

RESULTS:

PDGF acted as a potent mitogen in a dose-dependent manner in two osteosarcoma cell lines. STI571 (1.0 micro M) inhibited both PDGFR-alpha and PDGFR-beta phosphorylation and the downstream phosphorylation targets extracellular signal-regulated kinase and Akt. STI571 also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. To study the effect of STI571 alone or in combination with Taxol in an in vivo model, an osteosarcoma cell line (KRIB) was transplanted into the tibia of athymic nude mice. Mice were treated with STI571 (50 mg/kg p.o. q M-F), Taxol (8 mg/kg i.p. weekly), or STI571 plus Taxol for 6 weeks. There was no significant difference in tumor size between treatment and control mice. Aberrant signaling pathways downstream of the PDGFR in the v-Ki-ras oncogene-transformed KRIB cell line may in part explain this finding.

CONCLUSIONS:

Our data demonstrate that STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells in vitro by selective inhibition of the PDGFR tyrosine kinase. The effectiveness of STI571 in our studies suggests targeting of PDGFRs as a novel treatment for osteosarcoma.

• Authors: Eric C McGary, Kristy Weber, Lisa Mills, Michelle Doucet, Valerie Lewis, Dina Chelouche Lev, Isaiah J Fidler, Menashe Bar-Eli
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 11 Pg. 3584-91 (Nov 2002) ISSN: 1078-0432 [Print] United States
• PMID: 12429650 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Piperazines
• Platelet-Derived Growth Factor
• Pyrimidines
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-kit
• Receptors, Platelet-Derived Growth Factor
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Blotting, Western
• Bone Neoplasms (metabolism, pathology)
• Cell Division
• Cell Line, Transformed
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Imatinib Mesylate
• In Situ Nick-End Labeling
• Mice
• Neoplasm Transplantation
• Osteosarcoma (drug therapy, metabolism)
• Paclitaxel (pharmacology)
• Phosphorylation
• Piperazines (pharmacology)
• Platelet-Derived Growth Factor (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-kit (metabolism)
• Pyrimidines (pharmacology)
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Signal Transduction
• Tibia (metabolism)
• Time Factors
• Tumor Cells, Cultured