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Eur J Cancer. 2002 Sep;38 Suppl 5:S28-36.

Pharmacology of imatinib (STI571).

Author information

1
Oncology Research Department, Novartis Pharma AG, CH-4002 Basel, Switzerland. Elisabeth.buchdunger@pharma.novartis.com

Abstract

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.

PMID:
12528770
DOI:
10.1016/s0959-8049(02)80600-1
[Indexed for MEDLINE]

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