Pharmacology of imatinib (STI571)

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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.

References (58)

  • J Lasota et al.

    Mutations in exons 9 and 13 of kit gene are rare events in gastrointestinal stromal tumors

    Am J Pathol

    (2000)
  • ML Lux et al.

    Kit extracellular and kinase domain mutations in gastrointestinal stromal tumors

    Am J Pathol

    (2000)
  • DR Robinson et al.

    The protein tyrosine kinase family of the human genome

    Oncogene

    (2000)
  • FA Al-Obeidi et al.

    The protein tyrosine kinase family of the human genome

    Oncogene

    (2000)
  • E Buchdunger et al.

    Effects of a selective inhibitor of the Abl tyrosine-kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative

    Cancer Res

    (1996)
  • Jb Druker et al.

    Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells

    Nat Med

    (1996)
  • BJ Druker et al.

    Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia

    New Engl J Med

    (2001)
  • CD Blanke et al.

    Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients with unresectable or metatstatic gastrointestinal tumors (GSIT), and EORTC Phase I study

  • AT Van Oosterom et al.

    STI571, an active drug in metastatic gastrointestinal stromal tumors (GIST), an EORTC Phase I study

  • E Buchdunger et al.

    Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors

    J Pharmacol Exp Ther

    (2000)
  • M Uutela et al.

    Chromosomal location, exon structure and vascular expression patterns of the human PDGFC and PDGFD genes

    Circulation

    (2001)
  • T Kilic et al.

    Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyridine class

    Cancer Res

    (2000)
  • M Hermanson et al.

    Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops

    Cancer Res

    (1992)
  • A Guha et al.

    Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop

    Int J Cancer

    (1995)
  • L Uhrborn et al.

    Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus

    Cancer Res

    (1998)
  • J Vassbotn et al.

    Reversion of autocrine transformation by a dominant negative platelet-derived growth factor mutant

    Mol Cell Biol

    (1993)
  • SM Shamah et al.

    Dominant negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells

    Mol Cell Biol

    (1993)
  • CH Heldin et al.
  • A Shimizu et al.

    The dermatofibrosarcoma protuberans-associated collagen type 1alpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB

    Cancer Res

    (1999)
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