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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Amit Arora and Eric M. Scholar
Journal of Pharmacology and Experimental Therapeutics December 2005, 315 (3) 971-979; DOI: https://doi.org/10.1124/jpet.105.084145
Amit Arora
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Eric M. Scholar
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Abstract

Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review focuses on small molecule inhibitors of tyrosine kinase. They compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. They are orally active, small molecules that have a favorable safety profile and can be easily combined with other forms of chemotherapy or radiation therapy. Several tyrosine kinase inhibitors (TKIs) have been found to have effective antitumor activity and have been approved or are in clinical trials. The inhibitors discussed in this manuscript are imatinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SU11248), and leflunomide (SU101). TKIs are thus an important new class of targeted therapy that interfere with specific cell signaling pathways and thus allow target-specific therapy for selected malignancies. The pharmacological properties and anticancer activities of these inhibitors are discussed in this review. Use of these targeted therapies is not without limitations such as the development of resistance and the lack of tumor response in the general population. The availability of newer inhibitors and improved patient selection will help overcome these problems in the future.

Footnotes

  • doi:10.1124/jpet.105.084145.

  • ABBREVIATIONS: EGFR, epidermal growth factor receptor(s); HER, human epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor(s); PDGFR, platelet-derived growth factor receptor(s); Ph, Philadelphia chromosome; CML, chronic myeloid leukemia; ALL, acute lymphocytic leukemia; BMS-354825, N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide; GIST, gastrointestinal stromal tumor; VEGF, vascular endothelial growth factor; NSCLC, nonsmall cell lung cancer; TRIBUTE, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; TALENT, Tarceva Lung Cancer Investigation; FLK, fetal liver kinase; KDR, kinase domain region; PDGF, platelet-derived growth factor; INTACT, Iressa NSCLC Trial Assessing Combination Treatment.

    • Received January 25, 2005.
    • Accepted June 29, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Amit Arora and Eric M. Scholar
Journal of Pharmacology and Experimental Therapeutics December 1, 2005, 315 (3) 971-979; DOI: https://doi.org/10.1124/jpet.105.084145

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Amit Arora and Eric M. Scholar
Journal of Pharmacology and Experimental Therapeutics December 1, 2005, 315 (3) 971-979; DOI: https://doi.org/10.1124/jpet.105.084145
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