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      Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate

      review-article
      ,
      Therapeutics and Clinical Risk Management
      Dove Medical Press
      imatinib, STI-571, GIST, gastrointestinal, stromal, tumor

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          Abstract

          Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.

          Most cited references109

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          PDGFRA activating mutations in gastrointestinal stromal tumors.

          Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
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            Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

            The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
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              Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.

              Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                February 2008
                February 2008
                : 4
                : 1
                : 149-162
                Affiliations
                Academic Department of Clinical Oncology, University of Sheffield Weston Park Hospital, Sheffield, UK
                Author notes
                Correspondence: Omar Din Weston Park Hospital, Whitham Road, Sheffield, UK S10 2SJ Tel +1 0114 2265000 Email omarsdin@ 123456hotmail.com
                Article
                10.2147/TCRM.S1526
                2503651
                18728705
                1064d2d8-c353-45fc-9c71-c51506376c7f
                © 2008 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                gist,gastrointestinal,imatinib,stromal,tumor,sti-571
                Medicine
                gist, gastrointestinal, imatinib, stromal, tumor, sti-571

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