کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3299611 | 1209933 | 2006 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Effects of PKC412, Nilotinib, and Imatinib Against GIST-Associated PDGFRA Mutants With Differential Imatinib Sensitivity
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کلمات کلیدی
PKCPDGFRAPDGFRBCR-ABLbreakpoint cluster region-AbelsonGastrointestinal stromal tumor - تومور استرومائی گوارشیGist - مشتاقProtein kinase C - پروتئین کیناز سیplatelet-derived growth factor receptor α - گیرنده عامل فاکتور رشد فاکتور αplatelet-derived growth factor receptor - گیرنده عامل فاکتور رشد یافته پلاکت
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Background & Aims: Activating mutations in platelet-derived growth factor receptor α (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib. Methods: The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo. Results: PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA. Conclusions: Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 131, Issue 6, December 2006, Pages 1734-1742
Journal: Gastroenterology - Volume 131, Issue 6, December 2006, Pages 1734-1742
نویسندگان
Ellen Weisberg, Renee D. Wright, Jingrui Jiang, Arghya Ray, Daisy Moreno, Paul W. Manley, Doriano Fabbro, Elizabeth Hall-Meyers, Laurie Catley, Klaus Podar, Andrew L. Kung, James D. Griffin,