Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248
| العنوان: | Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248 |
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| المؤلفون: | A. Douglas Laird, Angela Barone, Dirk B. Mendel, Julie M. Cherrington, Guangmin Li, Katherine G. Moss, Olga Potapova, Michelle Nannini |
| المصدر: | Molecular Cancer Therapeutics. 5:1280-1289 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Cancer Research, Indoles, medicine.medical_treatment, Antineoplastic Agents, Mice, Inbred Strains, Pharmacology, Piperazines, Receptor tyrosine kinase, Mice, chemistry.chemical_compound, In vivo, Antineoplastic Combined Chemotherapy Protocols, Sunitinib, Tumor Cells, Cultured, medicine, Animals, Humans, Pyrroles, Receptors, Platelet-Derived Growth Factor, Receptor, Protein Kinase Inhibitors, biology, Growth factor, Receptor Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Vascular endothelial growth factor, Pyrimidines, Receptors, Vascular Endothelial Growth Factor, Oncology, chemistry, Benzamides, Cancer cell, Imatinib Mesylate, biology.protein, Angiogenesis Inducing Agents, Female, Propionates, Growth inhibition, HT29 Cells, Platelet-derived growth factor receptor |
| الوصف: | Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PDGFRβ and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors. [Mol Cancer Ther 2006;5(5);1280–9] |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cb7b56e1837fbb8cf98abe1e90e4d5e2 https://doi.org/10.1158/1535-7163.mct-03-0156 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....cb7b56e1837fbb8cf98abe1e90e4d5e2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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