A PHASE 1 SAFETY AND PHARMACOKINETIC STUDY OF SU011248 AND CAPECITABINE IN PA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Receptor tyrosine kinases (RTKs) are transmembrane proteins containing extracellular ligand-binding domains and intracellular catalytic domains. RTKs are activated following binding of their cognate ligands and many of the processes involved in tumor growth, progression and metastases are mediated by signaling molecules acting downstream from these proteins [1, 2]. Several members of the split-kinase domain family of RTKs are implicated in deregulated/autocrine proliferation and survival of solid and hematologic cancer cells. These include the platelet-derived growth factor receptors (PDGFR and ); vascular endothelial growth factor receptors (VEGFR) Type 1 and 2 (FLT1 and FLK 1/KDR); the stem cell factor (SCF) receptor, KIT; and the FLT3-ligand receptor. In addition RTKs PDGFR and VEGFR are implicated in tumor-dependent angiogenesis. SU011248 is a small molecule with the molecular formula C22H27FN4O2. The free base has a molecular weight of 398.48 and the L-malate salt, the form used in clinical trials (Error! Reference source not found.), has a molecular weight of 532.57. The chemical name of the L-malate salt is 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethylpyrrole-3-carbo ylic acid (2-diethylamino-ethyl)-amide, compound with (S)-2-hydroxy-succinic acid 1:1.