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In the models described here, administration of CP, as a single agent did not yield tumor regressions.However, when CP, was administered in combination with conventional cytotoxic drugs, tumor regressions were observed. The data demonstrate a statistically significant decrease of in the number of microvessels in vehicletreated versus drugtreated DLD tumors. It should be noted that the modifications to tumor vascular morphology and function in response to VEGFR inhibitors can be complex.Using PTK, it was found that although vascular density was reduced in tumors, there was an intriguing increase in partial blood volume; and whereas vascular permeability was decreased significantly, there were no measurable changes in extravasation. VEGF has also been implicated in promoting the microvascular invasion required for normal endochondral bone growth. An additional indication of an antiangiogenic effect of CP, was demonstrated in immature rat tibial Pregnenolone growth plates. Treatment of rats with CP, for days at doses mgkg produced widening of the growth plate.The hypertrophic zone of the epiphyseal cartilage was affected predominantly, exhibiting up to fold increases in thickness.Similar observations have also been made with ZD, a small molecule VEGFR inhibitor. A number of VEGFR signaling inhibitors are being developed as angiogenesis inhibitors. On the basis of the preclinical data implicating an important role for VEGFR in angiogenesis, VEGFR inhibitors represent one of the most promising classes of antiangiogenesis agents. There are a variety of compounds in clinical development, both small molecules. Key distinctions among the small molecules described to date include the pharmacology of the compounds as well as the enzyme selectivity profiles.CP, is a potent inhibitor of VEGFR, TK with immunoglobulin and epidermal growth factor homology Naloxone hydrochloride domains, and FGFR in various kinase, cell, or in vivo assays.Because of this selectivity pattern, the overall tumor growth inhibition observed with CP, may be a combination of any of these three targets.Moreover, deducing the role that any of these receptors have in inhibiting tumor cell or vessel growth is additionally complicated because different tumor models may have different susceptibilities to each target.These small molecule angiogenesis inhibitors can be tools to help dissect and understand tumor vascular biology; however, no compound to date has demonstrated specificity for a single growth factor receptor.Although some inhibitors demonstrate modest kinase selectivity in vitro, studies to confirm pharmacological selectivity in vivo require rigorous assessment of plasma and tumor concentrations of the compound or sidebyside comparison of target inhibition in the same animal model.These data are critical for the accurate interpretation of results and associating inhibition of a particular receptor with the resulting biological response.Failure to adequately characterize the in vivo pharmacology will invariably lead to erroneous conclusions about the role of particular targets and vascular cell types involved in the angiogenic process.In this article, we describe the identification and characterization of a novel TK inhibitor, CP. Finally, qd oral administration of this compound was able to significantly inhibit human tumor growth in murine models resulting in significant inhibition of tumor microvascular density in vivo.Taken together, these results demonstrate CP, to be a potent angiogenesis inhibitor with good oral bioavailability and in vivo antitumor efficacy.

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