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RTK Inhibitors (rtk + inhibitor)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Flavonoids as RTK inhibitors and potential anticancer agents

MEDICINAL RESEARCH REVIEWS, Issue 5 2008
Florence Teillet
Abstract Tyrosine kinase receptors (RTKs) play a crucial role in the regulation of the cell division cycle. Currently more than 50 RTKs divided into several subfamilies have been described. The inhibition of these enzymes has emerged as an important research-area. Compounds able to inhibit the activity of these enzymes are expected to display antiproliferative properties. Flavonoids are representative of various small molecules acting as RTK inhibitors. These naturally occurring compounds are able to bind to the ATP-binding site of several kinases. The most plausible current hypothesis explaining the action of these substances on kinases is that the chromenone moiety of the flavonoid acts as a mimetic of the adenine moiety of ATP, the receptor co-factor. In this review, we report recent results on the activity of natural and synthetic derivatives of flavonoids as inhibitors of RTKs. Mechanistic aspects, the therapeutic usefulness, and the potential clinical use are discussed. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 5, 715,745, 2008 [source]

Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2008
J. H. Fasig
Aims: Currently, there are no effective chemotherapeutic protocols for chordoma. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumours may respond to kinase inhibitor therapy. However, RTK signalling activity has not been extensively investigated in chordoma. Methods: A tissue microarray containing 21 cases of chordoma was analysed for expression of a number of proteins involved in signal transduction from RTKs by immunohistochemistry. Results: Platelet-derived growth factor receptor-,, epidermal growth factor receptor (EGFR), KIT and HER2 were detected in 100%, 67%, 33% and 0% of cases, respectively. Platelet-derived growth factor receptor-, staining was of moderate-to-strong intensity in 20 of 21 cases. In contrast, KIT immunoreactivity was weak and focal in each of the seven positive cases. Total EGFR staining was variable; weak staining for phosphorylated EGFR was detected in nine cases. Phosphorylated isoforms of p44/42 mitogen-activated protein kinase, Akt and STAT3, indicative of tyrosine kinase activity, were detected in 86%, 76% and 67% of cases, respectively. Conclusions: Chordomas commonly express RTKs and activated signal transduction molecules. Although there were no statistically significant correlations between the expression of any of the markers studied and disease-free survival or tumour location, the results nonetheless indicate that chordomas may respond to RTK inhibitors or modulators of other downstream signalling molecules. [source]

Evidence for activation of KIT, PDGFR,, and PDGFR, receptors in the Ewing sarcoma family of tumors

CANCER, Issue 8 2007
Fabio Bozzi PhD
Abstract BACKGROUND. The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with ESFT. The prognosis is still unsatisfactory for high-risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFR,, and PDGFR, receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT. METHODS. RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFR,, and PDGFR,. RESULTS. No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFR,, and PDGFR, were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFR, showed a greater protein expression and/or a stronger phosphorylation signal. CONCLUSIONS. The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFR,, and PDGFR, receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy. Cancer 2007. © 2007 American Cancer Society. [source]