Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.
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PMID:Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. 1580 Sep 44

Current treatments for cancer (surgery, radiation and chemotherapy) are successful for early stage localised disease but have severe side effects. New treatments are needed to increase the cure rate and life expectancy of patients. With the discovery of oncogenes, tumour suppressor genes and an understanding of their role in the development of the malignant disease, a new era of therapy has begun. Cancer is a manifestation of deregulated signalling pathways that mediate cell growth and programmed cell death. Protein kinases are essential elements in these signalling pathways. In the US, Novartis launched Gleevec (imantinib, STI-571) in May 2001 as the first anticancer drug whose mechanism of action is kinase inhibition. In Phase I trials, 23/24 patients with chronic myelogenous leukaemia (CML) had complete remissions and the drug is relatively non-toxic. Herceptin (trastuzumab) is a monoclonal antibody (mAb) against a member of the growth factor receptor family (HER-2/neu) that was launched in 1998 by Genentech for the treatment of breast cancer. Trastuzumab has an excellent antitumour profile, particularly when used in combination with doxorubicin and paclitaxol. These drugs are pioneering the treatment of cancer based on the molecular understanding of the disease. Numerous drugs that target growth factor receptors and their signalling pathways are in advanced clinical trials. Herein, antibodies against receptors and small molecule inhibitors of kinases in signalling pathways will be summarised. Inter-disciplinary preclinical studies have identified chemicals that target specific kinases. We believe that clinical studies of these agents will yield new anticancer agents that target specific diseases and that are less toxic than current agents.
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PMID:Drugs targeted against protein kinases. 1598 28