Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase II-alpha is the molecular target of doxorubicin, an active drug used in the therapy of breast cancer. From many in vitro studies, it is known that high levels of topo II-alpha expression correlate with drug sensitivity, and low levels of topo II-alpha correlate with drug resistance. In addition, the enzyme is known to be a marker of cell proliferation in normal tissues. Because the number of proliferating cells in a breast cancer has been shown to be prognostically important, and because doxorubicin is used in the treatment of breast cancer, we hypothesized that the measurement of topo II-alpha in breast cancer may not only give drug sensitivity information but also may yield important data on cell proliferation. In this study, formalin-fixed, paraffin-embedded tissue from 30 specimens of invasive breast cancer from 20 patients were immunohistochemically stained for topo II-alpha with a mouse monoclonal antibody. For each case, a topo II-alpha index was determined that represents the number of positive-staining tumor cells divided by the total number of tumor cells counted times 100. A similar index was determined for MIB1, a known cell proliferation marker. Each case was also graded according to the modified Bloom-Richardson criteria and evaluated for c-erbB-2 amplification, hormonal status, S-phase fraction, and mitotic index. The topo II-alpha index correlates better with the MIB1 index than with the S-phase fraction or mitotic index. The topo II-alpha expression in breast cancer ranges from low (topo II-alpha index <1) to high (topo II-alpha index = 86). Amplification of c-erbB-2 was observed in 4 of 28 cases (14%) but did not correlate with high topo II-alpha indices. We conclude that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells. In addition, because the enzyme is the molecular target of doxorubicin, the expression of the enzyme may relate also to the sensitivity or resistance of the tumor to doxorubicin-based chemotherapeutic protocols.
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PMID:Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer. 934 25

The soy isoflavone genistein attenuates growth factor- and cytokine-stimulated proliferation of both normal and cancer cells. This article reviews our current understanding of the potential mechanisms of action of genistein. In membrane preparations from mammalian cells, genistein is a potent and specific inhibitor of tyrosine autophosphorylation of the epidermal growth factor (EGF) receptor. However, in several cell systems in which it inhibits growth, genistein does not alter tyrosine phosphorylation of the EGF receptor or other tyrosine kinase substrates thought to be involved in signal transduction pathways, suggesting that other mechanisms may be responsible for its action. Alternatives include inhibition of DNA topoisomerase II activity, regulation of cell cycle checkpoints, and antiangiogenic and antioxidant activity. Experiments in our laboratory suggest a new concept, that genistein may inhibit cell growth by modulating transforming growth factor (TGF) beta1 signaling pathways. Such a link between genistein action and TGFbeta1 function is supported by preliminary results of studies in patients with hereditary hemorrhagic telangiectasia (a genetic disorder involving mutations in proteins that regulate TGFbeta receptor complex formation and signaling) in which several patients had dramatic attenuation of their symptoms after 1 wk of ingesting soy-based beverages. These preclinical studies in combination with our cell culture data suggest that the mechanism of genistein involves, if not requires, TGFbeta1-signaling.
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PMID:Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. 984 10

DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of anticancer drugs. These drugs are S-phase specific and require elevated topo I for tumor cell killing. To determine whether increased topo I expression occurs in testicular seminomas, 20 cases of testicular seminoma were retrieved from the surgical pathology files at the University of Utah Health Sciences Center and stained with an antibody that recognizes topo I in paraffin embedded human tissue sections. Topo I elevation was observed in 30% (6/20) of the seminomas. Because the response to topo I targeted drugs requires cell proliferation, the proliferative index of the seminomas was determined by immunohistochemical staining for DNA topoisomerase II-alpha (topo II-alpha) a new marker of cell proliferation. AU seminomas had easily detectable topo II-alpha. The average topo II-alpha index of the 20 cases was 52.1 +/- 15.3. Seminomas with elevated topo I had an average topo II-alpha proliferative index of 60.8 +/- 17.5 and seminomas with normal topo I expression had a topo II-alpha proliferative index of 48.4 +/- 13.2. This is significantly different at the 0.05% confidence level. Focal expression of CD30 was seen in 60% (12/20) of the neoplasms. None of the cases showed positive staining for CD15 and c-erbB-2. Our results suggest that chemotherapeutic protocols involving topoisomerase targeting drugs might be useful against testicular seminomas.
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PMID:Expression of DNA toposiomerase I and DNA topoisomerase II-alpha in testicular seminomas. 1087 53

DNA topoisomerase II-alpha (topo II-alpha) is the molecular target of several types of clinically useful anticancer drugs such as etoposide, teniposide, doxorubicin, and mitoxantrone. The enzyme is also a proliferation marker in normal cells and tissues. High levels of enzyme are present in the S and G2 phases of the cell cycle. New data are emerging which suggest that anticancer drugs which target the topoisomerases may be useful in the treatment of patients with ovarian neoplasms. However, there is relatively little data on the expression of these enzymes in human ovarian cancer. We have recently developed an in situ immunohistochemical stain which can detect the presence of topo II-alpha in formalin-fixed paraffin-embedded human tissue sections. In order to determine topo II-alpha levels in ovarian tumors, we immunostained for topo II-alpha, 30 ovarian neoplasms which ranged from benign to highly malignant. We correlated our results with expression of MIB1 in order to determine if topo II-alpha expression correlates with cell proliferation. Since the gene for topo II-alpha is closely linked to the gene for the c-erbB-2 oncogene, we also evaluated the cases for amplification of c-erbB-2. Our results indicate that topo II-alpha correlates well with MIB1 indicating that topo II-alpha may be useful in estimating cell proliferation in ovarian tumors. In addition, 1 of 15 patients with a malignant neoplasm had a carcinoma which expressed high levels of topo II-alpha. Since the sensitivity of cells to topo II targeted drugs is dependent on high topo II levels, this suggests that topo II-alpha immunostaining in ovarian cancer may also identify a subset of patients potentially treatable with topo II targeted drugs. None of the ovarian neoplasms showed amplification of c-erbB-2.
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PMID:Human DNA topoisomerase II-alpha. 2153 9

Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure-activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7-noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2). This SAR study revealed that a substantial increase in biological activity can be achieved by introduction of an indole-2-carboxamide group in place of 4-hydroxy-isopentylbenzamido group at C-3 of NB in addition to removal/derivatization of the 4-hydroxyl group from the coumarin ring. Methylation of the 4-hydroxyl group in the coumarin moiety moderately increased biological activity as shown by compounds 11 and 13. Our most potent new analogue 19 demonstrated biological activities consistent with known HSP90-binding agents, but with greater potency than NB.
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PMID:Synthesis and biological evaluation of novobiocin analogues as potential heat shock protein 90 inhibitors. 2385 77