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)

Radioimmunotherapy is hindered by a variety of factors linked to the utilization of monoclonal antibodies. These limitations include restricted tumor penetration as well as low levels of intratumoral antigen expression. To address the latter problem, we used a gene therapy approach to induce tumor cells to express enhanced levels of receptor with high binding affinity for a radiolabeled peptide. In this regard, a radiolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide receptor (mGRPr). A panel of human carcinoma cell lines was infected in vitro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a 125I-labeled bombesin peptide. All cell lines examined displayed high levels of induced peptide binding, with approximately 60-80% of the radioactivity bound to the cells, in a live-cell binding assay. The human ovarian carcinoma cell line SKOV3.ip1 was chosen for in vivo analysis of radiolabeled bombesin analogue tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in selective tumor uptake of the radiolabeled peptide and high tumor:blood ratios. The biodistribution results compared favorably to those obtained with 131I-labeled e21 anti-erbB-2 monoclonal antibody in animals bearing i.p. SKOV3.ip1 tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may result in augmented tumor cell targeting of radiopharmaceuticals.
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PMID:Adenoviral-mediated delivery of gastrin-releasing peptide receptor results in specific tumor localization of a bombesin analogue in vivo. 981 98

Radioimmunotherapy is limited by a variety of factors, including poor tumor penetration of monoclonal antibodies and low levels of intratumoral antigen expression. To address these limitations, a gene therapy strategy was devised to genetically induce tumor cells to express enhanced levels of membrane receptors with high affinity for a radiolabeled peptide. We designated this approach as genetic radioisotope targeting strategy. To this end, an adenoviral vector (AdCMVGRPr) encoding the murine gastrin-releasing peptide receptor (GRPr) was used to achieve a high level of binding of radiolabeled bombesin (BBN). To achieve genetic induction of membrane GRPr specifically to tumor cells, we constructed two adenoviral vectors encoding the GRPr gene under the control of the tumor-specific regulatory elements, DF3 (AdDF3GRPr) or erbB-2 (AderbGRPr). We investigated the binding of [125I]BBN to the GRPr following infection with AdDF3GRPr and AderbGRPr in a panel of human breast, pancreatic, and cholangiocarcinoma tumor cell lines. [125I]BBN binding and GRPr expression increased with increasing multiplicities of infection of AdCMVGRPr in all of the cell lines tested. Breast cancer cell lines expressing erbB-2 showed significant GRPr expression using AderbGRPr. A similar result was observed in breast and cholangiocarcinoma cells infected with AdDF3GRPr expressing MUC1 as detected by immunohistochemistry but was not seen in the pancreatic cell lines tested. Thus, adenoviral vectors with tissue-specific promoter elements can be used to achieve a selective expression of membrane receptors that can be targeted with a radiolabeled peptide. The use of such a transcriptional targeting approach may restrict gene expression to tumors and limit the radiation dose deposited in normal tissues in vivo.
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PMID:Specific membrane receptor gene expression targeted with radiolabeled peptide employing the erbB-2 and DF3 promoter elements in adenoviral vectors. 1035 6

Bombesin and its mammalian homologue gastrin-releasing peptide have been shown to be highly expressed and secreted by neuroendocrine cells in prostate cancer, and are thought to be related to the carcinogenesis and progression of this disease. We found, in this study, bombesin specifically induced mitogen-activated protein (MAP) kinase activation as shown by increased extracellular regulated kinase (ERK) phosphorylation and epidermal growth factor (EGF) receptor transactivation in prostate cancer cells, which express functional gastrin-releasing peptide receptor. The transactivation of EGF receptor was required for bombesin-induced ERK phosphorylation. Furthermore, non-receptor tyrosine kinase Src and cellular Ca2+ were shown to be involved in bombesin-induced EGF receptor transactivation and ERK phosphorylation. Inhibition of either EGF receptor transactivation or ERK activation blocked bombesin-induced DNA synthesis in these cells. Taken together, these data suggest bombesin may act as a mitogen in prostate cancer by activating MAP kinase pathway via EGFR transactivation.
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PMID:Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. 1287 8