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)

Single-chain Fv molecules in monovalent (sFv) and divalent [(sFv')2] forms exhibit highly specific tumor targeting in mice as a result of their small size and rapid systemic clearance. As a consequence, there is a rapid reversal of the sFv blood/tumor gradient, resulting in diminished retention of sFv species in tumors. In this report we investigate two distinct strategies, dose escalation and repetitive intravenous (i.v.) dosing, aiming to increase the absolute selective retention of radiolabeled anti-c-erbB-2 125I-741F8 (sFv')2 in c-erbB-2-overexpressing SK-OV-3 tumors in mice with severe combined immunodeficiency (SCID). A dose-escalation strategy was applied to single i.v. injections of 125I-741F8 (sFv')2. Doses from 50 micrograms to 1000 micrograms were administered without a significant decrease in tumor targeting or specificity. High doses resulted in large increases in the absolute retention of 125I-741F8 (sFv')2. For example, raising the administered dose from 50 micrograms to 1000 micrograms increased the tumor retention 24 h after injection from 0.46 microgram/g to 9.5 micrograms/g, and resulted in a net increase of greater than 9 micrograms/g. Over the same dose range, the liver retention rose from 0.06 microgram/g to 1 microgram/g, and resulted in a net increase of less than 1 microgram/g. The retention of 9.5 micrograms/g in tumor 24 h following the 1000-micrograms dose of (sFv')2 was comparable to that seen 24 h after a 50-micrograms dose of 125I-741F8 IgG, indicating that the use of large doses of (sFv')2 may partially offset their rapid clearance. When two doses were administered by i.v. injection 24 h apart, the specificity of delivery to tumor observed after the first dose was maintained following the second injection. Tumor retention of 125I-741F8 (sFv')2 was 0.32 microgram/g at 24 h and 0.22 micrograms/g at 48 h following a single injection of 20 micrograms, while 0.04 microgram/ml and 0.03 microgram/ml were retained in blood at the same assay times. After a second 20-micrograms injection at the 24-h assay time, tumor retention increased to 0.49 micrograms/g, and blood retention was 0.06 microgram/ml, at the 48-h point. These results suggest that multiple high-dose administrations of radiolabeled 741F8 (sFv')2 may lead to the selective tumor localization of therapeutic radiation doses.
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PMID:Optimization of in vivo tumor targeting in SCID mice with divalent forms of 741F8 anti-c-erbB-2 single-chain Fv: effects of dose escalation and repeated i.v. administration. 760 May 61

Bispecific monoclonal antibodies (BsmAb) can be used to specifically target tumor cells for cytotoxicity mediated by defined effector cells. One such BsmAb, 2B1, targets the extracellular domains of both the c-erbB-2 protein product of the HER-2/neu oncogene and Fc gamma RIII (CD16), the Fc gamma receptor expressed by human natural killer cells, neutrophils, and differentiated mononuclear phagocytes. 2B1 promotes the conjugation of cells expressing these target antigens. It efficiently promotes the specific lysis of tumor cells expressing c-erbB-2 by human NK cells and macrophages over a broad concentration range. 2B1 selectively targets c-erbB-2-positive human tumor xenografts growing in immunodeficient SCID mice. Treatment of such mice with 2B1 plus interleukin 2 (IL-2) inhibits the growth of early, established human tumor xenografts overexpressing c-erbB-2. A phase I clinical trial of 2B1 has been initiated to determine the toxicity profile and maximum tolerated dose (MTD) of this BsmAb and to examine the biodistribution of the antibody and the biologic effects of treatment. Preliminary results of this trial indicate that the dose-limiting toxicity for patients with extensive prior bone marrow-toxic therapy is thrombocytopenia for as yet undetermined reasons. Toxicities of fevers, rigors, and associated constitutional symptoms are explained, in part, by treatment-induced systemic expression of cytokines, such as tumor necrosis factor-alpha. Circulating, functional BsmAb is easily detectible in treatment patients' sera and exhibits complex elimination patterns. HAMA and anti-idiotypic treatment-induced antibodies are induced by 2B1 treatment. Some preliminary indications of clinical activity have been observed. BsmAb therapy targeting tumor antigens and Fc gamma RIII has potent immunologic effects. Future studies will include the development of more relevant animal models for BsmAb therapy targeting human Fc gamma RIII. The ongoing phase I trial will be completed to identify the MTD for patients without extensive prior bone marrow-toxic chemotherapy and radiation. A phase II clinical trial of 2B1 therapy in women with metastatic breast cancer is planned, as is a phase I trial incorporating treatment with both 2B1 and IL-2.
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PMID:Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 858 84

We have previously shown that adenoviral-mediated delivery of an anti-erbB-2 intracellular single-chain antibody (sFv) causes specific cytotoxicy in erbB-2-overexpressing ovarian carcinoma cells. Furthermore, intraperitoneal delivery of the anti-erbB-2 sFv enhances survival and reduces tumor burden in a xenograft model of human ovarian carcinoma in SCID mice. These findings have led to an RAC-approved Phase I clinical trial for patients with ovarian cancer. In this report, we show that expression of the anti-erbB-2 sFv could be readily detected in target tumor cells by in situ hybridization methodology. PCR analysis of DNA extracted from various murine tissues demonstrated that the anti-erbB-2 sFv remained localized to the peritoneum. Delivery of the sFv to the non-erbB-2-overexpressing REN mesothelial and Hep G2 hepatocellular carcinoma cell lines was not deleterious to either one, affirming the tumor specificity of this gene therapy strategy. In addition, histopathological analysis of various tissues showed that adenoviral-mediated delivery of the anti-erbB-2 sFv to immunocompetent mice with either primary exposure or previous vector challenge at different doses produced no abnormal changes when compared to untreated animals. These findings suggest that adenoviral-mediated delivery of the anti-erbB-2 sFv in a human context can be effectively assayed, is potentially free of vector-associated toxicity, and retains biologic utility based on tumor specificity.
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PMID:Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy. 906 38

Overexpression of the c-erbB-2 gene-encoded p185 has been reported in approximately 30% of human breast cancers and has been correlated with lymph node metastasis and poor prognosis in breast cancer patients. To investigate whether overexpression of p185 can enhance the metastatic potential of human breast cancer cells, we have introduced the human c-erbB-2 gene into the very low p185-expressing MDA-MB-435 human breast cancer cells and established 435.eB transfectants that express higher levels of p185. In this study, we compared the metastatic phenotypes of the parental MDA-MB-435 cells and the 435.eB transfectants. In vivo experimental metastasis assays in which we injected MDA-MB-435 parental cells or 435.eB transfectants into the tail veins of ICR-SCID mice demonstrated that mice injected with p185-overexpressing 435.eB transfectants formed significantly more metastatic tumors than the mice injected with parental and control cells. The changes in experimental metastatic potential in vivo were accompanied by increased invasiveness in vitro. In addition, the secretion of basement membrane-degradative enzymes, which is an important step in the invasion and metastasis process, was also increased in the p185-overexpressing 435.eB transfectants. These results indicated that p185 overexpression can enhance the metastatic potential of MDA-MB-435 human breast cancer cells. To investigate whether enhanced metastatic potential in the p185-overexpressing 435.eB transfectants was the result of increased cancer cell growth and transformation potential, we compared the growth rate, anchorage-independent growth ability, and tumorigenicity of the 435.eB transfectants with that of the parental cells. The transfectants and the parental cells all had similar growth rates and anchorage-independent growth abilities and demonstrated similar tumorigenic potential. These findings suggest that c-erbB-2 is a metastasis-promoting gene for breast cancers that is distinct from other tumor-promoting genes in that the c-erbB-2 gene can enhance the intrinsic metastatic potentials of MDA-MB-435 cells without increasing their transformation abilities.
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PMID:Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. 906 93

A cell line derived from human endometrial clear cell adenocarcinoma was newly established and named TEN. The tumor cells were obtained from uterine body of a 74-year-old who had been undergone an abdominal simple hysterectomy. The histologic features of the tumor cells showed abundant clear cytoplasm with diastase digested glycogen granule growing in solid nest and tubular pattern. The TEN cells were continuously propagated in vitro during the past 45 months and they were at 75th passage. They grew in a monolayered sheet with a doubling time of about 53 hours. The TEN cells resembled the structure of the original tumor and had abundant glycogen granules, lipid droplets in the cytoplasm. The histopathology of the transplanted tumor in SCID mice resembled that of the original tumors. The TEN cells secreted a high content of CA125. Immunohistochemically, the TEN cells had c-erbB-2 and Cathepsin D immunoreactivity in some parts of the cell population. But they did not have estrogen, progesterone and EGF receptor. Sensitivities of the TEN cells to a variety of anti-cancer drugs were examined. In in-vitro tests, MTT assays employed. The results suggested that the TEN cells were not sensitive to any of 13 agents. On the other hand, in-vivo sensitivity test of transplanted tumor in SCID mice, the tumors were sensitive to CPT-11 and paclitaxel. We conclude that the TEN cell line will be effective material for chemosensitivities against the endometrial clear cell adenocarcinoma.
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PMID:Characterization of a newly established human tumor cell line (TEN) from a patient with clear cell carcinoma of the uterine body and its sensitivity to anti-cancer agents. 943 40

This recent symposium featured speakers from several clinical and research disciplines. Among the findings: peptic ulcer disease is a significant predisposing risk factor (odds ratio = 3.9) for pancreatic cancer; as many as 50% of all intraductal papillary mucinous neoplasms are associated with invasive adenocarcinomas; alteration of gene expression via methylation of a gene promotor region constitutes a potentially reversible method of tumor suppressor gene inactivation; > 400 transcriptional alterations of gene expression have been identified for pancreatic cancer; some common molecular markers such as p53 and HER-2/neu may be related to morphologic alterations of in situ neoplasia and to transcriptional alterations of gene expression rather than mutational events; epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and related molecules may modulate gene transcription via "autocrine" or "paracrine" mechanisms; several cytokines, amylin (islet amyloid polypeptide), and other cachexia factors are responsible for paraneoplastic peripheral insulin resistance, ineffective utilization of glucose, and profound cachexia. In the clinical diagnostic arena: the World Health Organization established a standard nomenclature for intraductal papillary mucinous neoplasms, mucinous cystic tumors, intraductal mucinous hyperplasias, and solid pseudopapillary tumors; focal glandular differentiation may be commonly identified within pancreatic endocrine neoplasms (islet cell tumors) while not necessarily implying an unfavorable prognosis typical of ductal adenocarcinomas; positron emission tomography scanning may be used for evaluation of early tumor response to novel chemotherapeutic regimens; helical computed tomography (CT) is the state of the art in preoperative imaging for pancreatic cancer; neoadjuvant 5-fluorouracil (5-FU)-based chemoradiation in 39 "resectable" patients provided a median survival of 19 months, actuarial 4-year survival of 19%, and improved local tumor control; gemcitabine has shown promise in alleviating tumor-related symptoms with a significantly better "clinical benefit response" than single agent 5-FU (23.8 vs. 4.8%, p = 0.0022) based on change in pain intensity, daily analgesic consumption, performance status, and weight; a significant survival advantage was demonstrated in patients treated with conventional therapies whose tumors expressed p21WAF-1, an important inhibitor of cell cycle progression and downstream molecule of p53 and TGF-beta; a p21-adenovirus (rAD-p21) gene therapy resulted in significant growth inhibition of pancreatic cancer cell lines in tissue culture, and development of a successful SCID mouse-human pancreatic adenocarcinoma xenograft model provided an animal model for preclinical trials of rAD-p21.
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PMID:Current concepts in pancreatic cancer: symposium summary. 982 Nov 73

HER-2/neu is overexpressed on a variety of human adenocarcinomas and overexpression has been associated with a poor prognosis. For this reason, HER-2 has become an attractive target for immunotherapy. To facilitate testing of anti-HER-2-monoclonal antibodies (MAbs) and immunotoxins (ITs), we have evaluated the in vivo growth and metastatic spread of three HER-2-overexpressing human breast cancer cell lines (BT474, MDA-MB-453 and HCC1954) and one ovarian cancer cell line (SKOV3.ip1) in pre-irradiated male SCID mice using subcutaneous (s.c.), intravenous (i.v.) and intraperitoneal (i.p.) routes of injection. All the cell lines tested grew as s.c. tumors and the growth of BT474 and MDA-MB-453 cells after s.c. injection was improved by co-inoculation with Matrigel. Metastases to the lungs were detectable by PCR or histopathology after s.c. injection of BT474 and to a much lesser extent after s.c. injection of HCC1954, MD-MB-453 and SKOV3.ip1 cells. I.p. injection of HCC1954 and SKOV3.ip1 cells produced fatal ascites while i.v. injection of SKOV3.ip1, but not BT474 or MDA-MB-453 cells, resulted in infiltration of lungs and death within 9-11 weeks.
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PMID:The growth and metastasis of human, HER-2/neu-overexpressing tumor cell lines in male SCID mice. 1096 98

The c-erbB-2 product is thought to be a unique and useful target for antibody therapy of cancers that overxpress the c-erbB-2 gene. Its overexpression is also speculated to be correlated with chemoresistance to doxorubicin. The in vitro and in vivo anti-tumor effects of a humanized antibody directed against the extracellular domain of the c-erbB-2 gene product, rhu4D5, were examined. Rhu4D5 had direct antiproliferative activity against the SK-BR-3 cell line which overexpresses c-erbB-2. The in vivo treatment, using rhu4D5, of SCID mice carrying xenografts of 4-1ST human gastric carcinoma, which overexpresses c-erbB-2, revealed that the recombinant protein had potent anti-tumor activity. Furthermore, the cytotoxic action of human peripheral blood mononuclear cells against the SK-BR-3 cell line was significantly augmented with the administration of rhu4D5, but not with mu4D5. These results indicate that rhu4D5 might be a more efficacious treatment than previously predicted by preclinical studies.
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PMID:A Humanized Anti-c-erbB-2 Monoclonal Antibody for the Treatment of Breast Cancer. 1109 13

Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N(4)-(1-benzyl-1H-indazol-5-yl)-N(6),N(6)-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine 3B. This compound inhibited EGFr and c-erbB-2 enzymes selectively over other kinases. It inhibited the proliferation of a range of tumour cell lines in vitro and the growth of BT474 xenografts in SCID mice.
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PMID:Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2. 1137 64

Her-2 (p185(erbB-2)) is a transmembrane tyrosine kinase receptor, which is encoded by the Her-2/neu proto-oncogene. Her-2 is overexpressed on 30% of highly malignant breast cancers. Monoclonal antibodies (MAbs) against Her-2 inhibit the growth of Her-2-overexpressing tumor cells and this occurs by a variety of mechanisms. One such MAb, Herceptin (Trastuzumab), has been approved for human use. We have generated a panel of murine anti-Her-2 MAbs against nine different epitopes on the extracellular domain of Her-2 and have evaluated the antitumor activity of three of these MAbs alone and in combination, both in vitro and in vivo. We found that MAbs (against different epitopes) make a highly effective mixture, which was more effective than the individual MAbs in treating s.c. tumor nodules of BT474 cells in SCID mice. In vitro, the MAb mixture was also more effective than the single MAbs in inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, inhibiting cell growth and inducing apoptosis, and inhibiting the secretion of vascular endothelial growth factor. Taken together, these activities might explain the superior performance of the MAb mixture in vivo.
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PMID:Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. 1206 Jun 6


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