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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A signal transduction pathway, involving oncogenes and their normal counterparts the proto-oncogenes, analogous to that for cell growth and differentiation has been proposed to lead to the phenotype of cellular radioresistance (RR). In this report we provide evidence demonstrating the existence of such a pathway by using antisense oligonucleotides (ASO) to reverse the RR phenotype. Utilizing ASO directed against the raf-1 gene, a central component of this proposed pathway, we were able to reverse the RR phenotype of human tumor cell lines having elevated HER-2 expression or a mutant form of Ha-ras, two genes upstream of raf-1 in signal transduction. Additionally, anti-ras ASO were able to radiosensitize HER-2 overexpressing cells. These results, which verify the presence of a signaling pathway leading to cellular RR, also have possible clinical implications for the use of ASO as a means to sensitize radioresistant tumors to radiation therapy.
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PMID:Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells. 902 45

Ovarian cancer is the leading cause of death in gynecological cancers. To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and the course of the disease. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erbB-2 (HER2/neu) in various human cancers, including ovarian cancer. The c-erbB-2 proto-oncogene is located on the long arm of chromosome 17. It encodes a 185 kD transmembrane glycoprotein receptor (p185HER2) that has sequence similarities with the epidermal growth factor receptor (EGF-R). In ovarian cancer, the percentage of c-erbB-2 positive cases varies from 9 to 32%. Correlation with tumor stage and the degree of histological differentiation was not observed. The overexpression of c-erbB-2 is a new and statistically independent prognostic factor. The overexpression of oncogene c-erbB-2 in ovarian cancer can-be detected by immunohistochemistry staining for the protein p185 and characterizes a group with unfavorable tumor biology and a significantly worse prognosis. Elevated serum levels of the c-erbB-2 oncoprotein have been identified in patients with various cancers known to overexpress the c-erbB-2 oncogene. The detection of a p185 oncoprotein fragment in the sera of ovarian cancer patients was recently published by our group. Antiproliferative effects of monoclonal antibodies directed against p185 have been demonstrated in breast cancer patients. This may lead to a new approach in ovarian carcinoma therapy, too, over and above the diagnostic aspects.
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PMID:Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor. 913 62

Overexpression of neu (also known as c-erbB-2 or HER-2) commonly occurs in human cancer and is also known to enchance tumor metastasis and chemoresistance. Our earlier reports showed that the adenovirus 5 E1A can suppresss the neu-mediated transformation by repression of neu. Thus, E1A has the potential to be used as a therapeutic agent against the neu-overexpressing human cancers. However, a serious concern to this approach is that E1A is also capable of immortalizing primary culture cells and can co-operate with ras or E1B oncogenes to transform them. The E1A CR2 domain (amino acid residues 120 to 140) necessary for binding to RB is believed to be required for this oncogenic function. Here, we report that deletion of CR2 region did not affect E1A's capability to repress neu. Interestingly, deletion of the amino acid residues 4 to 25 or 40 to 80 completely disrupted E1A-mediated neu repression. By deleting the amino acid residues from 81 to 185, we have successfully generated a mini-E1A mutant that was sufficient to inhibit neu promoter activity and suppress neu-mediated transformation. The mini-E1A mutant does not contain the CR2 domain that is crucial for RB binding and immortalization, and hence, may serve as a more selective tumor suppressor, and a safer therapeutic agent. It may also be a useful tool to further investigate the molecular mechanism(s) of neu overexpression and E1A-mediated transcriptional repression in cancer cells.
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PMID:Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu. 915 Mar 63

The protooncogene HER2/neu encodes a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor. It is overexpressed in several human cancers of epithelial origin, such as pancreatic cancer. Previously, we demonstrated that cytotoxic T lymphocytes (CTL) derived from breast, ovarian, and non-small cell lung cancer recognized a peptide derived from HER2/neu. To evaluate whether this HLA-A2-binding peptide is a tumor-associated antigen (TAA) in pancreatic cancer, the ability of HER2/neu-reactive CTL to lyse human pancreatic carcinoma cells was tested. CTL were generated from tumor-associated T lymphocytes from HLA-A2+ HER2/neu+ breast and ovarian cancer patients. All CTL recognized autologous and allogeneic HER2/ neu+ tumor cells in an HLA-A2-restricted fashion. Furthermore, all CTL recognized p654-662 (GP2) derived from HER2/neu. These CTL also recognized HER2/neu+ pancreatic cancer cells in an HLA-A2-restricted fashion. HER2/neu+ HLA-A2- pancreatic cancer were not or only poorly lysed. Repeated stimulation of HLA-A2+ PBL from pancreatic cancer patients using the HER2/neu-derived peptide resulted in specific recognition of this peptide and, more importantly, HER2/neu+ pancreatic tumors in an HLA-A2-restricted fashion. Autologous HLA-A2+ fibroblasts or HLA-A2+ malignant melanoma cells were not recognized. HLA-A2- peptide-stimulated T lymphocytes showed no significant cytotoxicity. These results demonstrate that this HER2/neu-derived peptide is a shared TAA among several adenocarcinomas including pancreatic carcinoma, suggesting a common mechanism of recognition of these human tumors by T lymphocytes. The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies.
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PMID:The HER2/neu-derived peptide p654-662 is a tumor-associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes. 917

HER-2/neu and c-myc amplification or overexpression have been reported to be associated with poor prognosis in breast carcinoma. The prognostic significance, however, remains somewhat controversial, partly because of discrepancies among different methodologies used for detection of the oncogene amplification or overexpression. Fluorescence in situ hybridization (FISH) has recently been shown to be a useful technique for analyzing genetic alterations in interphase nuclei in various tumors. In this study, FISH was used to quantitate HER-2/ neu and c-myc gene amplification in touch preparations of frozen tissue from 100 node-negative breast carcinomas. HER-2/neu amplification was found to be associated with an abnormal DNA index (P < .001) and tumor size (P < .04). Amplification of c-myc was associated with S phase (P < .0003), abnormal DNA index (P < .003), and a negative estrogen receptor status (P < .01). The coamplification of both oncogenes was strongly associated with an abnormal DNA index (P < .0001) and with tumor size (P < .009). The use of FISH for detection of HER-2/neu gene amplification was 92% concordant with immunocytochemistry (ICC) used for detection of overexpression of HER-2/neu protein. Fifteen of the 100 cases were both amplified for HER-2/neu by FISH and positive by ICC analysis. Seven cases without HER-2/neu gene amplification demonstrated HER-2/neu protein overexpression by ICC. One HER-2/neu-amplified case was negative by ICC. Repeat analysis of a subset of cases showed FISH to be a more reproducible method than ICC in the analysis of HER-2/neu in touch preparations of breast carcinoma. FISH is a rapid and reproducible method that allows the accurate measurement of the level of oncogene amplification within interphase nuclei. The use of FISH should provide a more accurate assessment of the prognostic significance of oncogene amplification in breast carcinoma.
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PMID:Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescence in situ hybridization. 923 84

Recent studies indicate that oncogenes may be involved in determining the sensitivity of human cancers to chemotherapeutic agents. To define the effect of HER-2/neu oncogene overexpression on sensitivity to chemotherapeutic drugs, a full-length, human HER-2/neu cDNA was introduced into human breast and ovarian cancer cells. In vitro dose-response curves following exposure to 7 different classes of chemotherapeutic agents were compared for HER-2- and control-transfected cells. Chemosensitivity was also tested in vivo for HER-2- and control-transfected human breast and ovarian cancer xenografts in athymic mice. These studies indicate that HER-2/neu overexpression was not sufficient to induce intrinsic, pleomorphic drug resistance. Furthermore, changes in chemosensitivity profiles resulting from HER-2/neu transfection observed in vitro were cell line specific. In vivo, HER-2/neu-overexpressing breast and ovarian cancer xenografts were responsive to different classes of chemotherapeutic drugs compared to control-treated xenografts with no statistically significant differences between HER-2/neu-overexpressing and nonoverexpressing xenografts. We found no instance in which HER-2/neu-overexpressing xenografts were rendered more sensitive to chemotherapeutic drugs in vivo. HER-2/neu-overexpressing xenografts consistently exhibited more rapid regrowth than control xenografts following initial response to chemotherapy suggesting that a high rate of tumor cell proliferation rather than intrinsic drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in human cancers.
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PMID:The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. 924 7

Prognostic factors capable of detecting potential for aggressive disease in early stage endometrial cancer might be useful in selecting patients for early adjuvant therapy. Sixty-three patients with surgical Stage I endometrial carcinoma treated by hysterectomy with a mean follow-up of 55 months were evaluated for tumor type, grade, depth of myometrial invasion, presence of vascular invasion, DNA ploidy, and HER-2/neu overexpression by immunohistochemical techniques. These results were compared with HER-2/neu gene amplifications evaluated by fluorescence in situ hybridization (FISH) and their ability to predict disease survival. For FISH, sections 5 microns thick of formalin-fixed, paraffin-embedded tissues were processed using the Oncor Chromosome In Situ Hybridization System. Automated hybridization using the Ventana Gen was performed with the Oncor unique sequence digoxigenin-labeled HER-2/neu DNA probe. Gene copy numbers were evaluated using the Zeiss Axioskop50 fluorescence microscope. HER-2/neu amplification was noted in 24 (38%) of 63 cases. By multivariate analysis, only aneuploidy (P = .04) and HER-2/neu amplification by FISH (P = .04) independently correlated with survival. Although we saw a relationship between HER-2/neu protein expression and gene amplification, this trend did not achieve statistical significance. HER-2/neu oncogene amplification can be assessed using automated FISH on formalin-fixed, paraffin-embedded tissue. HER-2/ neu amplification predicts poor outcome in Stage I endometrial cancer. HER-2/neu amplification status has potential use in the identification of patients with high risk of disease recurrence who might benefit from intensified therapy.
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PMID:Identification of HER-2/neu oncogene amplification by fluorescence in situ hybridization in stage I endometrial carcinoma. 926 26

Experimental and clinical observations of the proliferation of cancer cells and their responses to cytotoxic drugs already have had an impact on the design of anticancer therapies and it is possible that further understanding of the natural history of tumors will enable better treatments to be developed. This review addresses several approaches to improving the prognosis for patients with breast cancer in which our understanding of tumor dynamics plays an important role. Increasing dose intensity can be achieved by dose escalation (increasing the amount of drug) or increasing dose density (reducing the time between treatments). The Gompertzian model of tumor growth, which is concordant with many experimental and clinical observations, can offer an explanation why, although dose escalation improves the number of clinical responses, cure is still uncommon. In the Gompertzian model, smaller tumors grow faster, so tumor regrowth between treatment cycles is more rapid when cell kill is greatest. Reducing the time available for tumor regrowth (increasing dose density), which is now possible through the use of colony-stimulating factors to hasten hematopoietic recovery, may have a greater impact on clinical outcome than dose escalation. Sequential schedules allow optimal doses to be used in dose-dense cycles. Several cycles of the optimal dose of agent A, followed by several cycles of the optimal dose of agent B, may be more effective than the simultaneous combination of suboptimal doses of A and B. In this context, agents A and B may be single agents or established combinations. This tactic allows new agents, such as the taxoids, to be used in conjunction with established therapies, such as doxorubicin plus cyclophosphamide, at optimal doses in dose-intensive regimens. Although such regimens may maximize cytoreduction, this may not be sufficient to improve significantly the long-term outcome for patients with breast cancer. A recent trial using high-dose consolidation chemotherapy with autologous bone marrow support has thrown doubt on the assertion, implicit in Gompertzian cytodynamics, that optimal cytotoxic therapy can kill all tumor cells. The results of this trial suggest that a consistent number of tumor cells remain whether high-dose chemotherapy with autologous bone marrow support is used in patients in complete pathologic remission or in patients with overt relapse. If there is a lower limit to cytoreduction, other approaches must be developed to control or prevent the regrowth of residual tumor cells. This will require a better understanding of the molecular biology of breast cancer and the ability to predict and assess the sensitivity of individual patient's tumors to particular therapies. Factors such as HER2 overexpression are already being linked to sensitivity to particular agents and the products of oncogenes such as HER2 may be targeted by biologic therapies such as monoclonal antibodies. Furthering our understanding of the biology and behavior of tumor cells may lead to significant improvements in the long-term prognosis for patients with early and advanced breast cancer.
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PMID:Evolving concepts in the systemic drug therapy of breast cancer. 927

A bispecific antibody, MDX-H210, was developed to target cytotoxic effector cells expressing Fc gamma receptor type I (Fc gammaRI, CD64) to HER2/neu-overexpressing tumor cells. HER2/neu is an appropriate target for immunotherapy due to the high level of expression of this proto-oncogene in a variety of malignancies. The expression of Fc gammaRI is limited primarily to cytotoxic immune cells, including monocytes, macrophages, and cytokine-activated polymorphonuclear (PMN) cells. Therefore, tumor cells bound with MDX-H210 can be selectively recognized by effector cells with cytotoxic potential. MDX-H210 was prepared by chemical conjugation of Fab' fragments derived from the HER2/neu-specific monoclonal antibody, 520C9, and the Fc gammaRI-specific monoclonal antibody, H22. This bispecific molecule demonstrated specific, dose-dependent, and saturable binding to both HER2/neu- and Fc gammaRI-expressing cells. A solid-phase immunoassay that demonstrated simultaneous and specific binding to both antigens was used to confirm the bispecific nature of MDX-H210. Monocytes and PMN cells mediated MDX-H210-dependent lysis of HER2/neu-overexpressing cell lines derived from breast, ovarian, and lung carcinomas. IFN-gamma treatment of monocytes enhanced antibody-dependent cellular cytotoxicity, whereas IFN-gamma and granulocyte colony-stimulating factor were required for PMN cell-mediated tumor cell lysis. In addition, MDX-H210 elicited tumor necrosis factor-alpha secretion from monocytes when cultured in the presence of HER2/neu-positive target cells. These in vitro data suggest that targeting tumor cells to Fc gammaRI with MDX-H210 may be an effective treatment for malignancies that overexpress HER2/neu. The in vivo cytotoxic potential of MDX-H210 may be enhanced by combination therapy with the cytokines granulocyte colony-stimulating factor and IFN-gamma, which up-regulate Fc gammaRI expression on cytotoxic effector cells.
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PMID:Bispecific antibody-dependent cellular cytotoxicity of HER2/neu-overexpressing tumor cells by Fc gamma receptor type I-expressing effector cells. 930 86

Members of the epidermal growth-factor-receptor tyrosine-kinase (EGFR) family play important roles both in normal growth regulation/cell differentiation and in the genesis and progression of human neoplasia. In the present study, we analysed distinct heregulin (HRG) signals mediated by the HRG receptors HER3 and HER4. In overexpression cell systems, we demonstrate that HRG-induced transformation by "kinase-impaired" HER3 is dependent on coexpression of kinase active HER2. In cells coexpressing HER2 and HER4, however, both kinases significantly contribute to the HRG-induced mitogenic stimulus. In addition, we show that HER3 is no substrate of HRG-activated HER4. Analysis of EGFR crosstalk in a panel of human carcinoma cell lines revealed mainly HRG-induced activation of HER2/HER3, whereas HER4 activation is also detectable to various extents. Evidence for HRG-induced activation of HER3 and/or HER4 indicates relevance of cell-specific expression patterns of these high- and low-affinity HRG receptors in the modulation of a ligand-induced stimulus. Specific signal modulation and definition can be demonstrated further by distinct time courses of mitogen-activated protein (MAP) kinase (MAPK) activation, which are induced by distinct HRG isotypes via differential binding to HER2/HER3 versus HER2/HER4. In concert, these mechanisms of signal modulation may be decisive for the diverse biological activities of HRG in different cell types.
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PMID:Distinct characteristics of heregulin signals mediated by HER3 or HER4. 936 20


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