Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.
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PMID:Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer. 1144 26

The peptide, EMTPVNPG, derived from alpha-fetoprotein, inhibits estrogen-stimulated growth of immature mouse uterus and estrogen-dependent proliferation of human breast cancer cells. However, the biological activities of the peptide diminish over time in storage, even when in the lyophilized state, probably because of peptide aggregation through hydrophobic interaction among monomers. Two analogs of EMTPVNPG were designed with the intent of minimizing aggregation and retaining biological activity during prolonged storage. EMTOVNOG, where O is 4-hydroxyproline, is a linear peptide generated by substituting 4-hydroxyproline for the two prolines, thereby increasing peptide hydrophilicity. This analog exhibited a dose-dependent inhibition of estrogen-stimulated growth of immature mouse uterus similar to that of EMTPVNPG (maximal activity at 1 microg/mouse). A second analog, cyclo-(EMTOVNOGQ), a hydrophilic, cyclic analog with increased conformational constraint, was as potent as the other peptides in its inhibition of estrogen-dependent growth of immature mouse uterus, and had an expanded effective dose range. Both linear and cyclized hydroxyproline-substituted analogs exhibited indefinite shelf-life. Furthermore, both analogs inhibited the estrogen-dependent growth of MCF-7 human breast cancer growing as a xenograft in SCID mice. These analogs may become significant, novel agents for the treatment of breast cancer.
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PMID:Development of a synthetic cyclized peptide derived from alpha-fetoprotein that prevents the growth of human breast cancer. 1157 31

We have recently characterized a human bladder cancer cell line T24 and a more aggressive lineage related variant of it, T24T. To gain further insights, we have studied their metastatic ability in an in vivo model system. Results show that T24 forms significantly fewer [4/12 (1/11) mice had metastases with 1-2 lesions/mouse] metastasis in SCID/bg mice than T24T [14/14 (6/6) mice had metastases with a mean of 24-28 lesions/mouse]. To begin exploring the mechanisms underlying this difference, we evaluated the mRNA and protein expression levels of metastasis-suppressor genes, known to be important in the progression of other cancers, in our model of bladder cancer progression. A higher mRNA expression of BRMS1, a metastasis suppressor in breast cancer, was observed in T24 cells. In addition, RhoGDI2 mRNA expression was only observed in T24 when compared to T24T, suggesting that Rho activation might play a significant role in the metastatic cascade. However, a basal level mRNA expression of KISS1, described as metastasis suppressor in melanoma and breast, was observed in both the lines and had slightly higher expression in T24T. No difference of Nm23-H1, KAI1, MKK4/SEK1 and E-Cadherin protein levels were noted between these two lines. In summary, it appears that the T24/T24T paired cell lines constitute a useful model for the study of human bladder cancer metastasis that will allow both the discovery and mechanistic evaluation of genes potentially involved in this process.
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PMID:The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines. 1159 9

Endoglin (EDG; CD105) is a proliferation-associated cell membrane antigen of endothelial cells and is strongly expressed on the tumor-associated angiogenic vascular endothelium. Furthermore, EDG is essential for angiogenesis and a component of the transforming growth factor (TGF)-beta receptor complex. The present three anti-EDG monoclonal antibodies (mAbs), SN6f, SN6j, and SN6k, react strongly with proliferating human endothelial cells but cross-react very weakly with murine endothelial cells. Analysis of Scatchard plot of direct binding of these mAbs to proliferating human umbilical vein endothelial cells showed equilibrium constants of 8.3 x 10(9), 3.1 x 10(9), and 1.0 x 10(9) liter/mol, respectively, for SN6f, SN6j, and SN6k. These mAbs did not react with MCF-7 human breast cancer cells. To facilitate antiangiogenic tumor therapy by these mAbs in animal models, we used human skin/severe combined immunodeficiency (SCID) mouse chimeras bearing tumors of MCF-7. Blood vessels in the chimeras were analyzed by immunostaining with species (human or mouse)-specific anti-CD31 and anti-EDG mAbs including an antihuman EDG mAb termed SN6h. Blood vessels in the completely healed grafted human skins consisted of a mixture of human (43.5%) and murine (56.5%) vessels, whereas only murine vessels were detected in the adjacent murine skins and s.c. tissues. Therefore, murine vessels infiltrate into the human skin grafts from the adjacent murine tissues, whereas the growth of human vessels is limited within the boundary of human skins. Growth of human MCF-7 tumors in the human skin grafts increased the ratio of human:murine vessels. Analyses of the grafted skins before and after tumor transplantation showed that SN6h reacted with tumor-induced angiogenic blood vessels but not with nonangiogenic vessels, whereas antihuman CD31 mAb reacted with both angiogenic and nonangiogenic vessels. The results show that SN6h is capable of distinguishing the tumor-induced angiogenic vasculature from the nonangiogenic vasculature in the present model. Antiangiogenic therapy of the chimeras bearing established MCF-7 tumors was carried out by i.v. administration of a mAb(s) via the tail vein of mice. SN6j and SN6k were effective for suppressing the established tumors, whereas tumor suppression was weaker with SN6f. The results indicate an absence of a direct correlation between antigen-binding avidity and in vivo antitumor efficacy of anti-EDG mAbs and suggest the importance of other factors (e.g., epitopes) in antitumor efficacy. No significant toxicity of the mAbs was detected. Combination of SN6f and SN6k that define mutually nonoverlapping epitopes showed an additive antitumor effect. Combination of SN6j and cyclophosphamide using an antiangiogenic schedule of drug dosing showed synergistic antitumor efficacy. The combination therapy induced lasting complete regression of the established tumors in two of the eight treated chimeras. We examined human and murine blood vessels in large human tumors from the chimeras at the end of therapeutic experiment. The test showed that SN6j therapy resulted in complete suppression of human vessels in the tumors but resulted in only weak suppression of murine vessels. Cyclophosphamide was not effective for suppressing human vessels and only weakly suppressive against murine vessels. Combination of SN6j and cyclophosphamide was effective for completely suppressing human vessels and also effective for partial (i.e., 35%) suppression of murine vessels. The results show that systemic administration of naked antihuman EDG mAbs can suppress established tumors, and the efficacy is markedly enhanced by combining a chemotherapeutic drug using an antiangiogenic schedule of drug dosing. These mAbs should show stronger antitumor efficacy in patients whose tumors depend entirely on human blood vessels.
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PMID:Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. 1169 2

In vivo pH measurements by magnetic resonance spectroscopy reveal the presence of large regions of acidic extracellular pH in tumours, with the intracellular pH being maintained in the neutral-to-alkaline range. This acid-outside plasmalemmal pH gradient acts to exclude weak base drugs such as the anthracyclines and vinca alkaloids, a behaviour that is predicted by the decrease in octanol-water partition coefficients of mitoxantrone and doxorubicin with decreasing solution pH. This pH gradient can be reduced or eliminated in mouse models of breast cancer by systemic treatment with sodium bicarbonate. We have demonstrated tumour alkalinization following chronic ad libitum administration of NaHCO3 and acute intraperitoneal administration of NaHCO3 to tumour-bearing mice. Chronic treatment of tumour-bearing SCID mice with NaHCO3 results in an enhancement in MCF-7 tumour xenograft response to doxorubicin. Intraperitoneal administration of NaHCO3 to tumour-bearing C3H/Hen mice prior to treatment with mitoxantrone results in a greater-than 4.5-fold increase in cell-kill in the syngeneic C3H mammary tumour model. Most combination chemotherapy regimens include at least one weak base drug. Our results suggest that agents such as sodium bicarbonate, Carbicarb and the diuretic furosemide--which are known to induce metabolic alkalosis in humans--may be useful in enhancing the efficacy of these treatment regimens in humans.
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PMID:pH and chemotherapy. 1172 30

MDA-MB-231 (MDA-231) human breast cancer cells have a high proliferation rate, lack the estrogen receptor, express the intermediate filament vimentin, the hyaluronan receptor CD44, and are able to form tumors in nude mice. The MDA-231 cell line has been used in our laboratory to examine the role of the peripheral-type benzodiazepine receptor (PBR) in the progression of cancer. During these studies 2 populations of MDA-231 cells were subcloned based on the levels of PBR. The subclones proliferated at approximately the same rate, lacked the estrogen receptor, expressed vimentin and CD44, and had the same in vitro chemoinvasive and chemotactic potential. Both restriction fragment length polymorphism and comparative genomic hybridization analyses of genomic DNA from these cells indicated that both subclones are of the same genetic lineage. Only the subclone with high PBR levels, however, was able to form tumors when injected in SCID mice. These data suggest that the ability of MDA-231 cells to form tumors in vivo may depend on the amount of PBR present in the cells.
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PMID:Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in SCID mice. 1174 9

Mucin1 stimulated hematopoietic mononuclear cells (M1SHMC) from patients with breast cancer, adoptively transferred to non-obese diabetic, severe combined immunodeficient (NOD SCID) mice, extended survival in a therapy model of gross adenocarcinoma and prevented tumor growth in a model of minimal disease. M1SHMC exhibited specific lysis of a human breast adenocarcinoma cell line expressing mucin1, MCF-7 and produced interferon gamma. M1SHMC were injected intraperitoneally (IP) in NOD SCID mice after gross, palpable tumors appeared after MCF-7 were injected subcutaneously (SC). Survival was increased as compared to no M1SHMC controls. However tumors eventually regrew in all mice. To determine whether minimal disease (MD) could be controlled, NOD SCID were injected with MCF-7 cells, and on the same day, injected IP with M1SHMC. The M1SHMC injected mice were protected from tumor growth. These results imply that M1SHMC can prolong survival, but not cure NOD SCID mice bearing gross palpable adenocarcinomas. However in a minimal disease model tumor growth was prevented.
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PMID:Adoptive immunotherapy of mucin1 expressing adenocarcinomas with mucin1 stimulated human peripheral blood mononuclear cells. 1189 36

Lung cancer is becoming increasingly common in women and in the United States accounts for more female cancer deaths annually than breast cancer. Many epidemiological studies have provided evidence that women are more susceptible than men to the adverse effects of tobacco smoke. These observations suggest the possible role of estrogens in lung carcinogenesis. We report here the expression of mRNA for estrogen receptor alpha (ERalpha) and beta (ERbeta) in cultured human non-small cell lung cancer cells, cultured lung fibroblasts, and primary cultures of normal bronchial epithelium. Western analysis of ERalpha suggested that the main protein expressed in lung tumor cells is a variant, probably attributable to alternative splicing. Protein for ERbeta was found to be a mixture of full-length as well as alternatively spliced variants. beta-Estradiol produced a proliferative response in vitro in both normal lung fibroblasts and cultured non-small cell lung tumor cells. This effect was also observed in vivo. In this regard, beta-estradiol stimulated growth of the non-small cell lung tumor line, H23, grown as tumor xenografts in SCID mice. This effect was blocked by fluvestrant (ICI 182,780). In paraffin sections of non-small cell lung tumors, ERbeta immunoreactivity was localized to the nucleus, whereas ERalpha immunoreactivity was mainly localized to the cytoplasm, suggesting that both nuclear and cytoplasmic signaling may be involved in estrogenic responses in the lung. To show that the ERs found in the lung are functional, we demonstrated that beta-estradiol stimulated transcription of an estrogen response element-luciferase construct transfected in non-small cell lung tumor cell lines. Antiestrogens blocked this effect. Treatment of lung fibroblasts with beta-estradiol also increased secretion of hepatocyte growth factor by 2-fold. These results suggest that estrogen signaling plays a biological role in both the epithelium and the mesenchyme in the lung and that estrogens could potentially promote lung cancer, either through direct actions on preneoplastic or neoplastic cells or through indirect actions on lung fibroblasts. Additionally, it is possible that antiestrogens may have therapeutic value to treat or prevent lung cancer.
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PMID:Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. 1192 36

MUC1 mucin is aberrantly expressed in many epithelial malignancies and is a promising tumor antigen for target-directed immunotherapy against human breast cancer. Mycobacterium BCG is an effective immunoadjuvant which is known to induce Th1 immune response. Recombinant BCG expressing tumor antigen and secreting cytokine may therefore potentiate the tumor antigen-specific immune responses. In this study, we constructed a recombinant BCG-MUC1-IL2, which expresses a high level of human MUC1 VNTR core protein and secretes functional interleukin 2 (IL2). The immune responses induced by BCG-MUC1-IL2 were examined using a SCID mouse model reconstituted with immunologically competent human lymphocytes, SCID/hu-PBL. The mucin-specific IFN-gamma was secreted only by the lymphocytes derived from animals immunized with BCG-MUC1-IL2, but not with BCG-vector or purified mucin protein for the vaccination. In contrast, in vitro secretion of IL4 by the immunized lymphocytes was only seen in the group of animals which received native MUC1 protein, but not BCG-MUC1-IL2 and BCG-vector. Minimal MUC1-specific IgG and IgM were detected in SCID/hu-PBL mice vaccinated with BCG-MUC1-IL2. These results suggest that BCG-MUC1-IL2 preferentially induces MUC1-specific cellular immune responses and it may serve as a vaccine for breast cancer prevention and treatment.
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PMID:Induction of MUC1-specific cellular immunity by a recombinant BCG expressing human MUC1 and secreting IL2. 1201 14

Tumor cell contamination of clinical grafts is a major concern in autologous hematopoietic stem cell transplantation because these contaminating cells can contribute to relapse. In the present work, we use a suicide gene therapy approach that successfully accomplishes the two main goals of any purging strategy: highly efficient elimination of contaminating tumor cells and preservation of the engraftment capability of the hematopoietic progenitor cells. Human CD34(+) cells spiked with breast cancer cells were infected with an adenoviral vector encoding the cytosine deaminase transgene (Ad-CMV-CD). In vitro, transduction with Ad-CMV-CD followed by exposure to 400 micro M 5-fluorocytosine resulted in complete elimination of clonogenic contaminating tumor cells without affecting the clonogenic potential of the human hematopoietic CD34(+) cells. Transplantation of nonobese diabetic/LtSz-scid/severe combined immunodeficient (NOD/SCID) mice with nonpurged contaminated grafts and purged contaminated grafts, allowed us to test the safety and efficacy of our procedure in two independent purging experiments. Hematopoietic engraftment kinetics as well as the quantity and quality of human engraftment were not affected by the purging therapy. Results showed a significant difference in survival between the nonpurged group (28%) and the purged group (100%; P = 0.012). Moreover, highly sensitive histological and molecular analyses confirmed the absence of tumor cells in the recipients of purged marrow. In contrast, metastatic tumors were detected in animals that received nonpurged grafts. We anticipate that this strategy will result in a safe and efficacious hematopoietic graft product for autologous transplantation for patients with multiple forms of epithelial cancers.
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PMID:Efficient and nontoxic adenoviral purging method for autologous transplantation in breast cancer patients. 1220 55


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