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)

The ability of metastatic cells to survive antiapoptotic signals may contribute to the organospecific-spread patterns of clinical metastasis and dormancy. MDA-MB-435 breast cancer cells (435/Bcl-x(L)), which overexpress the Bcl-x(L) gene, were labeled with the luciferase gene and injected orthotopically into homozygous athymic Balb/c (nude) mice to study the metastatic behavior of the breast cancer cells. The overexpression of Bcl-x(L) in tumors increased the overall metastatic burden in mice (bones, liver, kidneys, brain, lungs, and lymph nodes) in comparison with control tumors (435/NEO:luc) during the same time interval (ANOVA, p = 0.005). The principal differences after 110 days were found in bones, which had 1.5 x 10(5) +/- 1.2 x 10(5) tumor cell equivalents (p = 0.03), and lymph nodes, which had 7.0 x 10(6) +/- 6.0 x 10(6) tumor cell equivalents (p = 0.08). The analyses of light production by tissues at different times showed that cells from 435/NEO:luc and 435/Bcl-x(L).luc tumors were detectable in several organs by the second day after intramammary fat pad implantation. Although initially arriving at the target organs in similar numbers, 435/Bcl-x(L) cells developed more metastases than 435/Neo cells, indicating that the Bcl-x(L) gene might have a role in breast cancer dormancy, promoting survival of cells in metastatic foci. Thus, we suggest that overexpression of Bcl-x(L) could counteract the proapoptotic signals in the microenvironment and favor the successful development of metastasis in specific organs.
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PMID:Metastatic behavior of human breast carcinomas overexpressing the Bcl-x(L) gene: a role in dormancy and organospecificity. 1135 Oct 44

In addition to immunomodulatory and cytokine-modulatory properties, thalidomide has antiangiogenic activity. It has been investigated in a number of cancers including multiple myeloma, myelodysplastic syndromes, gliomas, Kaposi's sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Its role has been best explored in myeloma, where, at daily doses of 100 to 800 mg, it is remarkably active, causing clinically meaningful responses in one-third of extensively pretreated patients and in over half of patients treated early in the course of the disease. It also acts synergistically with corticosteroids and chemotherapy in myeloma. Thalidomide produces improvement of cytopenias characteristic of myelodysplastic syndrome, resulting in the reduction or elimination of transfusion dependence in some patients. Responses have also been seen in one-third of patients with Kaposi's sarcoma, in a small proportion of patients with renal cell carcinoma and high grade glioma and, in combination with irinotecan, in some patients with colon cancer. Thalidomide is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation and fatigue are common adverse effects seen in 75% of patients. Symptoms of peripheral neuropathy and skin rash are seen in 30%. A minority of patients experience bradycardia and thrombotic phenomena. Despite the high frequency of adverse effects, those severe enough to necessitate cessation of therapy are seen in only 10 to 15% of patients. A therapeutic trial of thalidomide should be considered in all patients with myeloma who are unresponsive to or relapse after standard therapy. In other malignant diseases, the most appropriate way to use the drug is in the setting of well designed clinical trials. In the absence of access to such studies, thalidomide could be considered singly or in combination with standard therapy in patients with no meaningful therapeutic options.
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PMID:Thalidomide in cancer: potential uses and limitations. 1143 82

The selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT) is a full agonist at the transforming growth factor (TGF) alpha gene in ER negative breast cancer cells stably transfected with ER alpha cDNA (Levenson et al., Br. J. Cancer 77 (1998) 1812-1819). E(2) and 4-OHT increase TGF alpha mRNA and protein in a concentration dependent manner. The responses to E(2) and 4-OHT are blocked by the pure antiestrogen ICI 182,780, which does not induce TGF alpha. Transfected MDA-MB-231 cells contain functional ER alpha but no ER beta function was detected. Neo transfected cells that did not express ER alpha or cells stably transfected with the DNA binding domain mutant C202R/E203V which prevents gene activation did not induce TGF alpha mRNA after either E(2) or 4-OHT treatment. An examination of the time course for either 10 nM E(2) or 1 microM 4-OHT for MDA-MB-231 cells stably transfected with cDNA for ER alpha showed increases in TGF alpha mRNA within 2 or 3 h respectively. Cells pretreated with cycloheximide (1 microg/ml) showed induced TGF alpha mRNA in response to E(2) or 4-OHT but TGF alpha mRNA induction was blocked by actinomycin D (1 microg/ml). We conclude that both E(2) and 4-OHT induce TGF alpha by direct interaction of ER alpha with DNA and that ER beta is not involved in the estrogen-like response to 4-OHT in the MDA-MB-231 cells.
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PMID:Estrogen receptor alpha mediated induction of the transforming growth factor alpha gene by estradiol and 4-hydroxytamoxifen in MDA-MB-231 breast cancer cells. 1153 Feb 83

Thalidomide has immunomodulatory and anti-angiogenic properties which may underlie its activity in cancer. After its success in myeloma, it has been investigated in other plasma cell dyscrasias, myelodysplastic syndromes, gliomas, Kaposi's sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Thalidomide causes responses in 30-50% of myeloma patients as a single agent, and acts synergistically with corticosteroids and chemotherapy. Thalidomide results in the reduction or elimination of transfusion-dependence in some patients with myelodysplastic syndrome. Responses have also been seen in one-third of patients with Kaposi's sarcoma, in a small proportion of patients with renal cell carcinoma and high-grade glioma, and in some patients with colon cancer in combination with irinotecan. The drug is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation, and fatigue are common side effects, whereas peripheral neuropathy and skin rash are seen in one-third. A minority of patients experience bradycardia. Thrombotic phenomena are especially common when thalidomide is combined with chemotherapy. Adverse effects severe enough to necessitate cessation of therapy are seen in around 20% of patients. A therapeutic trial of thalidomide is essential in all patients with relapsed or refractory myeloma. In other cancers, the best way to use the drug is in the setting of clinical trials. In the absence of access to studies or alternative therapeutic options, thalidomide could be considered singly or in combination with standard therapy.
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PMID:Thalidomide in cancer. 1190 8

Bag1 proteins bind heat shock protein M(r) 70,000 (Hsp 70) family molecular chaperones and regulate diverse pathways involved in cell proliferation, apoptosis, and stress responses. Four isoforms of Bag1 can be produced from a single gene in humans, including a nuclear-targeted long version (Bag1L)and a shorter cytosolic isoform (Bag1). Because overexpression of Bag1and Bag1L has been reported in breast cancers, we explored the effects of Bag1 and Bag1L on the growth of ZR-75-1 human breast cancer cells cultured in vitro and in tumor xenograft models using immunocompromised mice. Cells stably transfected with expression plasmids encoding either Bag1 or Bag1L displayed comparable rates of growth in cultures containing 10% serum, compared with control-transfected ZR-75-1 cells. In contrast, ZR-75-1 cells stably expressing mutants of Bag1 or Bag1L, which lack the COOH-terminal domain (DeltaC) required for heat shock protein M(r) 70,000 binding, displayed retarded growth rates. When cultured without serum, the viability of control-transfected, as well as Bag1DeltaC- and Bag1LDeltaC-expressing, cells declined with time, whereas Bag1- and Bag1L-overexpressing ZR-75-1 cells survived for over a week in culture. Caspase protease activation induced by serum deprivation was also prevented by stable expression of either Bag1 or Bag1L in ZR-75-1 cells. In addition, sensitivity to anchorage dependence was restored partially in ZR-75-1 cells expressing dominant-negative Bag1DeltaC and Bag1LDeltaC. In tumor xenograft studies involving injection of ZR-75-1 cells into mammary fat pads of female nu/nu mice, ZR-75-1 cells expressing Bag1 or Bag1L formed 1.4-1.6-fold larger tumors compared with control-transfected cells, whereas tumors formed by Bag1DeltaC- and Bag1LDeltaC-expressing cells grew very slowly and reached sizes < one-third of tumors generated by Neo-control ZR-75-1 cells. Altogether, these findings demonstrate that Bag1 and Bag1L provoke similar changes in breast cancer cell growth and survival and suggest that interference with Bag1 or Bag1L function might be a useful strategy for opposing breast cancer.
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PMID:Bag1 proteins regulate growth and survival of ZR-75-1 human breast cancer cells. 1191 72

Angiogenesis, in particular anti-angiogenesis, is an area of particular therapeutic interest in cancer treatment. Several anti-angiogenic agents are in the final stages of clinical trials. One of these agents, thalidomide, best known for its teratogenic potential, is showing promise against several tumor types. Thalidomide has been shown previously to require bio-activation to exert its anti-angiogenic effect in isolated blood vessels and endothelial cells. In this work, we confirmed these findings using the in utero chicken embryo chorioallantoic membrane (CAM) system. In particular, the anti-angiogenic effect of thalidomide is significantly enhanced by activation by human but not by rat liver microsomes. We also showed in the CAM assay that hydroxylation of thalidomide at either the 1'- or 5-position retained anti-angiogenic activity whereas its hydroxylation at the 4-position led to an inactive compound. We further demonstrated that thalidomide shows weak anti-proliferative activity against MDA-MB-231 human breast cancer cells in culture. Thalidomide showed slightly more anti-proliferative activity, however, against the SH-SY5Y human neuroblastoma and human umbilical vein endothelial cell (HUVEC) types. Furthermore, incubation of thalidomide with human liver microsomes added no additional anti-proliferative effect in these cell types versus thalidomide given alone. Finally, we report that none of the thalidomide metabolites tested had any anti-proliferative effect against the breast or neuroblastoma cells, but do possess appreciable anti-proliferative activity against the endothelial cells. In summary, this work suggests that hydroxylated thalidomide analogs based on putative metabolites of the drug possess significant anti-angiogenic activity and that exploring further derivatives of these as potential anti-angiogenic agents warrants further merit.
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PMID:Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation. 1203 99

Neo-adjuvant chemotherapy of epirubicin plus paclitaxel was administered to 23 patients with locally advanced breast cancer (including 13 cases of stage IIb, 6 of stage IIIa, and 4 of stage IIIb). All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v. followed paclitaxel 150 mg/m2 by 3 hours continuous infusion on day 2 and every 3 weeks repeatedly. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteric and allergic reactions before chemotherapy. Two to 4 cycles were used. Ten out of 23 patients had a complete response, 10 had partial response, and 3 had no change. The response rate was 87% (20/23). Six out of 23 patients underwent breast conserving surgery as tumor size had become smaller and downstaging was realized after neo-adjuvant chemotherapy. The major toxicities included neutropenia, myalgia, arthralgia, nephrotoxicity, gastroenteric reactions, alopecia and flushing to the face. However, these were well tolerated in these patients.
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PMID:[Clinical evaluation of effects from neo-adjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer]. 1214 94

Reduction in apoptosis has been associated with tumor metastases and response to chemotherapy in breast cancer. We examine the influence of apoptosis status and the expression of antiapoptotic proteins Bcl-2 and Bcl-x(L) on metastatic progression and response to therapy in an experimental model of breast cancer. We used human breast cancer cells (MDA-MB 435, MDA-MB 468 and MCF-7) to induce orthotopic xenograft tumors in nude mice. The overexpression of Bcl-2 or Bcl-x(L) influenced tumorigenicity, 468 transfectants being less tumorigenic than control (p < 0.0001). Lung metastasis appeared at day 120 in animals injected with 435/Bcl-2 or 435/Bcl-x(L) and they showed higher metastatic activity than control 435/Neo tumors (p = 0.02). In contrast, mice with 468 tumors were followed for 1 year after tumor excision, but they did not develop metastatic foci. 435/Bcl-2 and 435/Bcl-x(L) transfectant cells bound less readily to laminin (ANOVA, p < 0.0001), fibronectin (ANOVA, p < 0.0001) and collagen type-IV (ANOVA, p < 0.0001) than 435/Neo cells. The overexpression of antiapoptotic proteins in 435 transfectants rescued 20-40% of cells from anoikis at 64 hr in rocking conditions. In contrast, at this time only 5-10% of 468 and MCF-7 transfectant cells were rescued. Thus, the overexpression of the Bcl-2 or Bcl-x(L) associated with the loss of apoptosis in breast cancer cells in vivo may account for their metastatic behavior. These genes increase tumor metastasis when the oncogenic background has triggered the metastatic process, in which anoikis might determine tumor progression when the life span of the cells is extended.
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PMID:Inhibition of apoptosis in human breast cancer cells: role in tumor progression to the metastatic state. 1220 55

Biological response modifiers improve the body's ability to fight cancer by immunostimulation. Although a century has passed since the first attempt was made to stimulate the host immune system against cancer, only the past decade has witnessed the scientific use of biological response modifiers. Recent advances in tumour immunology have enabled the development of specific agents targeted against cancer cells. Various biological response modifiers include monoclonal antibodies, interferons, interleukins, tumour necrosis factor, colony stimulating factors and anticancer vaccines. Monoclonal antibodies directed against tumour-specific agents have been approved for the treatment of breast cancer (trastuzumab), non-Hodgkin's lymphoma (rituximab) and for the diagnosis of certain cancers (oncoscint). Interferons are indicated for the treatment of certain leukaemias and Kaposi's sarcoma to inhibit tumour proliferation and angiogenesis. Interleukin-2 is the most widely studied interleukin, and is used for immunostimulation in metastatic renal cell carcinoma and malignant melanoma. Haematopoletic growth factors are often combined with chemotherapy and radiotherapy to restore bone marrow function and treat complications such as infection and bleeding. Thalidomide, which suppresses tumour necrosis factor-alpha production and has antiangiogenic properties, is currently under evaluation in several cancers. Various anticancer vaccines are being developed using tumour cells, carbohydrates, peptides and heat-shock proteins as antigens. DNA-based vaccinations and the use of recombinant bacteria and viruses to deliver antigens or the DNA coding for them are also being investigated. However, the optimum choice of antigen, delivery vector and adjuvant, and administration regimen for some of these biological response modifiers are still being investigated.
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PMID:Biological response modifiers in cancer therapy. 1229 74

Neo-adjuvant, dose-dense docetaxel, 100 mg/m(2) every 2 weeks x 4 cycles, was administered to 12 patients with locally advance breast cancer (LABC) (10 stage IIIa and three stage IIIb). Eligibility requirements included a PS 0-2, normal hepatic and renal function, and radiologic absence of metastatic disease. Filgrastim [granulocyte colony stimulating factor (G-CSF)] was started 1 day after chemotherapy and was given for 6 days. Complete blood counts were determined weekly. Surgery was planned upon recovery from the last dose of docetaxel and followed by 4 cycles of adjuvant doxorubicin plus cyclophosphamide (AC) and radiotherapy. Patients with ER status received tamoxifen. The median age was 45 (range 34-73) and pre-treatment pathology revealed poorly differentiated infiltrating duct carcinoma in 11 and infiltrating lobular cancer in one, with positive ER/PR status in five. Twelve patients were treated, and all are evaluable for response and toxicity. Nine patients had a major clinical tumor response with five PR and four pathologic complete responses (pCR rate of 33%). Three patients (of whom two with stage IIIb) had progressive disease and went on to receive neo-adjuvant therapy with AC. There was one instance of grade 3 hematologic toxicity (neutropenic fever in one G-CSF non-compliant patient). There were two instances of grade 3 extra-hematologic toxicity: one patient had severe pain and one had treatment-related fatigue. After a median follow-up of 20 months (range 7-49 months) all patients are alive and eight of nine responders remain progression-free. Despite the small size of our study, we believe that dose-dense neo-adjuvant docetaxel is well tolerated and its activity warrants confirmation in a larger number of patients.
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PMID:Neo-adjuvant therapy with dose-dense docetaxel plus short-term filgrastim rescue for locally advanced breast cancer. 1239 62


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