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)

In our continuous studies of anticancer activity of steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca (Dioscoreaceae), methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787) were tested for cytotoxicity against human cancer cell lines from leukemia and eight solid tumor diseases. As a result, methyl protoneogracillin was cytotoxic against all the test cell lines with GI(50) < 100 micro M, especially selectively against two leukemia lines (CCRF-CEM and RPMT-8226), one colon cancer line (KM12), two central nervous system (CNS) cancer lines (SF-539 and U251), one melanoma line (M14), one renal cancer line (786-0), one prostate cancer line (DU-145), and one breast cancer line (MDA-MB-435), with GI(50) < or = 2.0 micro M. Leukemia, CNS cancer, and prostate cancer were the most sensitive subpanels, while ovarian cancer was the least sensitive subpanels. The preliminary toxicity studies showed that the maximum tolerant dose was 600 mg/kg for methyl protoneogracillin to mice. Gracillin was cytotoxic against most cell lines with GI(50), TGI and LC(50) at micromolar levels, but no activity against EKVX (non-small cell lung cancer), HT29 (colon cancer), OVCAR-5 (ovarian cancer), and SN12C (renal cancer). Based on structure-activity relationship, C-25 R/S con fi guration was critical for leukemia selectivity between methyl protoneogracillin and methyl protogracillin. F-ring was critical to selectivity between furostanol (methyl protoneogracillin and methyl protogracillin) and spirostanol (gracillin) saponins in this study. By an analysis of COMPARE software, no compounds in the NCI's database had similar mean graphs to those of methyl protoneogracillin and gracillin, respectively, indicating potential novel mechanism(s) of action involved. Put all in together, methyl protoneogracillin has been selected as a potential anticancer candidate for hollow fi ber assay to nude mice, but gracillin will not be pursued due to lack of selectivity against human cancer diseases.
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PMID:The cytotoxicity of methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787), two steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in vitro. 1282 Feb 29

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects cancer cells against apoptosis. Therefore, we investigated whether this transcription factor could modulate the expression of the Bcl-2 antiapoptotic protein. Bcl-2 promoter analysis showed multiple putative NF-kappaB binding sites. Transfection assays of bcl-2 promoter constructs in HCT116 cells showed that NF-kappaB can indeed transactivate bcl-2. We identified a kappaB site located at position -180 that can only be bound and transactivated by p50 or p52 homodimers. As p50 and p52 homodimers are devoid of any transactivating domains, we showed that they can transactivate the bcl-2 promoter through association with Bcl-3. We also observed that stable overexpression of p100 and its processed product p52 can induce endogenous Bcl-2 expression in MCF7AZ breast cancer cells. Finally, we demonstrated that, in breast cancer and leukemic cells (CLL), high NF-kappaB2/p100 expression was associated with high Bcl-2 expression. Our data suggest that Bcl-2 could be an in vivo target gene for NF-kappaB2/p100.
Leukemia 2003 Jul
PMID:NF- kappa B2/p100 induces Bcl-2 expression. 1283 24

The breast cancer susceptibility gene BRCA2 has recently been identified as identical to the Fanconi anemia (FA) gene FANCD1. Here we expand the clinical implications of this discovery. Notably, we identified 6 children in 5 kindreds exhibiting the co-occurrence of BRCA2 mutations, FA, and early onset acute leukemia. Leukemia occurred at a median of 2.2 years of age in the BRCA2 patients in contrast to a median onset of 13.4 years in all other FA patients in the International Fanconi Anemia Registry (IFAR; P <.0001). Breast cancer was noted in 4 of the 5 kindreds. Of the 6 children with leukemia, 4 were treated with bone marrow transplantation and 2 are alive at 3 and 9 months after treatment. Our results suggest that BRCA2 testing should be considered in all patients with FA in whom the complementation group cannot be defined or in whom leukemia is diagnosed at or before 5 years of age.
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PMID:Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. 1507 Jul 7

Adjuvant combination chemotherapy reduces the risk of relapse and death for patients with invasive breast cancer and adds to the benefits obtained with hormonal treatment. Generally, anthracycline-containing regimens are superior to non-anthracycline regimens, treatments longer than 6 months are not advantageous and high-dose chemotherapy regimens, which require autologous hematopoietic stem cell support, have not proved consistently superior. The development and evaluation of the taxanes was highly anticipated as they have shown high levels of efficacy while appearing to be non-cross-resistant with partially non-overlapping toxicities. A role for taxanes in the adjuvant or neoadjuvant setting is now widely acknowledged, although they are not currently approved for treatment of early breast cancer in Europe. In patients with aggressive lymphoma who receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, 40% to 70% of patients attain a complete remission, depending on risk factors such as age and extranodal involvement. Second- and third-generation regimens like m-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide), Pro-MACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate), and MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) have largely failed to improve treatment outcome. The use of monoclonal anti-CD20 antibodies or dose escalation have shown promising results in improving relapse-free and survival rates. In patients with breast cancer, the key Cancer and Leukemia Group B 9741 trial showed that dose-dense doxorubicin, cyclophosphamide, and paclitaxel chemotherapy with granulocyte colony-stimulating factor (G-CSF), repeated every 2 weeks, is superior to the same regimen administered at standard 3-weekly intervals. In lymphoma, dose-dense CHOP chemotherapy has shown superiority over standard CHOP regimens, particularly in elderly patients with aggressive non-Hodgkin's lymphoma. G-CSF factor is essential to enable the administration of dose-dense chemotherapy and any reduction in its use leads to significant increases in infectious complications. Current evidence suggests that dose-dense chemotherapy, enabled by G-CSF, is an important breakthrough in the evolution of chemotherapy for breast cancer and lymphoma.
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PMID:Dose-dense chemotherapy in breast cancer and lymphoma. 1518 5

Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas); hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias); and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor (Burkitt's lymphoma-EBV; mesothelioma - SV(40)). For others the association is inconsistent (Hodgkin's Disease, gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious agents will continue to illuminate molecular oncogenic processes.
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PMID:Infectious agents and cancer: criteria for a causal relation. 1548 39

The tAnGo trial is a randomized, open-label, multicenter phase III trial examining adjuvant treatment with epirubicin (Ellence)/cyclophosphamide (Cytoxan, Neosar) for four cycles followed by paclitaxel alone or combined with gemcitabine (Gemzar) for four cycles in patients with early-stage breast cancer. In the Cancer and Leukemia Group B (CALGB) 9344 trial, addition of paclitaxel to anthracycline/cyclophosphamide adjuvant therapy resulted in increased time to recurrence and improved survival. Because an unplanned subgroup analysis in CALGB 9344 indicated a significant benefit of paclitaxel in patients with estrogen receptor (ER)-negative disease but not ER-positive disease, the initial tAnGo trial design called for enrollment of patients with ER-negative disease. The tAnGo trial entry criteria were recently amended to allow any ER status, given experience suggesting that clinical benefit of taxane-containing regimens in ER-positive disease may emerge over a time frame longer than that required to detect benefit in ER-negative disease. Gemcitabine has been included as a partner for paclitaxel in the tAnGo trial based on high response rates, including high complete response rates, observed in phase II trials of the combination in more advanced disease and based on the tolerability and safety of the combination compared with those of other taxane-containing two-drug combinations. The tAnGo trial is currently accruing patients and has a target population of 3,000. Trial results should provide important information on the role of gemcitabine in adjuvant therapy for breast cancer.
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PMID:Adjuvant chemotherapy for early-stage breast cancer: the tAnGo trial. 1568 22

Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton-Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice.
Breast Cancer Res 2005
PMID:Dose-dense adjuvant chemotherapy for primary breast cancer. 1574 13

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.
Leukemia 2005 Jun
PMID:CLL family 'Pedigree 14' revisited: 1947-2004. 1580 Jun 70

Influence of the molecular structure of macrocyclic pyridinophanes, their analogues and some other compounds on anticancer activity (Leukemia, central nervous system (CNS) cancer, prostate cancer, breast cancer, melanoma, non-small cell lung cancer, colon cancer, ovarian cancer, renal cancer) was investigated by means of a new 4D-QSAR approach based on the simplex representation of molecular structures (SiRMS). For all the investigated molecules, the 3D structural models were first created and the set of conformers (fourth dimension) was used. Each conformer was represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). Statistic characteristics of the QSAR partial least squares (PLS) models were satisfactory (correlation coefficient r=0.990-0.861; cross-validation coefficient CVR=0.914-0.633). The molecular fragments increasing and decreasing anticancer activity were defined. This information may be useful for the design and direct synthesis of novel anticancer agents.
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PMID:Investigation of anticancer activity of macrocyclic Schiff bases by means of 4D-QSAR based on simplex representation of molecular structure. 1580 10

This article will review the strategy of dose-dense administration of chemotherapy for breast cancer. Increased dose density is achieved by reducing the interval between each dose of chemotherapy. The cumulative drug dose remains constant, but the same amount of drug is administered over a shorter period. Mathematical models of tumor growth have provided the basis for the clinical application of dose-dense chemotherapy. The Norton-Simon model suggests that increasing the dose density of chemotherapy will increase efficacy by minimizing the opportunity for regrowth of tumor cells between cycles of chemotherapy. Intergroup trial 9741, coordinated by the Cancer and Leukemia Group B (CALGB), tested the 2 hypotheses that dose-dense and sequential administration of chemotherapy regimens incorporating doxorubicin, cyclophosphamide, and paclitaxel would improve disease-free survival and overall survival. A statistically significant 4-year disease-free survival advantage was detected for the 2 dose-dense regimens compared with the regimens administered every 3 weeks. The mathematical concepts and previous clinical trials of dose density that contributed to the design of CALGB 9741 will be reviewed. The strengths and limitations of CALGB 9741 will then be discussed before the presentation of future directions of research and recommendations for clinical practice today.
Clin Breast Cancer 2005 Dec
PMID:Concepts and clinical trials of dose-dense chemotherapy for breast cancer . 1638 23


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