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1.
Mol Cancer Ther ; 5(4): 1079-86, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16648580

RESUMO

In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers.


Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Compostos de Fenilureia/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/fisiologia , Ureia/farmacologia , Animais , Animais Geneticamente Modificados , Neoplasias da Mama/fisiopatologia , Caspases/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos
2.
Thyroid ; 15(3): 222-31, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15785241

RESUMO

Troglitazone is a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) that is a ligand-activated transcription factor regulating cell differentiation and growth. PPARgamma may play a role in thyroid carcinogenesis since PAX8-PPARgamma1 chromosomal translocations are commonly found in follicular thyroid cancers. We investigated the antiproliferative and redifferentiation effects of troglitazone in 6 human thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hürthle cell), and ARO82-1 (anaplastic) cell lines. PPARgamma was expressed variably in these cell lines. FTC-236 and FTC-238 had a rearranged chromosome at 3p25, possibly implicating the involvement of the PPARgamma encoding gene whereas the other cell lines did not. Troglitazone significantly inhibited cell growth by cell cycle arrest and apoptotic cell death. PPARgamma overexpression did not appear to be a prerequisite for a response to treatment with troglitazone. Troglitazone also downregulated surface expression of CD97, a novel dedifferentiation marker, in FTC-133 cells and upregulated sodium iodide symporter (NIS) mRNA in TPC-1 and FTC-133 cells. Our investigations document that human thyroid cancer cell lines commonly express PPARgamma, but chromosomal translocations involving PPARgamma are uncommon. Troglitazone, a PPARgamma agonist, induced antiproliferation and redifferentiation in thyroid cancer cell lines. PPARgamma agonists may therefore be effective therapeutic agents for the treatment of patients with thyroid cancer that fails to respond to traditional treatments.


Assuntos
Cromanos/farmacologia , PPAR gama/agonistas , PPAR gama/genética , Tiazolidinedionas/farmacologia , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular , Ciclo Celular/genética , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Mapeamento Cromossômico , Cromossomos Humanos Par 3 , Rearranjo Gênico , Humanos , Cariotipagem , Inibidores da Agregação Plaquetária/farmacologia , Translocação Genética , Troglitazona
3.
J Clin Endocrinol Metab ; 88(7): 3346-53, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12843186

RESUMO

Heat shock protein 90 (HSP90) serves as a chaperone protein and plays a critical role in tumor cell growth and/or survival. Geldanamycin, a specific inhibitor of HSP90, is cytotoxic to several human cancer cell lines, but its effect in thyroid cancer is unknown. We, therefore, investigated the effect of geldanamycin on cell proliferation, oncoprotein expression, and invasion in human thyroid cancer cell lines. We used six thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hürthle cell), and ARO (anaplastic). We used the dimethyl-thiazol-diphenyltetrazolium bromide assay, a clonogenic assay, an apoptotic assay, and a Matrigel invasion assay. We evaluated oncoprotein expression using Western blots and flow cytometry. After 6 d of treatment with 50 nM geldanamycin, the percent inhibition of growth was 29.4% in TPC-1, 97.5% in FTC-133, 96.7% in FTC-236, 10.8% in FTC-238, 70.9% in XTC-1, and 45.5% in ARO cell lines. In the FTC-133 cell line, geldanamycin treatment decreased clonogenicity by 21% at a concentration of 50 nM; geldanamycin induced apoptosis and down-regulated c-Raf-1, mutant p53, and epidermal growth factor (EGF) receptor expression; geldanamycin inhibited EGF-stimulated invasion. In conclusion, geldanamycin inhibited cancer cell proliferation, down-regulated oncoproteins, and inhibited EGF-induced invasion in thyroid cancer cell lines.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma Papilar , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinonas/farmacologia , Neoplasias da Glândula Tireoide , Adenocarcinoma Folicular , Adenoma Oxífilo , Antibióticos Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzoquinonas , Divisão Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Humanos , Técnicas In Vitro , Lactamas Macrocíclicas , Mutação , Quinonas/metabolismo , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Thyroid ; 13(12): 1103-10, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14751030

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many human cancer cells but not in normal cells. Thyroid cancer cells, however, appear to be relatively resistant to TRAIL-induced apoptosis. We therefore investigated the effect of chemotherapy on TRAIL-induced apoptosis in thyroid cancer cells. We used six thyroid cancer cell lines: TPC-1, FTC-133, FTC-236, FTC-238, XTC-1, and ARO82-1. We used flow cytometry to measure apoptosis, dimethyl-thiazol-diphenyltetrazolium bromide (MTT) assay to measure antiproliferation effects and Western blot to determine the expression of Bcl family proteins. Troglitazone, paclitaxel, geldanamycin, and cycloheximide were used for pretreatment. We used the Student's t test and analysis of variance (ANOVA) for statistical analysis. All thyroid cancer cell lines, except the TPC-1 cell line, were resistant to TRAIL, and growth inhibition was less than 20% at concentration of 800 ng/mL of TRAIL. In both TPC-1 (TRAIL-sensitive) and FTC-133 (TRAIL-resistant) thyroid cancer cell lines, pretreatment with troglitazone, cycloheximide, and paclitaxel enhanced TRAIL-induced cell death significantly but pretreatment with geldanamycin did not. There were no significant changes in Bcl-2, Bcl-xl, and Bax protein expression after troglitazone treatment. In conclusion, TRAIL in combination with troglitazone, paclitaxel, and cycloheximide induces apoptosis in thyroid cancer cells at suboptimal concentrations that cannot be achieved using TRAIL alone.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Cicloeximida/farmacologia , Glicoproteínas de Membrana/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Neoplasias da Glândula Tireoide/fisiopatologia , Fator de Necrose Tumoral alfa/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteínas Reguladoras de Apoptose , Western Blotting , Linhagem Celular Tumoral , Cromanos/farmacologia , Sinergismo Farmacológico , Humanos , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF , Tiazolidinedionas/farmacologia , Neoplasias da Glândula Tireoide/metabolismo , Troglitazona
5.
In Vitro Cell Dev Biol Anim ; 38(6): 326-33, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12513120

RESUMO

Female murine mammary tumor virus (MMTV)/neu transgenic mice, expressing a wild-type rat neu oncogene driven by an MMTV promoter, develop focal mammary adenocarcinomas that are pathologically very similar to human breast tumors. Two new cell lines were established from a mammary tumor that arose in a female MMTV/neu transgenic mouse. One of these lines, mammary carcinoma from Neu transgenic mouse A (MCNeuA), has an epithelial morphology, is cytokeratin positive, and expresses high levels of the neu transgene. Karyotyping and comparative genomic hybridization analyses demonstrated genomic alterations in the MCNeuA cell line. The other line, N202Fb3, has a fibroblast morphology, is cytokeratin negative, and expresses the neu transgene at a very low level. This cell line also expresses smooth muscle alpha-actin, suggesting that it is a myofibroblast line. The MCNeuA cell line is tumorigenic when injected into syngeneic MMTV/neu transgenic mice, with an in vivo doubling time of about 14 d. The rationale for establishing this tumor cell line was to provide a tumor transplantation system for rapidly assessing immunotherapeutic interventions before testing in the more cumbersome model of spontaneous tumor development in the MMTV/neu transgenic mice. Mice immunized with a Neu extracellular domain protein vaccine were protected against a subsequent inoculation of MCNeuA cells, indicating that this cell line will be useful for evaluating cancer vaccine strategies. This tumor cell line may also prove useful in studying the biological properties of the neu oncogene and its role in the malignant process. In addition, the tumor-derived fibroblast line may be useful for studying tumor-stromal cell interactions.


Assuntos
Adenocarcinoma/patologia , Linhagem Celular , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo , Receptor ErbB-2/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/farmacologia , Sequência de Bases , Divisão Celular , Células Epiteliais/fisiologia , Feminino , Fibroblastos/fisiologia , Imuno-Histoquímica , Cariotipagem , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Células Tumorais Cultivadas
6.
Am J Clin Pathol ; 133(6): 870-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20472844

RESUMO

Ensuring accurate patient identification is central to preventing medical errors, but it can be challenging. We implemented a bar code-based positive patient identification system for use in inpatient phlebotomy. A before-after design was used to evaluate the impact of the identification system on the frequency of mislabeled and unlabeled samples reported in our laboratory. Labeling errors fell from 5.45 in 10,000 before implementation to 3.2 in 10,000 afterward (P = .0013). An estimated 108 mislabeling events were prevented by the identification system in 1 year. Furthermore, a workflow step requiring manual preprinting of labels, which was accompanied by potential labeling errors in about one quarter of blood "draws," was removed as a result of the new system. After implementation, a higher percentage of patients reported having their wristband checked before phlebotomy. Bar code technology significantly reduced the rate of specimen identification errors.


Assuntos
Erros Médicos/prevenção & controle , Sistemas de Identificação de Pacientes , Flebotomia/métodos , Centros Médicos Acadêmicos , Boston , Processamento Eletrônico de Dados , Humanos , Manejo de Espécimes/métodos , Fluxo de Trabalho
7.
Am J Clin Pathol ; 132(6): 914-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19926584

RESUMO

Our goals were to improve the overall patient experience and optimize the blood collection process in outpatient phlebotomy using Lean principles. Elimination of non-value-added steps and modifications to operational processes resulted in increased capacity to handle workload during peak times without adding staff. The result was a reduction of average patient wait time from 21 to 5 minutes, with the goal of drawing blood samples within 10 minutes of arrival at the phlebotomy station met for 90% of patients. In addition, patient satisfaction increased noticeably as assessed by a 5-question survey. The results have been sustained for 10 months with staff continuing to make process improvements.


Assuntos
Eficiência Organizacional , Ambulatório Hospitalar/organização & administração , Satisfação do Paciente , Flebotomia/métodos , Fluxo de Trabalho , Humanos , Pacientes Ambulatoriais , Fatores de Tempo
8.
Cancer Res ; 66(17): 8707-14, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16951186

RESUMO

Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB2(+) breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor kappaB (NF-kappaB). Key intermediates regulating cell survival by NF-kappaB activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-kappaB activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias da Mama/prevenção & controle , Linhagem Celular Tumoral , DNA de Neoplasias/química , DNA de Neoplasias/efeitos dos fármacos , Feminino , Humanos , NF-kappa B/metabolismo , Conformação de Ácido Nucleico
9.
Breast Cancer Res Treat ; 94(1): 37-46, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16142439

RESUMO

Nordihydroguaiaretic acid (NDGA) is a phenolic compound isolated from the creosote bush Larrea divaricatta that has anti-cancer activities both in vitro and in vivo. We can now attribute certain of these anti-cancer properties in breast cancer cells to the ability of NDGA to directly inhibit the function of two receptor tyrosine kinases (RTKs), the insulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/neu (HER2/neu) receptor. In MCF-7 human breast cancer cells, low micromolar concentrations of NDGA inhibited activation of the IGF-1R, and downstream phosphorylation of both the Akt/PKB serine kinase and the pro-apoptotic protein BAD. In mouse MCNeuA cells, NDGA also inhibited ligand independent phosphorylation of HER2/neu. To study whether this inhibitory effect in cells was due to a direct action on these receptors, we studied the IGF-1-stimulated tyrosine kinase activity of isolated IGF-1R, which was inhibited by NDGA at 10 muM or less. NDGA was also effective at inhibiting autophosphorylation of the isolated HER2/neu receptor at similar concentrations. In addition, NDGA inhibited IGF-1 specific growth of cultured breast cancer cells with an IC50 of approximately 30 muM. NDGA treatment (intraperitoneal injection 3 times per week) also decreased the activity of the IGF-1R and the HER2/neu receptor in MCNeuA cells implanted into mice. This inhibition of RTK activity was associated with decreased growth rates of MCNeuA cells in vivo. These studies indicate that the anti-breast cancer properties of NDGA are related to the inhibition of two important RTKs. Agents of this class may therefore provide new insights into potential therapies for this disease.


Assuntos
Neoplasias da Mama/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Masoprocol/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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