Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer ; 113(10): 2646-54, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18823053

RESUMO

BACKGROUND: Gemcitabine incorporation into DNA enhances cleavage complexes in vitro when combined with topoisomerase I inhibitors and demonstrates synergy in cancer cells when given with irinotecan. Topoisomerase I inhibitors require that topoisomerase I interacts with DNA to exert activity. METHODS: Patients who had received previous anthracycline therapy or were not candidates for anthracycline therapy received gemcitabine at a dose of 1000 mg/m2 intravenously over 30 minutes followed by irinotecan at a dose of 100 mg/m2 over 90 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was improvement in response from that historically observed with gemcitabine (from 25% to 45%) as measured by Response Evaluation Criteria in Solid Tumors. Correlative studies included characterization of cellular levels and nuclear distribution of topoisomerase I and pharmacokinetic analysis of gemcitabine and irinotecan. RESULTS: Forty-nine patients were assessed for response. The response rate was approximately 25% (all partial responses [PRs], 12 patients; 95% confidence interval [95% CI], 13-39). Six patients had stable disease (SD) for > or =6 months for a clinical benefit rate (PR + SD) of 39%. The median time to disease progression was 3.7 months (95% CI, 2.5 months-4.6 months), and median survival was 11.6 months (95% CI, 8.9 months-15 months). Toxicities included neutropenia, nausea, and vomiting. Seven of 9 tissue biopsies were assessable for topoisomerase I. Tumors with the 2 lowest nuclear to cytoplasmic ratios demonstrated no response to irinotecan. CONCLUSIONS: Gemcitabine and irinotecan are active in metastatic breast cancer, but response did not meet predetermined response parameters, and the null hypothesis was accepted. Topoisomerase I localization can be measured in metastatic breast cancer. Further validation is needed to determine whether this assay can predict response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo I/metabolismo , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Cromatografia Líquida de Alta Pressão , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Feminino , Imunofluorescência , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gencitabina
2.
Blood ; 108(12): 3881-9, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16917002

RESUMO

We investigated the role of the breast cancer resistance protein (BCRP/ABCG2) in drug resistance in multiple myeloma (MM). Human MM cell lines, and MM patient plasma cells isolated from bone marrow, were evaluated for ABCG2 mRNA expression by quantitative polymerase chain reaction (PCR) and ABCG2 protein, by Western blot analysis, immunofluorescence microscopy, and flow cytometry. ABCG2 function was determined by measuring topotecan and doxorubicin efflux using flow cytometry, in the presence and absence of the specific ABCG2 inhibitor, tryprostatin A. The methylation of the ABCG2 promoter was determined using bisulfite sequencing. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan and doxorubicin, and was greater in logphase cells when compared with quiescent cells. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after treatment with topotecan, and at relapse. Expression of ABCG2 is regulated, at least in part, by promoter methylation both in cell lines and in patient plasma cells. Demethylation of the promoter increased ABCG2 mRNA and protein expression. These findings suggest that ABCG2 is expressed and functional in human myeloma cells, regulated by promoter methylation, affected by cell density, up-regulated in response to chemotherapy, and may contribute to intrinsic drug resistance.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Mieloma Múltiplo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting/métodos , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Citometria de Fluxo/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Microscopia de Fluorescência/métodos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Topotecan/farmacologia , Topotecan/uso terapêutico , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
3.
Mol Cancer Ther ; 5(8): 2130-7, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16928835

RESUMO

PURPOSE: Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor. EXPERIMENTAL DESIGN: Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m(2)) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40-84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells. RESULTS: Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1-12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and IIalpha levels, we observed a decrease in topo IIalpha levels, whereas topo I levels were not significantly altered by 9-NC treatment. CONCLUSIONS: Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies.


Assuntos
Camptotecina/análogos & derivados , Etoposídeo/farmacocinética , Etoposídeo/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , DNA Topoisomerases Tipo I/sangue , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo II/sangue , DNA Topoisomerases Tipo II/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento
4.
Exp Cell Res ; 295(2): 421-31, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15093741

RESUMO

In this study we have investigated the role of topoisomerase (topo) IIalpha trafficking in cellular drug resistance. To accomplish this, it was necessary to separate the influence of cell cycle, drug uptake, topo protein levels, and enzyme trafficking on drug sensitivity. Thus, we developed a cell model (called accelerated plateau) using human myeloma H929 cells that reproducibly translocates topo IIalpha to the cytoplasm. Compared to log-phase cells, the cytoplasmic redistribution of topo IIalpha in plateau-phase cells correlated with a 10-fold resistance to VP-16 and a 40-60% reduction in the number of drug-induced double-strand DNA breaks. In addition, 7-fold more VP-16 was necessary to achieve 50% topo IIalpha band depletion, suggesting that there are fewer drug-induced topo-DNA complexes formed in quiescent cells than in log-phase cells. The total cellular amount of topo IIalpha and topo IIbeta protein in log- and plateau-phase cells was similar as determined by Western blot analysis. There was a 25% reduction in S-phase cell number in plateau cells (determined by bromodeoxyuridine (BrdU) incorporation), while there was no significant difference in the equilibrium concentrations of [(3)H]-VP-16 when log cells were compared with plateau cells. Furthermore, the nuclear/cytoplasmic ratio of topo IIalpha is increased 58-fold in accelerated-plateau H929 cells treated with leptomycin B (LMB) when compared to untreated cells. It appears that the nuclear-cytoplasmic shuttling of topo IIalpha, which decreases the amount of nuclear target enzyme, is a major mechanism of drug resistance to topo II inhibitors in plateau-phase myeloma cells.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Citoplasma/enzimologia , DNA Topoisomerases Tipo II/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/farmacocinética , Western Blotting , Linhagem Celular Tumoral , Núcleo Celular/enzimologia , Ensaio Cometa , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Eletroforese em Gel Bidimensional , Etoposídeo/farmacocinética , Ácidos Graxos Insaturados/farmacocinética , Ácidos Graxos Insaturados/uso terapêutico , Citometria de Fluxo , Células HL-60 , Humanos , Microscopia de Fluorescência , Mitoxantrona/farmacocinética , Mitoxantrona/uso terapêutico , Mieloma Múltiplo/enzimologia , Plasmocitoma/tratamento farmacológico , Plasmocitoma/enzimologia , Transporte Proteico , Frações Subcelulares
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...