RESUMO
The possibility of emergency prophylaxis of Marburg hemorrhagic fever with leukocytic and recombinant interferons was studied in experiments on Cercopithecus aethiops. None of the agents protected monkeys from the action of lethal doses of Marburg virus. Recombinant interferon-alpha(2)administered according to the emergency prophylaxis schedule prolonged the mean life-span of monkeys injected with Marburg virus in doses of 100 and 1000 LD50 by 1.9 and 6.1 days, respectively.
Assuntos
Interferon-alfa/uso terapêutico , Doença do Vírus de Marburg/prevenção & controle , Doença Aguda , Animais , Sangue/virologia , Temperatura Corporal , Chlorocebus aethiops , Cobaias , Humanos , Interferon alfa-2 , Interferon-alfa/imunologia , Doença do Vírus de Marburg/imunologia , Marburgvirus/fisiologia , Proteínas Recombinantes , Sobrevida , ViremiaRESUMO
A combination of four genetic suppressor elements (GSEs), two of which are derived from putative transcriptional regulators, was previously found to increase resistance to drugs inhibiting DNA replication in HT1080 fibrosarcoma cells. In the present study, two GSE-transduced cell lines, isolated with and without cytotoxic selection, were found to be resistant to a diverse group of DNA-interactive agents, including aphidicolin, hydroxyurea, cytarabine, etoposide, doxorubicin, and mafosfamide. Changes in gene expression associated with GSE-induced drug resistance were analyzed by cDNA array hybridization and reverse transcription-PCR. Twenty genes were found to be up-regulated in both of the resistant cell lines. These include genes involved in DNA replication and repair (e.g., PCNA, XRCC1, B-MYB, and GADD45), transcriptional regulators associated with stress response, and cell cycle checkpoint control (e.g., YB-1, DBPA, and ATF4), and genes for signal transduction proteins (e.g., protein tyrosine phosphatase 1B and regulatory subunits alpha and beta of cAMP-dependent protein kinase). The observed changes in gene expression may play a role in pleiotropic resistance to different classes of DNA-targeting drugs.
Assuntos
Reparo do DNA/genética , Replicação do DNA/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores/genética , Antineoplásicos/farmacologia , Afidicolina/farmacologia , Ciclo Celular/genética , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Resposta ao Choque Térmico/genética , Humanos , Antígeno Nuclear de Célula em Proliferação/biossíntese , Antígeno Nuclear de Célula em Proliferação/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transdução Genética , Células Tumorais CultivadasRESUMO
Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.
Assuntos
Afidicolina/farmacologia , Replicação do DNA/efeitos dos fármacos , Genes Supressores , Antineoplásicos/farmacologia , Sequência de Bases , DNA Antissenso/genética , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Doxorrubicina/farmacologia , Resistência a Medicamentos/genética , Biblioteca Gênica , Células HeLa , Humanos , Hidroxiureia/farmacologia , Dados de Sequência Molecular , Células Tumorais CultivadasRESUMO
The survival curves for bacteriophage lambda and vaccinia virus were shown theoretically and in experiments to have a plateau at prolonged inactivation by UV-irradiation or 8-methoxypsoralen. The level of the plateau is dependent of the accuracy of the repair process. The method for extrapolation of the survival curves is proposed.
