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1.
Exp Hematol ; 34(9): 1151-61, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16939808

RESUMO

OBJECTIVE: In vivo, several drugs have been shown to increase fetal hemoglobin (HbF), including 5-azacytidine (AZA), sodium butyrate (SB), and hydroxyurea (HU). Studies in K562 cells suggest that cyclic guanosine monophosphate (cGMP) is required for HbF induction; however, the role of cyclic nucleotides in HbF induction in primary erythroid cultures has not been established. METHODS: CD34-selected peripheral blood monocytes cultured in a semi-solid serum-free system that mimics in vivo F-cell production are utilized to explore the role of cyclic adenosine monophosphate (cAMP) and cGMP in HbF induction in response to HU, AZA, and SB. RESULTS: In serum-free CD34 cultures, HU, SB, and AZA all markedly stimulate FNRBC production up to 30-fold, associated with induction of gamma-globin mRNA and total HbF protein. Guanylate cyclase inhibition results in only minimal blunting of HbF induction by each agent. In contrast, adenylate cyclase inhibition markedly reduces HU, SB, and AZA-mediated FNRBC induction and gamma-globin mRNA induction. The adenylate cyclase activator forskolin modestly induces FNRBC production and augments the action of standard induction agents. HU, AZA, and SB, however, fail to significantly stimulate adenylate cyclase themselves. CONCLUSIONS: In human CD34(+) cultures, cAMP production is required for full induction of HbF by HU, SB, and AZA, while perturbation of cGMP production has only minimal effects. These findings are in marked contrast to data in K562 cells where cGMP production is critical for HbF induction while cAMP stimulation blunts HbF response, and suggest that these agents may share a common induction pathway.


Assuntos
Antígenos CD34 , Antidrepanocíticos/farmacologia , Azacitidina/análogos & derivados , Butiratos/farmacologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Hemoglobina Fetal/biossíntese , Hidroxiureia/farmacologia , Monócitos/metabolismo , Adenilil Ciclases/metabolismo , Azacitidina/farmacologia , Colforsina/farmacologia , Decitabina , Células Eritroides/citologia , Células Eritroides/metabolismo , Humanos , Células K562 , Monócitos/citologia , RNA Mensageiro/biossíntese
2.
Cancer Res ; 66(12): 6361-9, 2006 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-16778214

RESUMO

Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/enzimologia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/enzimologia , Acetilação/efeitos dos fármacos , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacocinética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Histona Desacetilases/genética , Histonas/metabolismo , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacocinética , Regiões Promotoras Genéticas , Resultado do Tratamento
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