Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells
作者:
Anne-Julie Boivin,
Louise Momparler,
Annie Hurtubise,
Richard Momparler,
期刊:
Anti-Cancer Drugs
(OVID Available online 2002)
卷期:
Volume 13,
issue 8
页码: 869-874
ISSN:0959-4973
年代: 2002
出版商: OVID
关键词: 5-Aza-2′-deoxycytidine;antitumor effect;DNA methylation;histone deacetylation;phenylbutyrate
数据来源: OVID
摘要:
Current chemotherapy of advanced non-small cell lung cancer produces only a modest increase in survival time. New approaches are needed to improve its effectiveness. During tumorigenesis, silencing of tumor suppressor genes can occur by aberrant methylation. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5-AZA-CdR), can reactivate the expression of these genes. Nucleosomes containing unacetylated positively charged histones bind tightly to DNA producing a compact configuration, which inhibits transcription. Phenylbutyrate (PB), an inhibitor of histone deacetylase (HDAC), increases histone acetylation, neutralizing its positive charge and resulting in DNA with a more open structure, which favors transcription. It has been reported that 5-AZA-CdR in combination with HDAC inhibitor can increase the expression of silent tumor suppressor genes. The objective of our study was to determine if these agents, in combination, produce an enhancement of their antitumor activity. We evaluated the antineoplastic activity of 5-AZA-CdR and PB alone or in combination on human A549 and Calu-6 lung carcinoma cell lines by inhibition of DNA synthesis and clonogenic assays. 5-AZA-CdR and PB in combination produced a greater inhibition of DNA synthesis than either agent alone. Also, in a clonogenic assay the combination of these drugs showed a significant synergistic antitumor effect. These results provide a rationale to investigate the combination of 5-AZA-CdR and PB in patients with advanced lung cancer.
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