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.