Lung cancer is the leading cause of cancer death in the United States. The severe morbidity and mortality from lung cancer have not been reduced and the discouraging <15% overall 5-year survival rate, has not been improved despite advancements in treatment modalities. For this reason, the identification of novel approaches to the prevention and treatment of lung cancer are urgently needed. Loss of expression of tumor suppressor genes is one of the hallmarks of cancer development. It occurs after loss of heterozygosity and mutations in tumor suppressor genes. In addition, epigenetic silencing of such genes can occur by aberrant methylation of CpG islands in gene promoter regions and by changes in chromatin structure resulting from alterations in histone acetylation state. Nucleosomes containing unacetylated positively charged histones bind tightly to DNA producing a compact configuration, which inhibits transcription. A recent approach to reverse the silencing of genes has been the use of the DNA methylation inhibitor, 5-aza-2’-deoxycytidine (5-AZA-CdR), and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Each of these agents can reactivate the expression of certain silenced genes. The objective of this study was to determine combination of these agents, can enhance their antitumor activity. We examined the ability of different concentrations of 5-AZA-CdR alone, SAHA alone and their combinations to induce growth inhibition in non-small cell lung cancer cell lines NCI-H460, NCI-H157, NCI-H1792, SK-MES-1, as well as in immortalized bronchial epithelial cells BEAS-2B and 1799, transformed 1198 cells, and tumorigenic 1170I cells. We also compared the response of the premalignant and malignant cells with the responses of normal bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). We used the sulforhodamine B assay to detect inhibition of cell growth. We found that in most cells tested, 5-AZA-CdR and SAHA in combination produced a greater inhibition of cell growth than either agent alone. These results provide a rationale to investigate the combination of 5-AZA-CdR and SAHA in animal models and eventually in patients with lung cancer. Supported by the Samuel Waxman Foundation’s David Workman Award and by a Department of Army Grant, DAMD17-02-1-0706.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]