Enhancement of Antineoplastic Action of 5-Aza-2′-deoxycytidine by Phenylbutyrate on L1210 Leukemic Cells

Abstract

Epigenetic changes, such as aberrant DNA methylation that silences tumor suppressor genes (TSGs), can play an important role in the development of leukemia. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5-AZA-CdR), can reactivate these silent TSGs and is an interesting agent to investigate for therapy of leukemia. It has been reported that the effectiveness of 5-AZA-CdR to reactivate TSG can be enhanced by inhibitors of histone deacetylase (HDIs). HDIs can convert a compact chromatin structure to an open configuration that facilitates gene expression. An interesting HDI is phenylbutyrate (PB), which has shown some clinical activity for the therapy of leukemia. In this report we have investigated the antineoplastic activity of 5-AZA-CdR and PB alone and in combination on murine L1210 lymphoid leukemic cells. The in vitro treatment of 5-AZA-CdR and PB in combination produced a greater inhibition of growth, DNA synthesis, and also a greater reduction on colony formation on both L1210 and human HL-60 leukemic cells as compared to either drug alone. The combination also produced a synergistic activation of the TSG, p15CDN2B, in the L1210 cells. In mice with L1210 leukemia the combination showed enhanced antineoplastic activity. We also observed an enhancement of the antineoplastic activity of this combination in mice with L1210 leukemia. These data provide a rationale to investigate 5-AZA-CdR and PB in patients with advanced leukemia.