Acquired and intrinsic resistance still remains a limitation to the clinical use of
5-fluorouracil (5-FU). The contribution of epigenetic changes to the development of drug resistance remains to be elucidated. Several genes that are hypermethylated and silenced have been identified in
colorectal cancer. Based on the findings described in the accompanying article, we hypothesized that acquired resistance to "pulse"
5-FU has an epigenetic origin and might be reversed. Here, we present a novel therapeutic approach to circumvent clinical resistance to bolus
5-FU, that is, treatment of bolus 5-FU-resistant
colorectal cancer cells with low-dose
5-azadeoxycytidine (DAC), an inhibitor of
DNA hypermethylation, restored sensitivity to
5-FU as well as
5-fluorouridine. Moreover, treatment of nude mice bearing a 5-FU-resistant
tumor, characterized by decreased levels of
UMP kinase (UMPK), with DAC overcame resistance to bolus
5-FU. DAC-mediated restoration of
5-FU sensitivity was associated with increases in UMPK levels. An increase in UMPK
protein and
mRNA levels following treatment with low-dose DAC was observed in cultured bolus 5-FU-resistant
colorectal cancer cells (HCT-8) and in mice bearing these
tumors. We conclude that DAC-mediated restoration of sensitivity to bolus
5-FU is mediated at least in part by increased UMPK levels and clinical resistance to
5-FU due to decreased UMPK in
colorectal cancer may be overcome by including methylation inhibitors such as DAC.