Resistance to
azacitidine is a major issue in the treatments of
myelodysplastic syndrome and
acute myeloid leukemia, and previous studies suggest that changes in
drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated
azacitidine-resistant cells derived from SKM-1 and MOLM-13
leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth-inhibitory effect of
azacitidine, expression levels of
uridine-cytidine kinase 2, and the concentrations of
azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that
azacitidine resistance is derived from metabolic changes. Cross-resistance of greater than 10-fold (shift in IC50 value) was observed in
azacitidine-resistant cells for
decitabine and for
cytarabine, but not for
gemcitabine or the inosine-5'-monophosphate
dehydrogenase (IMPDH) inhibitors FF-10501 and
mycophenolate mofetil (cross-resistance to
5-fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth-inhibitory activities in the
azacitidine-resistant cell lines, in which the levels of
adenine phosphoribosyltransferase (which converts FF-10501 to its active form, FF-10501 ribosylmonophosphate [FF-10501RMP]), FF-10501RMP, and the target
enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF-10501 could be an alternative therapeutic treatment for
leukemia patients with acquired resistance to
azacitidine.