Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit
DNA methyl
transferase. 5-aza-2',2'-diflurorodeoxycytidine (NUC013) is a novel
DNA methyl
transferase and
ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than
decitabine in the NCI 60
cancer cell line panel. NUC013 is more active than
decitabine against p53-null/mutant
cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0.0025). The maximum tolerated dose in mice of NUC013 is greater than 120 mg/kg administered intravenously for three consecutive days a week for three weeks. With this regimen and a dose of 20 mg/kg in a human
leukemia HL-60 (p53-null) NCr-nu/nu mouse xenograft model (n = 10/group), NUC013 demonstrated a survival benefit (saline median survival (MS) = 26.5 days, NUC013
MS = 32 days and hazard ratio (HR) = 0.26 (p = 0.032)). In a
colon cancer LoVo (TP53 WT) xenograft, mice treated with
decitabine at 5 mg/kg had worse survival than saline controls (
decitabine MS = 31 days, saline MS > 60 days and HR = 26.89 (p < 0.0001)). At a dose of 20 mg/kg NUC013, mean
tumor volume in the LoVo xenografts was lower than controls by 50.9% and at 40 mg/kg by 53.7% (both p < 0.0001).