Ribonucleotide reductase

Didox (NSC-324360) suppresses LPS-induced mRNA levels of iNOS, IL-6, IL-1, TNF-α, NF-κβ (p65), and p38-α, after 24 h of treatment. Treatment with Didox also suppresses the secretion of nitric oxide (NO), IL-6, and IL-10. Using mitochondrial dehydrogenase activity as a measure of cytotoxicity, the effects of Didox on cellular respiration in RAW264.7 are examined over a range of concentrations for 24 h. Cells exposures to 200 μM and below Didox, with and without LPS, do not exhibit significant cellular toxicity. Didox (NSC-324360) is active against all human and murine acute myeloid leukemia (AML) lines tested with IC ₅₀ values in the low micromolar range (mean IC ₅₀ 37 μM [range 25.89-52.70 μM]).

Once engraftment is established by bioluminescent imaging, the animals receive daily administrations of Didox at 425 mg/kg via IP injection over 5 days. Didox (NSC-324360) treatment significantly reduces leukemic burden compared to vehicle treated controls (p=0.0026 and p=0.0342). More importantly, Didox (NSC-324360) provides a significant survival benefit (p<0.0001 and p=0.0094).