Cancer Therapy: Preclinical Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models

Purpose: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. Experimental Design: We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. Results:We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in doseand hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1a expression, induced cell-cycle arrest, and enhanceddouble-strandedDNAbreaks inhypoxicAMLcells.Hypoxia-induced reactive oxygen species byAML cellswere alsodiminished. In systemic humanAMLxenografts (HEL,HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced thenumber of hypoxic cellswithin leukemic bonemarrows andwas not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Conclusions:Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. Clin Cancer Res; 1–14. 2013 AACR.