PURPOSE:
Acute myeloid leukemia (AML) is an aggressive hematological neoplasm. Recent evidence has demonstrated the bone marrow microenvironment in AML patients 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... More
PURPOSE:
Acute myeloid leukemia (AML) is an aggressive hematological neoplasm. Recent evidence has demonstrated the bone marrow microenvironment in AML patients 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 dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 (50 mg/kg i.p. five times per week) inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in non-leukemic 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 acute myeloid leukemia and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy.
