Authors' Affiliations: Departments of Medicine, Immunology, Roswell Park Cancer Institute, Buffalo, New York; and Threshold Pharmaceuticals Inc, South San Francisco, California.
Clin Cancer Res. 2013 Dec 1;19(23):6506-19. doi: 10.1158/1078-0432.CCR-13-0674. Epub 2013 Oct 2.
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.
We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models.
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 intraperitoneally (i.p.) 5 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 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.
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.
急性髓细胞白血病（AML）是一种侵袭性血液系统恶性肿瘤。最近的证据表明，AML 患者的骨髓微环境存在内在缺氧。白血病细胞为了在低氧环境下生存而产生的适应性细胞反应也赋予了它们对化疗药物的耐药性。因此，我们想知道通过缺氧激活的氮芥前体药物 TH-302 来治疗骨髓缺氧是否能有效抑制 AML 的生长。
我们评估了缺氧和 TH-302 对人 AML 细胞、原代样本和全身性异种移植模型的影响。
我们观察到，与常氧对照相比，在慢性缺氧（1%O2，72 小时）下培养的人 AML 细胞和原代 AML 集落对阿糖胞苷诱导的凋亡表现出较低的敏感性。TH-302 处理导致不同 AML 细胞中依赖剂量和缺氧的凋亡和细胞死亡。TH-302 优先降低增殖、减少 HIF-1α 表达、诱导细胞周期停滞，并增强缺氧 AML 细胞中的双链 DNA 断裂。AML 细胞中缺氧诱导的活性氧也减少了。在全身性人 AML 异种移植（HEL、HL60）中，TH-302[50mg/kg 腹腔内（i.p.）每周 5 次]抑制疾病进展并延长总生存期。TH-302 治疗减少了白血病骨髓中缺氧细胞的数量，并且在非白血病或白血病小鼠中与血液学毒性无关。在 AML 疾病的晚期开始 TH-302 治疗与在异种移植模型中早期开始 TH-302 治疗一样有效。
我们的结果确立了 TH-302 在 AML 中的临床前活性，并为进一步研究这种和其他用于白血病治疗的缺氧激活剂提供了依据。
