Time-course-dependent microvascular alterations in a model of myeloid leukemia in vivo

Schaefer, Christian; Krause, Matthias; Fuhrhop, Ina; Schroeder, Malte; Algenstaedt, Petra; Fiedler, Walter; Rüther, W.; Hansen-Algenstaedt, Nils

doi:10.1038/sj.leu.2404947

Cited by 23 publications

(33 citation statements)

References 40 publications

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“…Marrow hypoxia increases with progressive leukemia disease Prior data in animal models showed that progressive growth of AML cells within the marrow space was associated with worsening hypoxia (10,13,14). To confirm this and the hypoxic nature of the marrow microenvironment in our models, we assessed the expression of the hypoxia marker pimonidazole in the bone marrow of irradiated SCID mice before and at fixed time points following intravenous (tail vein) inoculation of human AML (HEL-luciferase) cells.…”

Section: Resultsmentioning

confidence: 80%

“…Preclinical evidence has shown that expansion of acute leukemia cells within the bone marrow is associated with further decreases in local oxygenation (10,13,14). We and other groups have shown that acute leukemia cells placed under hypoxia upregulate HIF-1a, undergo cellcycle arrest, and exhibit resistance to chemotherapy agents such as cytarabine (22,23).…”

Section: Discussionmentioning

confidence: 93%

“…Further development of TH-302 and other hypoxia-activated agents for acute leukemia therapy, however, may need to take into account the unique mechanism of action of such drugs within the leukemic marrow microenvironment (11,(38)(39)(40). Because hypoxic regions within the marrow expand as a consequence of acute leukemia progression, TH-302 may be most effectively used in later stage disease (10,13,14). Moreover, the presence of residual cells expressing hypoxic markers in leukemic marrows following cytarabine or doxorubicin treatment suggests that the administrating TH-302 together with or following standard chemotherapy may further improve outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Prior data in multiple animal models showed that acute leukemic progression within the bone marrow is associated with further decreases in overall marrow oxygenation and expansion of hypoxic bone marrow areas (10)(11)(12). This has been attributed, in part, to potentially compromised blood flow within a restricted noncompliant bony cavity (13,14).…”

Section: Introductionmentioning

confidence: 99%

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

Portwood

Lal

Hsu

et al. 2013

Clinical Cancer Research

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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% O 2 , 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-1a 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.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.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Portwood

Lal

Hsu

et al. 2013

Clinical Cancer Research

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“…Indeed, Schaefer et al . reported that the microvasculature in a murine AML model was heterogeneous, resembling the defective angiogenesis observed in solid tumors and associated with disease progression(46). The role of hypoxia in promoting resistance to chemotherapy and stemness and increasing tumor invasiveness has been widely studied, and our published work together with current findings support the presence of hypoxia in the leukemic BM microenvironment and provide a strong rationale for exploiting hypoxia as a therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models

Benito

Ramirez

Millward

et al. 2016

Clinical Cancer Research

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Purpose: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models.Experimental Design: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models.Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells.Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins.

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Dynamics of microvascular remodelling during tumor growth in bone

Fuhrhop¹,

Schroeder²,

Rafnsdóttir³

et al. 2009

Journal Orthopaedic Research

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Microcirculatory properties of tumors have been shown to play a pivotal role in tumor progression and inefficacy of therapies. Although the influence of the microenvironment on angiogenesis has been intensively investigated in soft tissue tumors, little is known about the microvascular properties in bone metastasis. To determine the impact of the bone microenvironment on tumor growth and microcirculation we performed intravital microscopy using the ''femur window'' after implantation of red-fluorescent-protein-transduced breast cancer cells into the femura of severe-combined-immunodeficient mice. Tumor size, functional vascular density, vessel diameter, and vessel distribution were quantified over 14 days. Tumor growth and microcirculation could be quantified at a high spatial resolution. Tumor progression was associated with a rapid remodeling process of the microcirculation within the tumor and the surrounding tissue. Although the total functional vascular density remained unaltered, we found a significant loss in small vessels and a concomitant increase in vascular diameter. The presented study demonstrates for the first time dynamics of morphological microcirculatory alterations of tumor growth in bone. The observed changes in tumor vascularization exhibit strong similarities to soft tissue tumors; however, the dynamics of vascular alterations are more rapid in the bone microenvironment. ß

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Time-course-dependent microvascular alterations in a model of myeloid leukemia in vivo

Cited by 23 publications

References 40 publications

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

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

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models

Dynamics of microvascular remodelling during tumor growth in bone

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