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Clin Cancer Res. 2017 Jan 15;23(2):536-548. doi: 10.1158/1078-0432.CCR-16-0725. Epub 2016 Jul 20.

Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.

Author information

1
Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins Hospital, Baltimore, Maryland.
2
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Pathology, Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins Hospital, Baltimore, Maryland.
6
Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
7
U/S Imaging and Interventions (UII), Philips Research North America, Cambridge, Massachusetts.
8
Threshold Pharmaceuticals, South San Francisco, California.
9
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut. jeff.geschwind@yale.edu.

Abstract

PURPOSE:

To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model.

EXPERIMENTAL DESIGN:

VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 μm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH).

RESULTS:

cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT.

CONCLUSIONS:

HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR.

PMID:
27440271
PMCID:
PMC5241187
[Available on 2018-01-15]
DOI:
10.1158/1078-0432.CCR-16-0725
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