Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer. Clin Cancer Res 2017 Jan 15;23(2):536-548
Date
07/22/2016Pubmed ID
27440271Pubmed Central ID
PMC5241187DOI
10.1158/1078-0432.CCR-16-0725Scopus ID
2-s2.0-85011283252 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
Author List
Duran R, Mirpour S, Pekurovsky V, Ganapathy-Kanniappan S, Brayton CF, Cornish TC, Gorodetski B, Reyes J, Chapiro J, Schernthaner RE, Frangakis C, Lin M, Sun JD, Hart CP, Geschwind JFAuthor
Toby Charles Cornish MD, PhD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Biomarkers, Tumor
Cell Proliferation
Circulating Tumor DNA
Combined Modality Therapy
Disease Models, Animal
Doxorubicin
Ethiodized Oil
Humans
Liver Neoplasms
Nitroimidazoles
Phosphoramide Mustards
Rabbits
Tumor Hypoxia