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

被引：28

作者：

Duran, Rafael ^{[1
,2
]}

Mirpour, Sahar ^{[1
]}

Pekurovsky, Vasily ^{[1
]}

Ganapathy-Kanniappan, Shanmugasundaram ^{[1
]}

Brayton, Cory F. ^{[3
]}

Cornish, Toby C. ^{[4
]}

Gorodetski, Boris ^{[1
]}

Reyes, Juvenal ^{[5
]}

Chapiro, Julius ^{[1
,2
]}

Schernthaner, Rudiger E. ^{[1
,2
]}

Frangakis, Constantine ^{[6
]}

Lin, MingDe ^{[2
,7
]}

Sun, Jessica D. ^{[8
]}

Hart, Charles P. ^{[8
]}

Geschwind, Jean- Francois ^{[2
]}

机构：

[1] Johns Hopkins Univ Hosp, Div Vasc & Intervent Radiol, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA

[2] Yale Univ, Sch Med, Dept Radiol & Biomed Imaging, New Haven, CT USA

[3] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA

[4] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Gastrointestinal & Liver Pathol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ Hosp, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA

[6] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[7] Philips Res North Amer, US Imaging & Intervent, Cambridge, MA USA

[8] Threshold Pharmaceut, San Francisco, CA USA

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 02期

关键词：

ENDOTHELIAL GROWTH-FACTOR; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; HEPATOCELLULAR-CARCINOMA; PRODRUG TH-302; INDUCIBLE FACTOR-1-ALPHA; TUMOR HYPOXIA; IN-VIVO; EXPRESSION; COMBINATION; DOXORUBICIN;

D O I：

10.1158/1078-0432.CCR-16-0725

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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) doxorubicinlipiodol emulsion followed by embolization with 100-300 mm 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 (gamma-H2AX, Annexin V, caspase-3, Ki67, HIF1 alpha, 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 g-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1 alpha/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. (C) 2016 AACR.

引用

页码：536 / 548

页数：13

共 56 条

[41] Regulation of cancer cell metabolism by hypoxia-inducible factor 1 [J].