TY - JOUR
T1 - Preclinical benefit of hypoxia-Activated intraarterial therapy with evofosfamide in liver cancer
AU - Duran, Rafael
AU - Mirpour, Sahar
AU - Pekurovsky, Vasily
AU - Ganapathy-Kanniappan, Shanmugasundaram
AU - Brayton, Cory F.
AU - Cornish, Toby C.
AU - Gorodetski, Boris
AU - Reyes, Juvenal
AU - Chapiro, Julius
AU - Schernthaner, Rudiger E.
AU - Frangakis, Constantine
AU - Lin, Ming De
AU - Sun, Jessica D.
AU - Hart, Charles P.
AU - Geschwind, Jean Fraņcois
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - 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 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 (g-H2AX, Annexin V, caspase-3, Ki- 67, HIF1a, 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 HIF1a/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.
AB - 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 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 (g-H2AX, Annexin V, caspase-3, Ki- 67, HIF1a, 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 HIF1a/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.
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U2 - 10.1158/1078-0432.CCR-16-0725
DO - 10.1158/1078-0432.CCR-16-0725
M3 - Article
C2 - 27440271
AN - SCOPUS:85011283252
SN - 1078-0432
VL - 23
SP - 536
EP - 548
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -