Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

// Félix Gremonprez 1 , Benedicte Descamps 2 , Andrei Izmer 3 , Christian Vanhove 2 , Frank Vanhaecke 3 , Olivier De Wever 4 , Wim Ceelen 1 1 Department of Surgery, Ghent University Hospital, Ghent, Belgium 2 Infinity (iMinds-IBiTech-MEDISIP), Department of Electronics and Information Systems, Ghent University, Ghent, Belgium 3 Atomic and Mass Spectrometry, Department of Analytical Chemistry, Ghent University, Ghent, Belgium 4 Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium Correspondence to: Félix Gremonprez, e-mail: Felix.gremonprez@ugent.be Keywords: peritoneal carcinomatosis, colorectal cancer, angiogenesis, oxaliplatin Received: June 26, 2015      Accepted: August 26, 2015      Published: September 07, 2015 ABSTRACT Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible.