Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model
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Félix Gremonprez1, Benedicte Descamps2, Andrei Izmer3, Christian Vanhove2, Frank Vanhaecke3, Olivier De Wever4, Wim Ceelen1
1Department of Surgery, Ghent University Hospital, Ghent, Belgium
2Infinity (iMinds-IBiTech-MEDISIP), Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
3Atomic and Mass Spectrometry, Department of Analytical Chemistry, Ghent University, Ghent, Belgium
4Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium
Félix Gremonprez, e-mail: Felix.email@example.com
Keywords: peritoneal carcinomatosis, colorectal cancer, angiogenesis, oxaliplatin
Received: June 26, 2015 Accepted: August 26, 2015 Published: September 07, 2015
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.
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