title: Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model.
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.
authors.affiliation: Department of Surgery, Ghent University Hospital, Ghent, Belgium.
authors.forename: Félix
authors.initials: F
authors.lastname: Gremonprez
authors.affiliation: Infinity (iMinds-IBiTech-MEDISIP), Department of Electronics and Information Systems, Ghent University, Ghent, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.affiliation: Atomic and Mass Spectrometry, Department of Analytical Chemistry, Ghent University, Ghent, Belgium.
authors.forename: Andrei
authors.initials: A
authors.lastname: Izmer
authors.affiliation: Infinity (iMinds-IBiTech-MEDISIP), Department of Electronics and Information Systems, Ghent University, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: Atomic and Mass Spectrometry, Department of Analytical Chemistry, Ghent University, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Vanhaecke
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Department of Surgery, Ghent University Hospital, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Ceelen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D007191:Indazoles; D007263:Infusions, Parenteral; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D065629:Peritoneal Absorption / Q000187:drug effects; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011312:Pressure; D011743:Pyrimidines / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007191:Indazoles; D009944:Organoplatinum Compounds; D011743:Pyrimidines; D013449:Sulfonamides; D000077150:Oxaliplatin; D000068258:Bevacizumab; C516667:pazopanib; D000068877:Imatinib Mesylate; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: angiogenesis; colorectal cancer; oxaliplatin; peritoneal carcinomatosis