title: Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy.
abstract: Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. This process can potentially increase interstitial fluid pressure impairing intra-tumoral blood flow and oxygen supply, and can affect drug uptake. Anti-angiogenic therapies are believed to reduce vascular permeability, potentially reducing interstitial fluid pressure and improving the extravasation of small molecule-based chemotherapeutics. Here we show that pretreatment of human ovarian carcinoma tumors with sub-optimal doses of the VEGFR targeting tyrosine kinase inhibitor axitinib, but not the EGFR targeting kinase inhibitor erlotinib, induces a transient period of increased tumor oxygenation. Doxorubicin administered within this window was found to enter the extravascular tumor space more rapidly compared to doxorubicin when applied alone or outside this time window. Treatment with the chemotherapeutics, doxorubicin and RAPTA-C, as well as applying photodynamic therapy during this period of elevated oxygenation led to enhanced tumor growth inhibition. Improvement of therapy was not observed when applied outside the window of increased oxygenation. Taken together, these findings further confirm the hypothesis of angiostasis-induced vascular normalization and also help to understand the interactions between anti-angiogenesis and other anti-cancer strategies.
authors.affiliation: 1] Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland [2] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Débora
authors.initials: D
authors.lastname: Bonvin
authors.affiliation: 1] Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland [2] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Berndsen
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Scherrer
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Tse J
authors.initials: TJ
authors.lastname: Wong
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: 1] Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland [2] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000077784:Axitinib; D045744:Cell Line, Tumor; D002642:Chick Embryo; D003131:Combined Modality Therapy; D000081007:Cymenes; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009942:Organometallic Compounds / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010778:Photochemotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000081007:Cymenes; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); D004317:Doxorubicin; D000077784:Axitinib; D000077210:Sunitinib