title: Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect.
abstract: The extent of tumor oxygenation is an important factor contributing to the efficacy of radiation therapy (RTx). Interestingly, several preclinical studies have shown benefit of combining RTx with drugs that inhibit tumor blood vessel growth, i.e. angiostatic therapy. Recent findings show that proper scheduling of both treatment modalities allows dose reduction of angiostatic drugs without affecting therapeutic efficacy. We found that whilst low dose sunitinib (20 mg/kg/day) did not affect the growth of xenograft HT29 colon carcinoma tumors in nude mice, the combination with either single dose RTx (1x 5Gy) or fractionated RTx (5x 2Gy/week, up to 3 weeks) substantially hampered tumor growth compared to either RTx treatment alone. To better understand the interaction between RTx and low dose angiostatic therapy, we explored the effects of RTx on tumor angiogenesis and tissue perfusion. DCE-MRI analyses revealed that fractionated RTx resulted in enhanced perfusion after two weeks of treatment. This mainly occurred in the center of the tumor and was accompanied by increased tissue viability and decreased hypoxia. These effects were accompanied by increased expression of the pro-angiogenic growth factors VEGF and PlGF. DCE-MRI and contrast enhanced ultrasonography showed that the increase in perfusion and tissue viability was counteracted by low-dose sunitinib. Overall, these data give insight in the dynamics of tumor perfusion during conventional 2 Gy fractionated RTx and provide a rationale to combine low dose angiostatic drugs with RTx both in the palliative as well as in the curative setting.
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Esther A
authors: EA
authors: Kleibeuker
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Emmanouil
authors: E
authors: Fokas
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Philip D
authors: PD
authors: Allen
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Veerle
authors: V
authors: Kersemans
authors: Department of Medical Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Arjan W
authors: AW
authors: Griffioen
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: John
authors: J
authors: Beech
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Jaehong H
authors: JH
authors: Im
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Sean C
authors: SC
authors: Smart
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Kitty C
authors: KC
authors: Castricum
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Jaap
authors: J
authors: van den Berg
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Iris A
authors: IA
authors: Schulkens
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Sally A
authors: SA
authors: Hill
authors: Department of Molecular Oncology, University of Oxford, Oxford, UK.
authors: Adrian L
authors: AL
authors: Harris
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Ben J
authors: BJ
authors: Slotman
authors: Department of Medical Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Henk M
authors: HM
authors: Verheul
authors: Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
authors: Ruth J
authors: RJ
authors: Muschel
authors: Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands.
authors: Victor L
authors: VL
authors: Thijssen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D011878:Radiotherapy / Q000379:methods; D014463:Ultrasonography / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents
keywords: angiogenesis; cancer; combination therapy; radiotherapy; tumor perfusion