title: Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction.
abstract: The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting.
authors.affiliation: Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Kleibeuker
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Matthijs A
authors.initials: MA
authors.lastname: Ten Hooven
authors.affiliation: Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Kitty C
authors.initials: KC
authors.lastname: Castricum
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Honeywell
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Slotman
authors.affiliation: Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Victor L
authors.identifier: http://orcid.org/0000-0002-6146-1842
authors.initials: VL
authors.lastname: Thijssen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D011758:Pyrroles / Q000494:pharmacology*; D011829:Radiation Dosage; D011839:Radiation, Ionizing; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: Angiogenesis; combination therapy; preclinical tumor model; radiotherapy; sunitinib
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