Oncotarget

Research Papers:

Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect

Esther A. Kleibeuker _, Emmanouil Fokas, Philip D. Allen, Veerle Kersemans, Arjan W. Griffioen, John Beech, Jaehong H. Im, Sean C. Smart, Kitty C. Castricum, Jaap van den Berg, Iris A. Schulkens, Sally A. Hill, Adrian L. Harris, Ben J. Slotman, Henk M. Verheul, Ruth J. Muschel and Victor L. Thijssen

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Oncotarget. 2016; 7:76613-76627. https://doi.org/10.18632/oncotarget.12814

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Abstract

Esther A. Kleibeuker1,2, Emmanouil Fokas3, Philip D. Allen3, Veerle Kersemans3, Arjan W. Griffioen2, John Beech3, Jaehong H. Im3, Sean C. Smart3, Kitty C. Castricum1, Jaap van den Berg1, Iris A. Schulkens1, Sally A. Hill3, Adrian L. Harris4, Ben J. Slotman1, Henk M. Verheul2, Ruth J. Muschel3,* and Victor L. Thijssen1,2,*

1 Department of Radiation Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands

2 Department of Medical Oncology, VU University Medical Centre, De Boelelaan, HV Amsterdam, The Netherlands

3 Oxford Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK

4 Department of Molecular Oncology, University of Oxford, Oxford, UK

* Jointly supervised

Correspondence to:

Victor L. Thijssen, email:

Keywords: cancer, radiotherapy, angiogenesis, tumor perfusion, combination therapy

Received: July 28, 2016 Accepted: October 13, 2016 Published: October 21, 2016

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.


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