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      Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia

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          Abstract

          Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.

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          Most cited references138

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          Hyperthermia in combined treatment of cancer.

          Hyperthermia, the procedure of raising the temperature of tumour-loaded tissue to 40-43 degrees C, is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. The potential to control power distributions in vivo has been significantly improved lately by the development of planning systems and other modelling tools. This increased understanding has led to the design of multiantenna applicators (including their transforming networks) and implementation of systems for monitoring of E-fields (eg, electro-optical sensors) and temperature (particularly, on-line magnetic resonance tomography). Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma). Therefore, further development of existing technology and elucidation of molecular mechanisms are justified. In recent molecular and biological investigations there have been novel applications such as gene therapy or immunotherapy (vaccination) with temperature acting as an enhancer, to trigger or to switch mechanisms on and off. However, for every particular temperature-dependent interaction exploited for clinical purposes, sophisticated control of temperature, spatially as well as temporally, in deep body regions will further improve the potential.
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            Repair of strand breaks by homologous recombination.

            In this review, we discuss the repair of DNA double-strand breaks (DSBs) using a homologous DNA sequence (i.e., homologous recombination [HR]), focusing mainly on yeast and mammals. We provide a historical context for the current view of HR and describe how DSBs are processed during HR as well as interactions with other DSB repair pathways. We discuss the enzymology of the process, followed by studies on DSB repair in living cells. Whenever possible, we cite both original articles and reviews to aid the reader for further studies.
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              Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.

              The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                09 January 2019
                January 2019
                : 11
                : 1
                : 60
                Affiliations
                [1 ]Department of Experimental Clinical Oncology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; pernille.elming@ 123456oncology.au.dk (P.B.E.); bsin@ 123456oncology.au.dk (B.S.S.); jens@ 123456oncology.au.dk (J.O.)
                [2 ]Department of Radiation Oncology, Amsterdam University Medical Centers, University of Amsterdam, 1105AZ Amsterdam, The Netherlands; a.l.oei@ 123456amc.uva.nl (A.L.O.); n.a.franken@ 123456amc.uva.nl (N.A.P.F.); h.crezee@ 123456amc.uva.nl (J.C.)
                Author notes
                [* ]Correspondence: mike@ 123456oncology.au.dk ; Tel.: +45-78462622
                Author information
                https://orcid.org/0000-0002-3955-4735
                https://orcid.org/0000-0002-5522-9406
                https://orcid.org/0000-0002-7474-0533
                https://orcid.org/0000-0002-0814-8179
                Article
                cancers-11-00060
                10.3390/cancers11010060
                6356970
                30634444
                8b605b50-28e8-47c2-b62c-067e72a0a4b0
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 November 2018
                : 29 December 2018
                Categories
                Review

                hyperthermia,radiation therapy,hypoxia
                hyperthermia, radiation therapy, hypoxia

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