Mechanism of radiosensitization by hyperthermia (43°C) as derived from studies with DNA repair defective mutant cell lines

Kampinga, Harm H.; Dynlacht, Joseph R.; Dikomey, Ekkehard

doi:10.1080/02656730310001627713

Cited by 95 publications

(72 citation statements)

References 24 publications

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“…Three synergistic mechanisms have been identified: (1) Inhibition of DNA damage repair: HT enhances the effectiveness of radiotherapy by inhibiting repair of DNA damage [9][10][11], (2) Direct cell killing: HT selectively kills radioresistant hypoxic tumour cells [11][12][13][14], (3) Reoxygenation: HT increases tissue perfusion resulting in reoxygenation, thereby reducing hypoxia and increasing radiosensitivity [15][16][17][18][19]24,25].…”

Section: Synergistic Mechanisms Of Hyperthermiamentioning

confidence: 99%

“…Ideally all three mechanisms of radiosensitisation by hyperthermia suggested in the literature should be modelled: inhibition of DNA damage repair [9][10][11], direct cell killing of radioresistant hypoxic tumour cells [11][12][13][14] and reoxygenation by increased tissue perfusion [15][16][17][18][19]. The contribution of each of these mechanisms to radiosensitisation is still a subject of debate and due to this complicated mix of synergistic effects the optimal treatment scheme for combined radiotherapy and hyperthermia is difficult to determine based on the present literature.…”

Section: Introductionmentioning

confidence: 99%

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Thermoradiotherapy planning: Integration in routine clinical practice

Crezee

Leeuwen

Oei

et al. 2015

International Journal of Hyperthermia

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Planning of combined radiotherapy and hyperthermia treatments should be performed taking the synergistic action between the two modalities into account. This work evaluates the available experimental data on cytotoxicity of combined radiotherapy and hyperthermia treatment and the requirements for integration of hyperthermia and radiotherapy treatment planning into a single planning platform. The underlying synergistic mechanisms of hyperthermia include inhibiting DNA repair, selective killing of radioresistant hypoxic tumour tissue and increased radiosensitivity by enhanced tissue perfusion. Each of these mechanisms displays different dose-effect relations, different optimal time intervals and different optimal sequences between radiotherapy and hyperthermia. Radiosensitisation can be modelled using the linear-quadratic (LQ) model to account for DNA repair inhibition by hyperthermia. In a recent study, an LQ model-based thermoradiotherapy planning (TRTP) system was used to demonstrate that dose escalation by hyperthermia is equivalent to $10 Gy for prostate cancer patients treated with radiotherapy. The first step for more reliable TRTP is further expansion of the data set of LQ parameters for normally oxygenated normal and tumour tissue valid over the temperature range used clinically and for the relevant time intervals between radiotherapy and hyperthermia. The next step is to model the effect of hyperthermia in hypoxic tumour cells including the physiological response to hyperthermia and the resulting reoxygenation. Thermoradiotherapy planning is feasible and a necessity for an optimal clinical application of hyperthermia combined with radiotherapy in individual patients.

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Section: Synergistic Mechanisms Of Hyperthermiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thermoradiotherapy planning: Integration in routine clinical practice

Crezee

Leeuwen

Oei

et al. 2015

International Journal of Hyperthermia

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“…Agents inhibiting DNA repair processes potentiate the cytotoxicity of DSBs in cancer therapy (3). Elevated temperature is one such agent that, via unclear mechanisms, interferes with multiple pathways of DNA repair (4)(5)(6) and is clinically applied (7).…”

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confidence: 99%

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

Krawczyk

Eppink²,

Essers³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

302

288

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Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5°C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized ondemand induction of HR deficiency, an approach that we term induced synthetic lethality.anti-cancer treatment | RAD51 | double-strand break M any anti-cancer therapies are based on cytotoxicity of DNA double strand breaks (DSBs) induced by ionizing radiation or, indirectly, by chemical agents. However, efficient DSB repair mechanisms protect cells from the genotoxic effects of DSBs, thereby reducing the effectiveness of the therapies. Two major pathways are involved in DSB repair in mammalian cells: homologous recombination (HR) and nonhomologous end joining (NHEJ). HR uses intact homologous DNA sequences, usually the sister chromatid in postreplicative chromatin, to faithfully restore DNA breaks (1), whereas NHEJ operates throughout the entire cell cycle and does not require a DNA template (2). Agents inhibiting DNA repair processes potentiate the cytotoxicity of DSBs in cancer therapy (3). Elevated temperature is one such agent that, via unclear mechanisms, interferes with multiple pathways of DNA repair (4-6) and is clinically applied (7). ResultsTo investigate if HR, among other processes and DSB repair pathways, is influenced by elevated temperature, we used an isogenic set of mouse embryonic stem (ES) cells that are either HR proficient (wild-type) or HR deficient (Rad54 −/− ) due to the disruption of the Rad54 gene, which is important for HR activity (1). We compared radiosensitization of these cells by incubating them at 37°C or 41°C before irradiation. For this and subsequent experiments we chose temperatures below 43°C, because they are relevant in clinical practice (8). Interestingly, we observed that wild-type but not Rad54 −/− cells were radiosensitized by preincubation at 41°C compared with cells incubated at 37°C (Fig. 1A). Similarly, HeLa cells, in which the important HR factors XRCC3 or BRCA2 were down-regulated using siRNA, were refractory to further temperature-mediated radiosensitization (Fig. 1B and Fig. S1). These results suggest that elevated temperature inactivates HR. To directly measure the effect of temperature on HR, we quantitated HR-mediated gene targeting in ES cells (9) and found that the efficiency of gene targeting was significantly reduced by preincubation at 41°C compared with 37°C (Fig. 1C). Similarly, preincubation at 41°C reduced the frequency of spontaneous and mitomycin C-induced sister chromatid exchanges in SW-1573 cells (Fig. S2A), w...

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“…More specifically, hyperthermia induces degradation of the BRCA2 protein and thereby inactivates homologous recombination, one of the major pathways responsible for repairing DNA double-strand breaks [161,162]. Furthermore, hyperthermia (above 43 C) has been found to interfere with base excision repair [163,164], leading to more severe breaks. Interference with DNA repair pathways is important to increase levels of DNA breaks, causing accumulation of unrepaired DNA lesions, resulting in cell death.…”

Section: Dna Repairmentioning

confidence: 99%

Targeting therapy-resistant cancer stem cells by hyperthermia

Oei

Vriend

Krawczyk

et al. 2017

International Journal of Hyperthermia

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Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia -a therapeutic approach based on local heating of a tumour -is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs.ARTICLE HISTORY

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Mechanism of radiosensitization by hyperthermia (43°C) as derived from studies with DNA repair defective mutant cell lines

Cited by 95 publications

References 24 publications

Thermoradiotherapy planning: Integration in routine clinical practice

Thermoradiotherapy planning: Integration in routine clinical practice

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

Targeting therapy-resistant cancer stem cells by hyperthermia

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