Hyperthermic radiosensitization: mode of action and clinical relevance

Kampinga, Harm H.; Dikomey, Ekkehard

doi:10.1080/09553000010024687

Cited by 236 publications

(161 citation statements)

References 84 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…In addition to complementary biologic effects with radiation and chemotherapy, mechanisms for direct effect include protein denaturization including inhibition of sub-lethal and potentially lethal damage repair through inactivation of DNA repair pathways leading to mitotic catastrophe, induction of senescence, apoptosis, and necrosis. (21)(22)(23)(24)(25)(26)(27)(28) Research has revealed that protein denaturization is a key biologic effect of hyperthermia at modest temperature elevations. (29) The activation energeries for protein denaturization and heat induced cell death were noted to be within the same range.…”

Section: Mechanism Of Cell Death With Hyperthermiamentioning

confidence: 99%

“…Specifically, heat induces changes in DNA repair foci such as the MRN complex which includes MRE11, rad 50, and nbs1, key proteins involved in double strand break repair, the nucleolus and on the complexes that anchor DNA to the nuclear matrix thus contributing to radiosensitization. (33)(34) Chromosomal aberrations may also occur due to heat sensitivity of the centriole. (35) Failure of DNA replication in S-Phase of the cell cycle results in mitotic catastrophe.…”

Section: Mechanism Of Cell Death With Hyperthermiamentioning

confidence: 99%

See 1 more Smart Citation

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Hurwitz

Stauffer

2014

Seminars in Oncology

118

104

View full text Add to dashboard Cite

Section: Mechanism Of Cell Death With Hyperthermiamentioning

confidence: 99%

Section: Mechanism Of Cell Death With Hyperthermiamentioning

confidence: 99%

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Hurwitz

Stauffer

2014

Seminars in Oncology

118

104

View full text Add to dashboard Cite

“…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).…”

mentioning

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.

298

288

View full text Add to dashboard Cite

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...

show abstract

“…It also has the ability to kill cells under conditions of hypoxia and low pH, which in turn are reasons for developing resistance to radiation and chemotherapy (Kampinga 2001). Hyperthermic temperatures of 43 °C have been shown to have more than an additive or synergistic cytotoxic effect when employed with several anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

“…In terms of optimal timing of hyperthermia and other therapies, Overgaard et al showed that application of hyperthermia at 42-43 °C three to four hours after radiation was optimal for radiosensitization of cells (Overgaard 1982). Radiosensitization and chemosensitization to DNA-intercalating agents such as DOX both result in cytotoxic effects by preventing DNA damage repair mechanisms (Kampinga 2001;Blasiak, Widera et al 2003). Therefore, the optimal timing between chemotherapy and hyperthermia can be expected to be similar to the timing between radiotherapy and hyperthermia.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Nanoparticles for Theranostic Applications

Srinivasan¹

View full text Add to dashboard Cite

iii DEDICATION I want to dedicate this dissertation to my husband Karthikeyan who lent never ending love and support throughout my journey in graduate school. He had immense belief in me that I would be able to make my way through graduate school. There was not a single day in four years of our married life that he complained about my absence. He always had more confidence in me than I did in myself. I regretted those times when I could not attend his call or wasn't able to hear to his problems during his difficult times. However, he was patient and was there for me, no matter what the circumstances were. He was always there when I was close to giving up, trying to make me understand the importance of what I was doing. I also want to dedicate my dissertation to my mother, father, motherin-law and father-in-law. I would like to thank them for all the support they extended during my journey. Multifunctional agents for the management of highly heterogeneous diseases, like cancer, are gaining increased interest with the intent of improving the diagnostics and therapy of cancer patients. These agents are also important because more than one treatment modality is typically used for cancer therapy in the clinic. Further, nanotechnology offers a platform where more than one agent can be combined to help provide improved cancer diagnosis and therapy. Near-infrared light-activatable phototherapeutic agents have great potential in vivo. Body tissues have minimum absorption in the near-infrared range.They also have been shown to enhance the cytotoxic effect of chemotherapeutic drugs when used in combination with them. We have, hence, investigated the potential of two multifunctional targeted nanoparticles for combined chemo-phototherapy (employing near-infrared light activable agent) and for understanding their underlying cellular responses. The first is employing polymeric Poly-lactic acid-co-glycolic acid (PLGA) nanoparticles with simultaneous incorporation of Indocyanine Green (ICG) (a nearinfrared light-activatable photothermal agent) and Doxorubicin (DOX) and surface conjugated with anti-Human Epithelial Receptor-2 (HER-2). The PLGA nanoparticles were subjected to two modes of hyperthermia, incubator and laser hyperthermia, to vii mimic whole-body and localized hyperthermia used clinically. These nanoparticles upon laser exposure showed a rapid heat shock protein 70 (HSP70) response in comparison to the cellular HSP70 response upon incubator hyperthermia exposure. However, 12h posttreatment, downregulation of HSP70, was observed, thus, causing cellular apoptosis or necrosis based on the degree of thermal insult. These targeted nanoparticles, simultaneously incorporating agents, suffer from the limitation of release of both the agents from the nanoparticles and the need to control their release for bringing in effective therapy. Therefore, the second multifunctional nanoparticle employing silver nanoparticles (AgNPs) conjugated with Doxorubicin was formulated. AgNP serve as a near-infrared activatable agent itself, o...

show abstract

Hyperthermic radiosensitization: mode of action and clinical relevance

Cited by 236 publications

References 84 publications

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

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

Multifunctional Nanoparticles for Theranostic Applications

Contact Info

Product

Resources

About