HORSLEY, R. J., BANERJEE, S. N., LASZLO, A., AND PARKER, K., Lethal Damage after X- and UV-irradi... more HORSLEY, R. J., BANERJEE, S. N., LASZLO, A., AND PARKER, K., Lethal Damage after X- and UV-irradiation and Its Modifications by Hypoxia and Cycloheximide. Radiat. Res. 54, 110-120 (1973). The results of further investigations on giant cell formation after x-irradiation under hypoxia and oxygenated conditions and after uv-irradiation are presented. The maximum yield of giant cells in the progeny from G2 cells x-irradiated in the presence of N2 in the dark or in the presence of 02 in the light is about the same with the exception that the peak value for cells irradiated in N2 occurs at a higher dose than that for cells irradiated in 02. This difference in dose at the peak values may be reconciled on the basis of equivalent loss of cellular reproductive ability. Similar to the results after x-irradiation, giant cell formation is a maximum in the progeny for G2 cells irradiated with uv. Cycloheximide treatment after x-ray and uv-irradiation of G2 populations inhibits giant cell formation while at the same time percentage of survival increases at all the dose levels studied It is postulated that giant cells are formed due to abnormal protein synthesis, presumably, due to malformed microtubules in the cell wall. Cycloheximide treatment aft^r an insult through radiation prevents this expression of potentially lethal radiation damage by
Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is ... more Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT and discuss challenges and future directions.
Publikationsansicht. 5101559. Characterization of the genome of Paeonia Brownii. (1972). Laszlo, ... more Publikationsansicht. 5101559. Characterization of the genome of Paeonia Brownii. (1972). Laszlo, Andrei. Abstract. Thesis (MS in Chemistry)--Univ. of California, Dec. 1972.. Bibliography: leaves 62-67. Details der Publikation. Download, http://worldcat.org/oclc/29480619. ...
Publikationsansicht. 31001907. Characterization of an inducible enzyme : maize pyruvate decarboxy... more Publikationsansicht. 31001907. Characterization of an inducible enzyme : maize pyruvate decarboxylase / (1981). Laszlo, Andrei. Abstract. Thesis (Ph. D. in Genetics)--University of California, Berkeley, Dec. 1981.. Bibliography: leaves 279-300. Details der Publikation. ...
One of the properties of hyperthermia which makes its use in cancer therapy feasible is the abili... more One of the properties of hyperthermia which makes its use in cancer therapy feasible is the ability of heat to systematically kill cells. The kinetics of this killing process has been established in the late 1970s (reviewed by Conner et al. 1977; Henle and Dethlefsen ...
Chronic exposure of asynchronous HeLa cell cultures to 41.5 degrees C leads to an accumulation of... more Chronic exposure of asynchronous HeLa cell cultures to 41.5 degrees C leads to an accumulation of cells in the S-phase, spontaneous premature chromosome condensation, and loss of clonogenicity (M.A. Mackey, S. L. Anolik, and J. L. Roti Roti. Cancer Res., 52: 1101-1106, 1992). In this report, we show that increases in histone H1 kinase activity during 41.5 degrees C exposure occur coincidentally with the appearance of premature chromosome condensation. Furthermore, this kinase activity is shown to be associated with M-phase kinase complexes containing cyclin B1. These increases in the activity of M-phase kinase were found to occur concomitantly with an elevation in cyclin B1 mRNA and an accumulation of cyclin B1 protein. Because cyclin B1 transcription begins in the S-phase, it is probable that the heat-induced delay in the S-phase allows the accumulation of abnormally high cyclin B1 levels. Elevated cyclin B1 levels could then account for the observed abrogation of the cell cycle checkpoint, which usually assures that mitosis does not proceed until DNA replication is complete. This involvement of M-phase kinase in heat-induced cytotoxicity demonstrates the importance of the coordinate regulation of the processes of DNA replication and entry into mitosis.
There has been considerable interest in the biological effects of exposure to radiofrequency elec... more There has been considerable interest in the biological effects of exposure to radiofrequency electromagnetic radiation, given the explosive growth of cellular telephone use, with the possible induction of malignancy being a significant concern. Thus the determination of whether nonthermal effects of radiofrequency electromagnetic radiation contribute to the process leading to malignancy is an important task. One proposed pathway to malignancy involves the induction of the stress response by exposures to cell phone frequency microwaves. The first step in the induction of the stress response is the activation of the DNA-binding activity of the specific transcription factor involved in this response, the heat-shock factor (HSF). The DNA-binding activity of HSF in hamster, mouse and human cells was determined after acute and continuous exposures to frequency domain multiple access (FDMA)- or code domain multiple access (CDMA)-modulated microwaves at low (0.6 W/kg) or high (approximately 5 W/kg) SARs at frequencies used for mobile communication. The DNA-binding activity of HSF was monitored using a gel shift assay; the calibration of this assay indicated that an increase of approximately 10% in the activation of the DNA-binding activity of HSF after a 1 degrees C increase in temperature could be detected. We failed to detect any increase in the DNA-binding ability of HSF in cultured mammalian cells as a consequence of any exposure tested, within the sensitivity of our assay. Our results do not support the notion that the stress response is activated as a consequence of exposure to microwaves of frequencies associated with mobile communication devices.
Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is ... more Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT and discuss challenges and future directions.
Proceedings of the National Academy of Sciences of the United States of America, Dec 1, 1985
Heat-resistant variants of the Chinese hamster HA-1 line have been isolated after repeated heat t... more Heat-resistant variants of the Chinese hamster HA-1 line have been isolated after repeated heat treatments. The heat-resistant phenotype has been stable for over 70 passages. One of the members of the 70-kDa heat shock protein family was found to be synthesized at greater levels in the heat-resistant variants under normal growth conditions. Mild heat treatment of the variant lines induced a transient thermotolerance that was accompanied by additional increase in the synthesis of the 70-kDa heat shock proteins. Cell-free translation of total cellular RNA revealed greater amounts of 70-kDa heat shock protein mRNA in both control and heated variant cells. The greater levels of 70-kDa heat shock protein synthesized in the variant cells presumably are a reflection of altered levels of its messenger mRNA. In addition, we found that translational control plays a role in the elevated expression of heat shock proteins in heat-shocked HA-1 cells and their heat-resistant variants. The association of the heat-resistant phenotype with increased levels of a 70-kDa heat shock protein suggests strongly that this gene product plays a role in protecting cells from damage inflicted by elevated temperatures.
The synthesis of the major heat-shock proteins (hsp) was compared in normal and heat-resistant Ch... more The synthesis of the major heat-shock proteins (hsp) was compared in normal and heat-resistant Chinese hamster fibroblasts which express higher levels of the 70 kDa heat-shock protein (hsp70). Following exposure to a variety of experimental conditions that induce the elevated synthesis of the hsp, higher relative levels of hsp70 and lower relative levels of hsp89 and hsp110 were found in the heat-resistant variants. This effect was observed with all inducers tested. The relatively greater synthesis of hsp70 and relatively lower synthesis of hsp89 occurred at all temperatures tested and was found to be independent of cell culture conditions. The relatively greater increase in the levels of hsp70 in the heat-resistant variants after a mild heat shock was found to be a reflection of elevated levels of messenger RNA coding for this polypeptide. These results indicate that the heat-shock response in mammalian cells displays coordinate regulatory features and that the alteration of the expression of one of the hsp may affect the expression of the others.
The heat induced delay in 53BP1 complex formation is reversible. MCF cells were treated at 43°C f... more The heat induced delay in 53BP1 complex formation is reversible. MCF cells were treated at 43°C for 60 min, irradiated with 2 Gy of X-rays at various times post heat treatment, allowed to recover for 30 min, then stained for 53BP1 foci and the fraction of cells with greater than 6 53BP1 foci was determined. Supplementary Figure S-2. Recovery from the heat-induced delay of 53BP1 complex formation is independent of de-novo protein synthesis. MCF 7 cells were irradiated with 2 Gy of X-rays and treated at 43°C for 60 min and then allowed to recover at 37°C in the presence (■) and absence (•) of 100μg/ml of cycloheximide for various lengths of time and then fixed and stained for 53BP1 foci and the fraction of cells containing greater than 6 53BP1 foci was determined. Supplementary Figure S-3. Heating of pre-existing 53BP1 complexes leads to their dispersal. MCF7 cells irradiated with 4 Gy allowed to recover for 2 hr (A), irradiated with 2 Gy allowed to recover for 2 hr and then treated at 43°C for 60 min (B) or irradiated with 2 Gy allowed to recover for 3 hr (C) were fixed and stained for 53BP1 foci. Supplementary Figure S-4. The effect of heat and radiation on the solubility of 53BP1. Control MCF7 cells(C), MCF 7 cells treated at 43°C for 60 min (H) or MCF7 cells irradiated with 8 Gy of X-rays and allowed to recover for 30 min (IR) were fractionated and immunoblotted with an antibody against 535BP1 as described under "Materials and Methods". (P) insoluble pellet, (WC) whole cells. The arrows indicated the band corresponding to 53BP1 Supplementary Figure S-5. Transiently thermotolerant cells are resistant to heat radiosensitization. Control (C), and transiently thermotolerant (TT)(cells heated at 43°C for 30 min and allowed to recover at 37°C for 24 hr) HA-1 cells were irradiated with 2 Gy of X-rays alone (■,•) or irradiated with 2 Gy of X-rays and then heated at 43°C for 60 min (▲,▼), and clonogenic survival was determined as described under "Materials and Methods". Supplementary Figure S-6. Correlation between TER and the length of the heat induced delay in 53BP1 complex formation in heated-irradiated cells. The TER values from Table 1 were plotted against the time for the length of the delay in 53BP1 complex formation as determined from Figures 1B, 4A and 4B. Supplementary Figure S-7. Heat induces a delay in the formation of Chk2 p68T foci in heated-irradiated cells. A) MCF cells irradiated with 2 Gy of X-rays (IR), treated at 43°C for 60 min (H) or irradiated with 2 Gy of X-rays followed by treatment at 43°C for 60 min (RH) were stained for Chk2 p68T foci at various times post treatments. B) The fraction of MCF cells containing more than 7 Chk2 p68T foci was determined after various time of recovery from irradiation with 2 Gy X-rays (■), treatment at 43°C for 60 min (•) or irradiation with 2 Gy of X-rays followed by treatment at 43°C for 60 min (▲).
Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that ... more Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that hyperthermia is a good adjuvant for radiotherapy at several different cancer sites. However, the mechanism(s) involved in the interaction of heat and radiation that lead to radiosensitization remain to be elucidated. In this report, we have determined that heat induces perturbations in some of the earliest events in the cellular response to DNA damage induced by ionizing radiation. We studied the effect of heat on the formation of complexes containing γ-H2AX/MDC1/53BP1 in heated-irradiated cells. We found that the formation of this complex was delayed in heated-irradiated cells, in a heat but not radiation dose–dependent manner. The length of the heat-induced delay of complex formation was attenuated in thermotolerant and heat radiosensitization–resistant cells. The length of the delay of γ-H2AX/MDC1/53BP1 complex formation correlated with the magnitude of heat radiosensitization and was modulated by the molecular chaperone Hsc70. Heat radiosensitization was attenuated in 53BP1-null cells, implying that the delay of the formation of the γ-H2AX/MDC1/53BP1 complex plays a role in heat radiosensitization. Heat also induced a delay of events in the DNA damage response that are downstream from 53BP1. Our results support the notion that heat-induced perturbations in the earliest events of the cellular response to ionizing radiation–induced DNA damage play a role in heat radiosensitization. [Cancer Res 2009;69(5):2042–9]
HORSLEY, R. J., BANERJEE, S. N., LASZLO, A., AND PARKER, K., Lethal Damage after X- and UV-irradi... more HORSLEY, R. J., BANERJEE, S. N., LASZLO, A., AND PARKER, K., Lethal Damage after X- and UV-irradiation and Its Modifications by Hypoxia and Cycloheximide. Radiat. Res. 54, 110-120 (1973). The results of further investigations on giant cell formation after x-irradiation under hypoxia and oxygenated conditions and after uv-irradiation are presented. The maximum yield of giant cells in the progeny from G2 cells x-irradiated in the presence of N2 in the dark or in the presence of 02 in the light is about the same with the exception that the peak value for cells irradiated in N2 occurs at a higher dose than that for cells irradiated in 02. This difference in dose at the peak values may be reconciled on the basis of equivalent loss of cellular reproductive ability. Similar to the results after x-irradiation, giant cell formation is a maximum in the progeny for G2 cells irradiated with uv. Cycloheximide treatment after x-ray and uv-irradiation of G2 populations inhibits giant cell formation while at the same time percentage of survival increases at all the dose levels studied It is postulated that giant cells are formed due to abnormal protein synthesis, presumably, due to malformed microtubules in the cell wall. Cycloheximide treatment aft^r an insult through radiation prevents this expression of potentially lethal radiation damage by
Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is ... more Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT and discuss challenges and future directions.
Publikationsansicht. 5101559. Characterization of the genome of Paeonia Brownii. (1972). Laszlo, ... more Publikationsansicht. 5101559. Characterization of the genome of Paeonia Brownii. (1972). Laszlo, Andrei. Abstract. Thesis (MS in Chemistry)--Univ. of California, Dec. 1972.. Bibliography: leaves 62-67. Details der Publikation. Download, http://worldcat.org/oclc/29480619. ...
Publikationsansicht. 31001907. Characterization of an inducible enzyme : maize pyruvate decarboxy... more Publikationsansicht. 31001907. Characterization of an inducible enzyme : maize pyruvate decarboxylase / (1981). Laszlo, Andrei. Abstract. Thesis (Ph. D. in Genetics)--University of California, Berkeley, Dec. 1981.. Bibliography: leaves 279-300. Details der Publikation. ...
One of the properties of hyperthermia which makes its use in cancer therapy feasible is the abili... more One of the properties of hyperthermia which makes its use in cancer therapy feasible is the ability of heat to systematically kill cells. The kinetics of this killing process has been established in the late 1970s (reviewed by Conner et al. 1977; Henle and Dethlefsen ...
Chronic exposure of asynchronous HeLa cell cultures to 41.5 degrees C leads to an accumulation of... more Chronic exposure of asynchronous HeLa cell cultures to 41.5 degrees C leads to an accumulation of cells in the S-phase, spontaneous premature chromosome condensation, and loss of clonogenicity (M.A. Mackey, S. L. Anolik, and J. L. Roti Roti. Cancer Res., 52: 1101-1106, 1992). In this report, we show that increases in histone H1 kinase activity during 41.5 degrees C exposure occur coincidentally with the appearance of premature chromosome condensation. Furthermore, this kinase activity is shown to be associated with M-phase kinase complexes containing cyclin B1. These increases in the activity of M-phase kinase were found to occur concomitantly with an elevation in cyclin B1 mRNA and an accumulation of cyclin B1 protein. Because cyclin B1 transcription begins in the S-phase, it is probable that the heat-induced delay in the S-phase allows the accumulation of abnormally high cyclin B1 levels. Elevated cyclin B1 levels could then account for the observed abrogation of the cell cycle checkpoint, which usually assures that mitosis does not proceed until DNA replication is complete. This involvement of M-phase kinase in heat-induced cytotoxicity demonstrates the importance of the coordinate regulation of the processes of DNA replication and entry into mitosis.
There has been considerable interest in the biological effects of exposure to radiofrequency elec... more There has been considerable interest in the biological effects of exposure to radiofrequency electromagnetic radiation, given the explosive growth of cellular telephone use, with the possible induction of malignancy being a significant concern. Thus the determination of whether nonthermal effects of radiofrequency electromagnetic radiation contribute to the process leading to malignancy is an important task. One proposed pathway to malignancy involves the induction of the stress response by exposures to cell phone frequency microwaves. The first step in the induction of the stress response is the activation of the DNA-binding activity of the specific transcription factor involved in this response, the heat-shock factor (HSF). The DNA-binding activity of HSF in hamster, mouse and human cells was determined after acute and continuous exposures to frequency domain multiple access (FDMA)- or code domain multiple access (CDMA)-modulated microwaves at low (0.6 W/kg) or high (approximately 5 W/kg) SARs at frequencies used for mobile communication. The DNA-binding activity of HSF was monitored using a gel shift assay; the calibration of this assay indicated that an increase of approximately 10% in the activation of the DNA-binding activity of HSF after a 1 degrees C increase in temperature could be detected. We failed to detect any increase in the DNA-binding ability of HSF in cultured mammalian cells as a consequence of any exposure tested, within the sensitivity of our assay. Our results do not support the notion that the stress response is activated as a consequence of exposure to microwaves of frequencies associated with mobile communication devices.
Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is ... more Hyperthermia therapy (HT) raises tissue temperature to 40À45˚C for up to 60 min. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT and discuss challenges and future directions.
Proceedings of the National Academy of Sciences of the United States of America, Dec 1, 1985
Heat-resistant variants of the Chinese hamster HA-1 line have been isolated after repeated heat t... more Heat-resistant variants of the Chinese hamster HA-1 line have been isolated after repeated heat treatments. The heat-resistant phenotype has been stable for over 70 passages. One of the members of the 70-kDa heat shock protein family was found to be synthesized at greater levels in the heat-resistant variants under normal growth conditions. Mild heat treatment of the variant lines induced a transient thermotolerance that was accompanied by additional increase in the synthesis of the 70-kDa heat shock proteins. Cell-free translation of total cellular RNA revealed greater amounts of 70-kDa heat shock protein mRNA in both control and heated variant cells. The greater levels of 70-kDa heat shock protein synthesized in the variant cells presumably are a reflection of altered levels of its messenger mRNA. In addition, we found that translational control plays a role in the elevated expression of heat shock proteins in heat-shocked HA-1 cells and their heat-resistant variants. The association of the heat-resistant phenotype with increased levels of a 70-kDa heat shock protein suggests strongly that this gene product plays a role in protecting cells from damage inflicted by elevated temperatures.
The synthesis of the major heat-shock proteins (hsp) was compared in normal and heat-resistant Ch... more The synthesis of the major heat-shock proteins (hsp) was compared in normal and heat-resistant Chinese hamster fibroblasts which express higher levels of the 70 kDa heat-shock protein (hsp70). Following exposure to a variety of experimental conditions that induce the elevated synthesis of the hsp, higher relative levels of hsp70 and lower relative levels of hsp89 and hsp110 were found in the heat-resistant variants. This effect was observed with all inducers tested. The relatively greater synthesis of hsp70 and relatively lower synthesis of hsp89 occurred at all temperatures tested and was found to be independent of cell culture conditions. The relatively greater increase in the levels of hsp70 in the heat-resistant variants after a mild heat shock was found to be a reflection of elevated levels of messenger RNA coding for this polypeptide. These results indicate that the heat-shock response in mammalian cells displays coordinate regulatory features and that the alteration of the expression of one of the hsp may affect the expression of the others.
The heat induced delay in 53BP1 complex formation is reversible. MCF cells were treated at 43°C f... more The heat induced delay in 53BP1 complex formation is reversible. MCF cells were treated at 43°C for 60 min, irradiated with 2 Gy of X-rays at various times post heat treatment, allowed to recover for 30 min, then stained for 53BP1 foci and the fraction of cells with greater than 6 53BP1 foci was determined. Supplementary Figure S-2. Recovery from the heat-induced delay of 53BP1 complex formation is independent of de-novo protein synthesis. MCF 7 cells were irradiated with 2 Gy of X-rays and treated at 43°C for 60 min and then allowed to recover at 37°C in the presence (■) and absence (•) of 100μg/ml of cycloheximide for various lengths of time and then fixed and stained for 53BP1 foci and the fraction of cells containing greater than 6 53BP1 foci was determined. Supplementary Figure S-3. Heating of pre-existing 53BP1 complexes leads to their dispersal. MCF7 cells irradiated with 4 Gy allowed to recover for 2 hr (A), irradiated with 2 Gy allowed to recover for 2 hr and then treated at 43°C for 60 min (B) or irradiated with 2 Gy allowed to recover for 3 hr (C) were fixed and stained for 53BP1 foci. Supplementary Figure S-4. The effect of heat and radiation on the solubility of 53BP1. Control MCF7 cells(C), MCF 7 cells treated at 43°C for 60 min (H) or MCF7 cells irradiated with 8 Gy of X-rays and allowed to recover for 30 min (IR) were fractionated and immunoblotted with an antibody against 535BP1 as described under "Materials and Methods". (P) insoluble pellet, (WC) whole cells. The arrows indicated the band corresponding to 53BP1 Supplementary Figure S-5. Transiently thermotolerant cells are resistant to heat radiosensitization. Control (C), and transiently thermotolerant (TT)(cells heated at 43°C for 30 min and allowed to recover at 37°C for 24 hr) HA-1 cells were irradiated with 2 Gy of X-rays alone (■,•) or irradiated with 2 Gy of X-rays and then heated at 43°C for 60 min (▲,▼), and clonogenic survival was determined as described under "Materials and Methods". Supplementary Figure S-6. Correlation between TER and the length of the heat induced delay in 53BP1 complex formation in heated-irradiated cells. The TER values from Table 1 were plotted against the time for the length of the delay in 53BP1 complex formation as determined from Figures 1B, 4A and 4B. Supplementary Figure S-7. Heat induces a delay in the formation of Chk2 p68T foci in heated-irradiated cells. A) MCF cells irradiated with 2 Gy of X-rays (IR), treated at 43°C for 60 min (H) or irradiated with 2 Gy of X-rays followed by treatment at 43°C for 60 min (RH) were stained for Chk2 p68T foci at various times post treatments. B) The fraction of MCF cells containing more than 7 Chk2 p68T foci was determined after various time of recovery from irradiation with 2 Gy X-rays (■), treatment at 43°C for 60 min (•) or irradiation with 2 Gy of X-rays followed by treatment at 43°C for 60 min (▲).
Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that ... more Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that hyperthermia is a good adjuvant for radiotherapy at several different cancer sites. However, the mechanism(s) involved in the interaction of heat and radiation that lead to radiosensitization remain to be elucidated. In this report, we have determined that heat induces perturbations in some of the earliest events in the cellular response to DNA damage induced by ionizing radiation. We studied the effect of heat on the formation of complexes containing γ-H2AX/MDC1/53BP1 in heated-irradiated cells. We found that the formation of this complex was delayed in heated-irradiated cells, in a heat but not radiation dose–dependent manner. The length of the heat-induced delay of complex formation was attenuated in thermotolerant and heat radiosensitization–resistant cells. The length of the delay of γ-H2AX/MDC1/53BP1 complex formation correlated with the magnitude of heat radiosensitization and was modulated by the molecular chaperone Hsc70. Heat radiosensitization was attenuated in 53BP1-null cells, implying that the delay of the formation of the γ-H2AX/MDC1/53BP1 complex plays a role in heat radiosensitization. Heat also induced a delay of events in the DNA damage response that are downstream from 53BP1. Our results support the notion that heat-induced perturbations in the earliest events of the cellular response to ionizing radiation–induced DNA damage play a role in heat radiosensitization. [Cancer Res 2009;69(5):2042–9]
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