Pub Date : 2011-09-20DOI: 10.3191/THERMALMED.27.61
Zhang Lin, Shi Deng-Ping, Yang Wen-tao, Hu Bing, Weng Zhi-Ying, Xi Jian-dong, Jiang Shao-Lian, Kong Ya-mei, Li Wen-wen
The aim of this study was to evaluate the effectiveness of regional hyperthermia combined with lamivudine (LAM) for treatment of chronic hepatitis B (CHB) and explore its possible mechanism. Forty CHB patients were randomly divided into the combination group (treated with regional hyperthermia and LAM ; n=17) and control group (treated with LAM alone ; n=23). Laboratory examinations were performed for hepatic function, hepatitis B virus (HBV) markers, and HBV DNA. Lymphocyte subpopulations including CD3+ (total T cells), CD4+CD8- (helper T cells) and CD4-CD8+ (cytotoxic T cells) were detected with flow cytometry. The side effects and tolerance were observed. Aspartate aminotransferase and HBV-DNA levels were significantly lower in the combination group than in the control group (P< 0.05). Hepatitis e antigen/antibody conversion rate was similar between the two groups, whereas the combination group had significantly higher rates of CD4+/CD8+ T cells than the control group (P< 0.05). Regional hyperthermia combined with LAM is superior to LAM alone for treatment of CHB, which may be achieved by enhancing cellular immune function.
{"title":"Effectiveness of Regional Hyperthermia Combined with Lamivudine in Treating Chronic Hepatitis B","authors":"Zhang Lin, Shi Deng-Ping, Yang Wen-tao, Hu Bing, Weng Zhi-Ying, Xi Jian-dong, Jiang Shao-Lian, Kong Ya-mei, Li Wen-wen","doi":"10.3191/THERMALMED.27.61","DOIUrl":"https://doi.org/10.3191/THERMALMED.27.61","url":null,"abstract":"The aim of this study was to evaluate the effectiveness of regional hyperthermia combined with lamivudine (LAM) for treatment of chronic hepatitis B (CHB) and explore its possible mechanism. Forty CHB patients were randomly divided into the combination group (treated with regional hyperthermia and LAM ; n=17) and control group (treated with LAM alone ; n=23). Laboratory examinations were performed for hepatic function, hepatitis B virus (HBV) markers, and HBV DNA. Lymphocyte subpopulations including CD3+ (total T cells), CD4+CD8- (helper T cells) and CD4-CD8+ (cytotoxic T cells) were detected with flow cytometry. The side effects and tolerance were observed. Aspartate aminotransferase and HBV-DNA levels were significantly lower in the combination group than in the control group (P< 0.05). Hepatitis e antigen/antibody conversion rate was similar between the two groups, whereas the combination group had significantly higher rates of CD4+/CD8+ T cells than the control group (P< 0.05). Regional hyperthermia combined with LAM is superior to LAM alone for treatment of CHB, which may be achieved by enhancing cellular immune function.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"63 1","pages":"61-68"},"PeriodicalIF":0.0,"publicationDate":"2011-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74590852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-01-01DOI: 10.3191/THERMALMED.27.51
Naoyuki Sakamoto, S. Kokura, T. Ishikawa, M. Tanigawa, Y. Naito, T. Yoshikawa
Use of hyperthermia as cancer treatment has often been impossible to continue at once following exacerbation of general condition due to cancer growth. However, no formal consensus has yet been defined regarding the acceptability of hyperthermia, so selection of patients for hyperthermia is not based on agreed clinical criteria. Aiming at the establishment of agreed clinical criteria concerning the selection of patients for hyperthermia, this report examined the treatment acceptability of hyperthermia based on patient backgrounds before advanced cancer treatment. Subjects comprised 45 patients with various advanced cancers treated with regional hyperthermia combined with chemo- or immunotherapy who visited our clinic between July 2008 and May 2009. Group A (n=24) underwent hyperthermia ≥ 8 times, while Group B (n=21) underwent hyperthermia ≤ 7 times (mean, 4.19 times). We investigated pretreatment laboratory data, body mass index, performance status (PS), Glasgow prognostic score (GPS), and quality of life (QOL). Patients with poor scores for both PS and GPS dropped out early. In these patients, elevations in both lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels tended to be present in addition to hypoalbuminemia. QOL in Group B was already impaired before initiation of hyperthermia. PS and GPS appear to represent the most important factors when judging the acceptability of hyperthermia, while LDH, CRP, and albumin levels may help such judgments. The acceptability of hyperthermia can be predicted using patient background as evidenced by laboratory data and general conditions, including QOL, before cancer treatment. The results justified further examination in a large number of patients to aim the establishment of agreed clinical criteria concerning the selection of patients for hyperthermia.
{"title":"Selecting Patients for Hyperthermia Treatment Based on Patient Backgrounds","authors":"Naoyuki Sakamoto, S. Kokura, T. Ishikawa, M. Tanigawa, Y. Naito, T. Yoshikawa","doi":"10.3191/THERMALMED.27.51","DOIUrl":"https://doi.org/10.3191/THERMALMED.27.51","url":null,"abstract":"Use of hyperthermia as cancer treatment has often been impossible to continue at once following exacerbation of general condition due to cancer growth. However, no formal consensus has yet been defined regarding the acceptability of hyperthermia, so selection of patients for hyperthermia is not based on agreed clinical criteria. Aiming at the establishment of agreed clinical criteria concerning the selection of patients for hyperthermia, this report examined the treatment acceptability of hyperthermia based on patient backgrounds before advanced cancer treatment. Subjects comprised 45 patients with various advanced cancers treated with regional hyperthermia combined with chemo- or immunotherapy who visited our clinic between July 2008 and May 2009. Group A (n=24) underwent hyperthermia ≥ 8 times, while Group B (n=21) underwent hyperthermia ≤ 7 times (mean, 4.19 times). We investigated pretreatment laboratory data, body mass index, performance status (PS), Glasgow prognostic score (GPS), and quality of life (QOL). Patients with poor scores for both PS and GPS dropped out early. In these patients, elevations in both lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels tended to be present in addition to hypoalbuminemia. QOL in Group B was already impaired before initiation of hyperthermia. PS and GPS appear to represent the most important factors when judging the acceptability of hyperthermia, while LDH, CRP, and albumin levels may help such judgments. The acceptability of hyperthermia can be predicted using patient background as evidenced by laboratory data and general conditions, including QOL, before cancer treatment. The results justified further examination in a large number of patients to aim the establishment of agreed clinical criteria concerning the selection of patients for hyperthermia.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"15 1","pages":"51-60"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80462352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-12-20DOI: 10.3191/THERMALMED.26.109
晃久 竹内, 蓮村 ひろみ, 関谷 巳知秋, 正一 白髭, 恵美 原山, 幸子 琴寄, 隆子 竹内
Matrix metalloproteinase-1 (MMP-1) has received a considerable attention as one of factors, enhancing tumor infiltration and metastasis. We determined serum levels of MMP-1 and TIMP-2, a tissue inhibitor of metalloproteinase-2 (a protein that suppresses all MMPs activity). Furthermore, we monitored changes in serum levels of MMP-1 and TIMP-2 after Whole Body Hyperthermia (WBH). Samples were collected from 46 patients with advanced cancers and 20 healthy volunteers were also examined for MMP-1 and TIMP-2. Furthermore, they were monitored for 36 patients undergoing one cycle of WBH, three weeks after completion of WBH. Mean serum level of MMP-1 in patients was increased to a significant extent whereas mean serum level of TIMP-2 was markedly lowered, compared to healthy individuals. MMP-1 activity was assessed by MMP-1/TIMP-2 ratio, and the ratio was 0.43 for cancer patients and 0.15 for healthy individuals, thus showing that cancer patients exhibited an apparently higher MMP-1/TIMP-2 ratio than healthy individuals. MMP-1 activity was nearly normalized in 9 responders after WBH, i .e ., from 0.37 (before) to 0.21 (after), whereas MMP-1 activity was increased from 0.43 (before) to 0.51 (after) in 27 non-responders. MMP-1 activity was increased approximately by 3-fold in patients, compared to healthy individuals. MMP-1 activity was normalized in WBH-responders.
{"title":"Whole body hyperthermiaによる間質コラゲナーゼ活性の変化と間質リモデリング仮説","authors":"晃久 竹内, 蓮村 ひろみ, 関谷 巳知秋, 正一 白髭, 恵美 原山, 幸子 琴寄, 隆子 竹内","doi":"10.3191/THERMALMED.26.109","DOIUrl":"https://doi.org/10.3191/THERMALMED.26.109","url":null,"abstract":"Matrix metalloproteinase-1 (MMP-1) has received a considerable attention as one of factors, enhancing tumor infiltration and metastasis. We determined serum levels of MMP-1 and TIMP-2, a tissue inhibitor of metalloproteinase-2 (a protein that suppresses all MMPs activity). Furthermore, we monitored changes in serum levels of MMP-1 and TIMP-2 after Whole Body Hyperthermia (WBH). Samples were collected from 46 patients with advanced cancers and 20 healthy volunteers were also examined for MMP-1 and TIMP-2. Furthermore, they were monitored for 36 patients undergoing one cycle of WBH, three weeks after completion of WBH. Mean serum level of MMP-1 in patients was increased to a significant extent whereas mean serum level of TIMP-2 was markedly lowered, compared to healthy individuals. MMP-1 activity was assessed by MMP-1/TIMP-2 ratio, and the ratio was 0.43 for cancer patients and 0.15 for healthy individuals, thus showing that cancer patients exhibited an apparently higher MMP-1/TIMP-2 ratio than healthy individuals. MMP-1 activity was nearly normalized in 9 responders after WBH, i .e ., from 0.37 (before) to 0.21 (after), whereas MMP-1 activity was increased from 0.43 (before) to 0.51 (after) in 27 non-responders. MMP-1 activity was increased approximately by 3-fold in patients, compared to healthy individuals. MMP-1 activity was normalized in WBH-responders.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"9 1","pages":"109-119"},"PeriodicalIF":0.0,"publicationDate":"2010-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83783522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-01-01DOI: 10.3191/THERMALMED.27.25
K. Terashima, Y. Shioyama, S. Nomoto, Saiji Ohga, Takeshi Nonoshita, Tadamasa Yoshitake, K. Ohnishi, K. Asai, Keiji Matsumoto, Koichi Takayama, Katsumasa Nakamura, Hiromi Terashima, H. Honda
A case of lung cancer with chest wall invasion treated by preoperative thermo-chemo-radiotherapy revealed a histologically complete response after complete resection is reported. A 55-year-old male was diagnosed as primary lung cancer originating from the right upper lobe, cT3N0M0, stage IIB. The tumor invaded the right chest wall accompanied with obstructive pneumonia at its dorsal side and was rapidly growing. Thus, preoperative thermo-chemo-radiotherapy was performed. He was treated with conventional irradiation with a 10 MV X-ray, a total dose of 40 Gy, and concurrent chemotherapy with cisplatin (CDDP) and vinorelbine (VNR). Hyperthermia was applied within 30 min after each radiotherapy with a RF-capacitive heating apparatus (Thermotron RF-8, Ymamamoto Vinyter, Osaka, Japan), 40 min/time, once a week, for a total of 4 times. The tumor revealed necrotic change on CT images after thermo-chemo-radiotherapy and was completely resected. No viable cancer cells were observed in the histological examination (Ef 3). Even 17 months later, there was no recurrence.
{"title":"術前温熱化学放射線療法が著効し組織学的に完全奏功が証明された原発性肺癌の一例(A Case of Lung Cancer with Chest Wall Invasion Showed a Pathologically Complete Response to Preoperative Thermo-chemo-radiotherapy)","authors":"K. Terashima, Y. Shioyama, S. Nomoto, Saiji Ohga, Takeshi Nonoshita, Tadamasa Yoshitake, K. Ohnishi, K. Asai, Keiji Matsumoto, Koichi Takayama, Katsumasa Nakamura, Hiromi Terashima, H. Honda","doi":"10.3191/THERMALMED.27.25","DOIUrl":"https://doi.org/10.3191/THERMALMED.27.25","url":null,"abstract":"A case of lung cancer with chest wall invasion treated by preoperative thermo-chemo-radiotherapy revealed a histologically complete response after complete resection is reported. A 55-year-old male was diagnosed as primary lung cancer originating from the right upper lobe, cT3N0M0, stage IIB. The tumor invaded the right chest wall accompanied with obstructive pneumonia at its dorsal side and was rapidly growing. Thus, preoperative thermo-chemo-radiotherapy was performed. He was treated with conventional irradiation with a 10 MV X-ray, a total dose of 40 Gy, and concurrent chemotherapy with cisplatin (CDDP) and vinorelbine (VNR). Hyperthermia was applied within 30 min after each radiotherapy with a RF-capacitive heating apparatus (Thermotron RF-8, Ymamamoto Vinyter, Osaka, Japan), 40 min/time, once a week, for a total of 4 times. The tumor revealed necrotic change on CT images after thermo-chemo-radiotherapy and was completely resected. No viable cancer cells were observed in the histological examination (Ef 3). Even 17 months later, there was no recurrence.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"58 1","pages":"25-30"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73200681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-01-01DOI: 10.3191/THERMALMED.26.51
H. Ohwada, Y. Ishihara
To improve the efficacy of hyperthermia treatment, a novel method of noninvasive measurement of body temperature change is proposed. The proposed technology, thermometry, is based on changes in the electromagnetic field distribution inside the heating applicator with temperature changes and the temperature dependence of the dielectric constant. In addition, an image of the temperature change distribution inside a body is reconstructed by applying a computed tomography (CT) algorithm. The proposed thermometry method can serve as a possible noninvasive method to monitor the temperature change distribution inside the body without the use of enormous thermometers such as in the case of magnetic resonance imaging (MRI). Furthermore, this temperature monitoring method can be easily combined with a heating applicator based on a cavity resonator, and the novel integrated treatment system can possibly be used to treat cancer effectively while noninvasively monitoring the heating effect. In this paper, the phase change distributions of the electromagnetic field with temperature changes are simulated by numerical analysis using the finite difference time domain (FDTD) method. Moreover, to estimate the phase change distributions inside a target body, the phase change distributions with temperature changes are reconstructed by a filtered back-projection. In addition, the reconstruction accuracy of the converted temperature change distribution from the phase change is evaluated
{"title":"A Fundamental Numerical Analysis for Noninvasive Thermometry Integrated in a Heating Applicator Based on the Reentrant Cavity","authors":"H. Ohwada, Y. Ishihara","doi":"10.3191/THERMALMED.26.51","DOIUrl":"https://doi.org/10.3191/THERMALMED.26.51","url":null,"abstract":"To improve the efficacy of hyperthermia treatment, a novel method of noninvasive measurement of body temperature change is proposed. The proposed technology, thermometry, is based on changes in the electromagnetic field distribution inside the heating applicator with temperature changes and the temperature dependence of the dielectric constant. In addition, an image of the temperature change distribution inside a body is reconstructed by applying a computed tomography (CT) algorithm. The proposed thermometry method can serve as a possible noninvasive method to monitor the temperature change distribution inside the body without the use of enormous thermometers such as in the case of magnetic resonance imaging (MRI). Furthermore, this temperature monitoring method can be easily combined with a heating applicator based on a cavity resonator, and the novel integrated treatment system can possibly be used to treat cancer effectively while noninvasively monitoring the heating effect. In this paper, the phase change distributions of the electromagnetic field with temperature changes are simulated by numerical analysis using the finite difference time domain (FDTD) method. Moreover, to estimate the phase change distributions inside a target body, the phase change distributions with temperature changes are reconstructed by a filtered back-projection. In addition, the reconstruction accuracy of the converted temperature change distribution from the phase change is evaluated","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"20 1","pages":"51-62"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82910548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-01-01DOI: 10.3191/THERMALMED.26.87
T. Ohguri, K. Yahara, M. Murakami, H. Imada, H. Terashima, Y. Korogi
Hyperthermia(HT)using a 8-MHz radiofrequency-capacitive heating device at University of Occupational and Environmental Health(UOEH)was initiated in 1988,and over 1000 patients have been treated with HT. The heat had been performed by radiation oncologist for long period. In recent years, it has been supported by medical engineer and nurse as instructed in radiation oncologist. Basically,HT has been performed concurrent with radiotherapy or chemoradiotherapy,and the combined therapy of systemic chemotherapy with regional HT has been increasing since 2004. Recently,advances in physics for radiotherapy cause a significant improvement of tumor control rates. However, a further improvement of the local tumor control rate is still demanded for a lot of locally advanced cancer or loco-regional recurrent cancer. The regional HT may remain important role for those advanced tumors. In the patients with locally advanced lung or esophageal cancers, the combined therapy of chemoradiotherapy and regional HT has been used actively at UOEH. In addition,we have tried the adding of regional HT in the patients with the limited treatment choices,such as re-irradiation for the patients with in-field recurrence, and re-administration of chemotherapy for multidrug-resistant cases. Here,we review current status of HT,especially for heating methods of deep regional HT,at UOEH,and discuss future direction for deep regional HT to improve clinical outcome of HT inclusive therapy.
{"title":"Current Status and Future Directions of Hyperthermia at the University of Occupational and Environmental Health","authors":"T. Ohguri, K. Yahara, M. Murakami, H. Imada, H. Terashima, Y. Korogi","doi":"10.3191/THERMALMED.26.87","DOIUrl":"https://doi.org/10.3191/THERMALMED.26.87","url":null,"abstract":"Hyperthermia(HT)using a 8-MHz radiofrequency-capacitive heating device at University of Occupational and Environmental Health(UOEH)was initiated in 1988,and over 1000 patients have been treated with HT. The heat had been performed by radiation oncologist for long period. In recent years, it has been supported by medical engineer and nurse as instructed in radiation oncologist. Basically,HT has been performed concurrent with radiotherapy or chemoradiotherapy,and the combined therapy of systemic chemotherapy with regional HT has been increasing since 2004. Recently,advances in physics for radiotherapy cause a significant improvement of tumor control rates. However, a further improvement of the local tumor control rate is still demanded for a lot of locally advanced cancer or loco-regional recurrent cancer. The regional HT may remain important role for those advanced tumors. In the patients with locally advanced lung or esophageal cancers, the combined therapy of chemoradiotherapy and regional HT has been used actively at UOEH. In addition,we have tried the adding of regional HT in the patients with the limited treatment choices,such as re-irradiation for the patients with in-field recurrence, and re-administration of chemotherapy for multidrug-resistant cases. Here,we review current status of HT,especially for heating methods of deep regional HT,at UOEH,and discuss future direction for deep regional HT to improve clinical outcome of HT inclusive therapy.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"7 1","pages":"87-96"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84362851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Kawashima, Minoru Soga, Rika Takeuchi, H. Matsumoto, K. Ohtsuka
The tumor suppressor gene p53 encodes a transcription factor and is known to be the most frequently mutated gene (approximately 50%) in human cancer. The functional restoration of mutant p53 protein is considered to be one type of anticancer treatment ; and some chemical compounds, including CP-31398, PRIMA-1 (p53 reactivation and induction of massive apoptosis), and glycerol, have been shown to restore its function. We here investigated whether molecular chaperone inducers such as carbenoxolone (CBX), paeoniflorin (PF), and sodium salicylate (SA) could restore the functional defect of a temperature-sensitive mutant p53 protein (V143A). Functional restoration of p53 was detected by the induction of wild-type p53 activated fragment 1 (WAF1) and mouse double minute 2 (MDM2), both of which are gene products transactivated by an active p53. When H1299/tsp53 cells were cultured continuously at a nonpermissive temperature (37°C), no apparent expression of WAF1 and MDM2 was observed. Upon the temperature shift-down from 37°C to a permissive temperature (32°C), WAF1 and MDM2 gradually accumulated in the cells at 6 to 12 h later, probably owing to the gradual appearance of wild-type p53. When the cells were treated with molecular chaperone inducers at 37°C and then the temperature was shifted down, WAF1 and MDM2 appeared much earlier at 3 to 6 h, and also in much higher amounts than those in the control cells. Inhibition of molecular chaperone induction by quercetin or heat shock factor 1 (HSF1) siRNA diminished the facilitative effect of molecular chaperone inducers. Also, long-term overexpression (48 h) of molecular chaperones by CBX led to the accumulation of wild-type p53 even at 37°C. These results suggested that moderately overexpressed molecular chaperones could facilitate the correct folding and functional restoration of mutant p53 protein.
{"title":"Molecular Chaperone Inducers Facilitate the Functional Restoration of Temperature-sensitive Mutant p53 Protein","authors":"D. Kawashima, Minoru Soga, Rika Takeuchi, H. Matsumoto, K. Ohtsuka","doi":"10.3191/THERMALMED.26.1","DOIUrl":"https://doi.org/10.3191/THERMALMED.26.1","url":null,"abstract":"The tumor suppressor gene p53 encodes a transcription factor and is known to be the most frequently mutated gene (approximately 50%) in human cancer. The functional restoration of mutant p53 protein is considered to be one type of anticancer treatment ; and some chemical compounds, including CP-31398, PRIMA-1 (p53 reactivation and induction of massive apoptosis), and glycerol, have been shown to restore its function. We here investigated whether molecular chaperone inducers such as carbenoxolone (CBX), paeoniflorin (PF), and sodium salicylate (SA) could restore the functional defect of a temperature-sensitive mutant p53 protein (V143A). Functional restoration of p53 was detected by the induction of wild-type p53 activated fragment 1 (WAF1) and mouse double minute 2 (MDM2), both of which are gene products transactivated by an active p53. When H1299/tsp53 cells were cultured continuously at a nonpermissive temperature (37°C), no apparent expression of WAF1 and MDM2 was observed. Upon the temperature shift-down from 37°C to a permissive temperature (32°C), WAF1 and MDM2 gradually accumulated in the cells at 6 to 12 h later, probably owing to the gradual appearance of wild-type p53. When the cells were treated with molecular chaperone inducers at 37°C and then the temperature was shifted down, WAF1 and MDM2 appeared much earlier at 3 to 6 h, and also in much higher amounts than those in the control cells. Inhibition of molecular chaperone induction by quercetin or heat shock factor 1 (HSF1) siRNA diminished the facilitative effect of molecular chaperone inducers. Also, long-term overexpression (48 h) of molecular chaperones by CBX led to the accumulation of wild-type p53 even at 37°C. These results suggested that moderately overexpressed molecular chaperones could facilitate the correct folding and functional restoration of mutant p53 protein.","PeriodicalId":23299,"journal":{"name":"Thermal Medicine","volume":"405 1","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84862343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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