E Kano

University of Fukui, Hukui, Fukui, Japan

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Publications (59)122.72 Total impact

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    ABSTRACT: The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA topoisomerase II inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments.
    International Journal of Molecular Medicine 12/2006; 18(5):909-15. · 1.96 Impact Factor
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    ABSTRACT: The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cell line to hyperthermia at 44 degrees C were investigated. The cell phase response as well as the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of 44 degrees C hyperthermia on A549 cells exhibited low thermosensitivity with a T(0) value of 12 min. The slope of the survival curve in the exponential phase, described semilogarithmically, in 44 degrees C hyperthermia combined treatment with AMROH (0.02 microg/ml) was approximately parallel to 44 degrees C hyperthermia alone. The initial shoulder shape portion of the survival curve from 44 degrees C hyperthermia alone, indicating the repair of sublethal thermal damage (SLTDR), was reduced with the sequential combined treatment of AMR or AMROH. Sequential treatments with AMR or AMROH prior to 44 degrees C hyperthermia resulted in additive thermo-enhancement effect by reducing not only survival but was shoulder wide. Furthermore, like AMR and AMROH, adriamycin (ADM) and etoposide (VP-16) are DNA topoisomerase II inhibitors, and the effects of these 4 agents on 44 degrees C hyperthermia were compared. All 4 agents exhibited comparable thermo-enhancement effects. Using synchronized A549 cells, AMR or AMROH did not elicit cell phase responses, irrespective of the concentration. The induction of apoptosis was investigated at 48 and 72 h after AMROH treatment, 44 degrees C hyperthermia or the combined treatment, in which apoptosis was not significantly induced after any treatment. Furthermore, the incidence of necrosis was examined as well as apoptosis. The incidence of necrosis at 48 and 72 h after AMROH was 2.4 and 4.3%, respectively; after 44 degrees C hyperthermia was 3.3 and 4.0%, respectively; and after the combined treatment it was 10.7 and 8.7%, respectively. The necrosis induced after the combined treatment was circa 3 times higher than that in either of the single treatments.
    International Journal of Molecular Medicine 10/2005; 16(3):381-7. · 1.96 Impact Factor
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    ABSTRACT: To elucidate the relationship between p53 functions and the interactive effects of the combined treatment with mild hyperthermia and mitomycin C. p53-deficient human non-small-cell lung cancer H1299 cells were transfected with a vector carrying a neomycin-resistant gene (neo) or together with a wild-type or mutant p53 gene. Sensitivities of these transfectants to mild hyperthermia at 42 degrees C, mitomycin C (0.05 microg/mL) at 37 degrees C, or the combination treatment were determined by colony formation assay. After these treatments, the induction of apoptosis, the changes in cell cycle distribution, and the accumulation of Hsp72 were examined. The combined treatment resulted in an enhanced cell killing effect in H1299 cells in a p53-independent manner, which was partially the result of an enhancement of heat-induced apoptosis. The treatment also caused a marked G(2)/M arrest in the neo and the mutant p53 cells, but not in the wild-type p53 cells. The subsequent release of G(2)/M arrest was accompanied with an increase in the sub-G(1) fractions. Mitomycin C did not affect the accumulation of Hsp72 induced by hyperthermia in H1299 cells regardless of their p53 gene status. Our findings demonstrate a p53-independent mechanism for an interactively cytotoxic enhancement by combined treatment with mild hyperthermia and mitomycin C.
    International Journal of Radiation OncologyBiologyPhysics 08/2004; 59(3):852-60. · 4.52 Impact Factor
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    ABSTRACT: Our research group has reported the enhanced cytotoxicity of combined treatment with bleomycin (BLM) and low hyperthermia at 40 degrees C, using murine L cells, and suggested that post-heating could inhibit BLM-induced sublethal damage repair. For further understanding of the involved mechanisms, we subsequently investigated the kinetics of the cellular accumulations of inducible 72-kDa heat shock protein (hsp72) after 40 degrees C hyperthermia and/or BLM treatment using the same cell line. Western blot analysis showed significantly enhanced accumulation of hsp72 after a low hyperthermia at 40 degrees C for 40, 105 or 180 min, and no significant enhancement of it after exposure to 10 microg/ml BLM at 37 degrees C for either 40 or 105 min. When the cells were heated in the presence of BLM, the accumulations of hsp72 were markedly suppressed, with the maxima of hsp72 accumulation decreasing to 38% and 63% of those induced by hyperthermia alone for 40 or 105 min, respectively. On the other hand, sequential treatment with hyperthermia either before or after BLM treatment did not show significant alteration of the heat-induced accumulations of hsp72. It was demonstrated that BLM was necessary during heating to effectively suppress the heat-induced accumulation of hsp72. This study indicates that the suppression of heat-induced accumulation of hsp72 by BLM may partially contribute to enhance cytotoxicity of the simultaneous treatment of 40 degrees C hyperthermia and BLM.
    International Journal of Oncology 02/2002; 20(1):137-42. · 2.66 Impact Factor
  • Methods in Enzymology 02/2002; 359:280-6. · 2.00 Impact Factor
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    ABSTRACT: Both adriamycin (ADM) and hyperthermia show thermal chemo-enhancement. Tolerance induction against ADM in heated cells has been reported resulting in clinical difficulty of cancer therapy. We investigated thermo-enhancement induced with ADM (0.2 microg/ml) treatment alone or combined with ADM and 42 degrees C hyperthermia in Chinese hamster V79 cells in vitro. Intracellular accumulation of hsc70 and hsp72 proteins after hyperthermia or ADM was observed to examine the possible relationship between cell killing effect and their accumulations. Thermosensitivity of V79 cells at 42 degrees C after the simultaneous treatments with ADM showed marked thermo-enhancement within the short-term treatments for less than 1 h, while the combined treatments for longer than 1 h, the cells showed reduced thermosensitivity. Survival from the simultaneous treatments for less than 1 h was reduced markedly less than the single treatment both with ADM or 42 degrees C hyperthermia alone. Thermotolerance was markedly induced in a step-up hyperthermia (42 degrees C 2 h-44 degrees C). The combined treatments with ADM and 44 degrees C hyperthermia following the 42 degrees C preheating alone does not inhibit thermotolerance development. The combined treatments with ADM and 42 degrees C preheating showed markedly interactive cell killing, but no thermo-enhancement to the following 44 degrees C hyperthermia was shown. The leveling slope of the 44 degrees C heating period-survival curve was drawn. In the Western blot analyses, hsc70 existed constitutively in the V79 cells. Following the 42 or 44 degrees C hyperthermia alone, intracellular accumulation of hsp72 was determined. ADM treatment alone did not induce any accumulation of hsp72. In the simultaneous treatments with ADM and hyperthermia, the accumulation of hsp72 was markedly reduced. The accumulation of hsp72 after the combined treatment with ADM and hyperthermia was not observed as markedly as that after hyperthermia alone.
    International Journal of Molecular Medicine 11/2001; 8(4):417-22. · 1.96 Impact Factor
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    ABSTRACT: Ohtsubo, T., Igawa, H., Saito, T., Matsumoto, H., Park, H. J., Song, C. W., Kano, E. and Saito, H. Enhancement of Cell Killing by Induction of Apoptosis after Treatment with Mild Hyperthermia at 42 degrees C and Cisplatin. Radiat. Res. 156, 103-109 (2001). We examined the interactive effects of cisplatin (1.0 microg/ml) combined with hyperthermia on cell killing and on the induction of apoptosis in IMC-3 human maxillary carcinoma cells. The cytotoxic effects of hyperthermia on IMC-3 cells at 44 degrees C were greater than at 42 degrees C, as has been reported for many other cells. The induction of apoptosis, DNA fragmentation and poly(ADP-ribose) polymerase cleavage were greater after hyperthermia at 44 degrees C for 30 min compared with treatment at 42 degrees C for 105 min, even though both of these heat doses were isoeffective in reducing cell survival to 50%. Treatment with cisplatin at 37 degrees C for up to 120 min did not result in cytotoxicity or the induction of apoptosis. The enhancement ratio for treatment with cisplatin at 42 degrees C was greater than that at 44 degrees C. More apoptosis was induced after the treatment with cisplatin at 42 degrees C compared to treatment with cisplatin at 44 degrees C. Taking these findings together, the combination of cisplatin and hyperthermia at 42 degrees C appeared to be more effective than cisplatin with hyperthermia at 44 degrees C for the induction of apoptosis in IMC-3 cells.
    Radiation Research 08/2001; 156(1):103-9. · 2.70 Impact Factor
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    ABSTRACT: The effects of hyperthermia or irradiation on cell killing and induction of apoptosis were evaluated using human maxillary carcinoma IMC-3 cells and low pH (pH 6.8) adapted cells (IMC-3-pH). Cellular heat-sensitivity or radiosensitivity was determined using the clonogenic assay. Apoptosis was assessed on the basis of a flow cytometric determination of the DNA content, DNA fragmentation, and poly(ADP-ribose)polymerase cleavage. When IMC-3 cells or IMC-3-pH cells were exposed to heat at 44 degrees C in pH 6.8 medium, an increase in thermosensitivity was observed compared with when the IMC-3 cells were exposed to heat at 44 degrees C in pH 7.4 medium. However, the selective reduction in survival was not observed after irradiation. In IMC-3 cells, apoptosis after heating at 44 degrees C for 60 min in pH 7.4 medium occurred earlier than that after 8 Gy irradiation, although both thermal and irradiated doses decreased the cell count to 10%. The degree of apoptosis after heating at pH 6.8 in IMC-3 cells or IMC-3-pH cells was greater than that at pH 7.4 in IMC-3 cells. However, the degree of apoptosis after 8 Gy irradiation at pH 6.8 in IMC-3 cells or IMC-3-pH cells was smaller than that at pH 7.4 in IMC-3 cells. Hyperthermia treatment is more effective at inducing apoptosis than radiation is in tumors that contain a population of low pH adapted cells.
    International Journal of Radiation OncologyBiologyPhysics 05/2001; 49(5):1391-8. · 4.52 Impact Factor
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    ABSTRACT: To elucidate whether nitric oxide secreted from irradiated cells affects cellular radiosensitivity, we examined the accumulation of inducible nitric oxide synthase, TP53 and HSP72, the concentration of nitrite in the medium of cells after X irradiation, and cellular radiosensitivity using two human glioblastoma cell lines, A-172, which has a wild-type TP53 gene, and a transfectant of A-172 cells, A-172/mp53, bearing a mutated TP53 gene. Accumulation of inducible nitric oxide synthase was caused by X irradiation of the mutant TP53 cells but not of the wild-type TP53 cells. Accumulation of TP53 and HSP72 in the wild-type TP53 cells was observed by cocultivation with irradiated mutant TP53 cells, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase, aminoguanidine, to the medium. Likewise, accumulation of these proteins was observed in the wild-type TP53 cells after exposure to conditioned medium from irradiated mutant TP53 cells, and the accumulation was abolished by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. The radiosensitivity of wild-type TP53 cells was reduced when the cells were cultured in conditioned medium from irradiated mutant TP53 cells compared to conventional fresh growth medium. Collectively, these findings indicate the potential importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to ionizing radiation.
    Radiation Research 04/2001; 155(3):387-96. · 2.70 Impact Factor
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    ABSTRACT: To investigate whether nitric oxide excreted from cells irradiated with accelerated carbon-ion beams modulates cellular radiosensitivity against irradiation in human glioblastoma A-172 and T98G cells. Western-blot analysis of inducible nitric oxide synthase, hsp72 and p53, the concentration assay of nitrite in medium and cell survival assay after irradiation with accelerated carbon-ion beams were performed. The accumulation of inducible nitric oxide synthase was caused by accelerated carbon-ion beam irradiation of T98G cells but not of A-172 cells. The accumulation of hsp72 and p53 was observed in A-172 cells after exposure to the conditioned medium of the T98G cells irradiated with accelerated carbon-ion beams, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase to the medium. The radiosensitivity of A-172 cells was reduced in the conditioned medium of the T98G cells irradiated with accelerated carbon-ion beams compared with conventional fresh growth medium, and the reduction of radiosensitivity was abolished by the addition of an inducible nitric oxide synthase inhibitor to the conditioned medium. Nitric oxide excreted from the irradiated donor cells with accelerated carbon-ion beams could modulate the radiosensitivity of recipient cells. These findings indicate the importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to accelerated heavy ions.
    International Journal of Radiation Biology 01/2001; 76(12):1649-57. · 1.84 Impact Factor
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    ABSTRACT: Nitric oxide is known to be a multifunctional physiological substance. Recently, it was suggested that nitric oxide is involved in p53-dependent response to many kinds of stress, such as heat shock and changes in cellular metabolism. To verify this hypothesis, we examined the effect of nitric oxide produced endogenously by heat-shocked cells on nonstressed cells using a human glioblastoma cell line, A-172, and its mutant p53 (mp53) transfectant (A-172/mp53). The accumulation of inducible nitric oxide synthase was caused by heat treatment of the mtp53 cells but not of the wild-type p53 (wtp53) cells. The accumulation of heat shock protein 72 (hsp72) and p53 was observed in nontreated mtp53 cells cocultivated with heated mp53 cells, and the accumulation of these proteins was suppressed by the addition of a specific inducible nitric oxide synthase inhibitor, aminoguanidine, to the medium. Furthermore, the accumulation of these proteins was observed in the wtp53 cells after exposure to the conditioned medium by preculture of the heated mp53 cells, and the accumulation was completely blocked by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. In addition, the accumulation of hsp72 and p53 in the wtp53 cells was induced by the administration of an nitric oxide-generating agent, S-nitroso-N-acetylpenicillamine, to the medium. Finally, the thermosensitivity of the wtp53 cells was reduced in the conditioned medium by preculture of the heated mp53 cells as compared with conventional fresh growth medium. Our finding of the accumulation of hsp72 and p53 in nitric oxide-recipient cells cocultivated with heated nitric oxide-donor cells provides the first evidence for an intercellular signal transduction pathway via nitric oxide as intermediate without cell-to-cell interactions such as gap junctions.
    Cancer Research 08/1999; 59(13):3239-44. · 8.65 Impact Factor
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    ABSTRACT: Murine L cells showed markedly high lethal thermosensitivity. Survivals from fractionated heating at 44 degrees C with variety of interval time at 37 degrees C (44 degrees C for 10 min--variety of interval time at 37 degrees C-44 degrees C for 10 min) increased markedly in accordance with elongation of the internal time; i.e. survival fraction of 0.9% from 44 degrees C for 20 min alone without the interval time to those of 25% from the fractionated heating with interval time at 37 degrees C for 3-10 hrs. Incidence of apoptosis of the L cells from heating at 44 degrees C for 6.5 min (LD50) increased from 7% immediately after the heating to 30% 6-12 hrs after the post-incubation time at 37 degrees C. Accumulation of both hsp72 and p53 proteins markedly increased after a heating at 44 degrees C for 10 min alone in accordance with elongation of post-incubation time at 37 degrees C, representing a peak 6 hrs after the post incubation. Status of p53 gene in L cells were determined with Reverse Transcription-Polymerase Chain Reaction-Single Strand Conformational Polymorphism (RT-PCR-SSCP), i.e. wild type.
    Journal of experimental & clinical cancer research: CR 07/1999; 18(2):181-9. · 1.50 Impact Factor
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    ABSTRACT: The accumulation of inducible nitric oxide synthase was caused by heat shock of human glioblastoma T98G cells but not of A-172 cells. The accumulation of hsp72 and p53 was observed in A-172 cells cocultivated with heat-shocked T98G cells, which was suppressed by the addition of aminoguanidine to the medium. The accumulation of these proteins was observed in A-172 cells after exposure to the conditioned medium of heat-shocked T98G cells, which was completely blocked by the addition of 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide to the medium. In addition, the accumulation of these proteins in A-172 cells was induced by the administration of S-nitroso-N-acetylpenicillamine to the medium. Finally, the thermosensitivity of A-172 cells was reduced in the conditioned medium of heat-shocked T98G cells compared with conventional fresh growth medium. Our findings demonstrate that the accumulation of stress-induced proteins and thermoresistance in NO recipient cells cocultivated with heat-shocked NO donor cells is induced through an intercellular signal transduction pathway initiated by NO without cell-to-cell interactions such as gap junctions.
    Nitric Oxide 02/1999; 3(2):180-9. · 3.27 Impact Factor
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    ABSTRACT: We showed that the prominent suppressions of heat-induced accumulation and activation of p53 by CDDP or X-rays were observed in A-172 cells, but not in T98G cells. In addition, the interactive hyperthermic enhancement of CDDP or X-ray cytotoxicity was observed in A-172 cells, but not in T98G cells. Our findings indicate that suppressions of heat-induced accumulation and activation of p53 by CDDP or X-rays contribute positively to an interactive hyperthermic enhancement of CDDP- or X-ray cytotoxicity.
    International Journal of Oncology 11/1998; 13(4):741-7. · 2.66 Impact Factor
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    ABSTRACT: Hyperthermia has been introduced as a new modality of treatment for glioma. In these experiments, the cytotoxicity of hyperthermia in C6 glioma cells was enhanced by increasing the intracellular acidity with amiloride and/or 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid (DIDS). Intracellular pH (pHi) is regulated mainly by Na+/H+ and HCO3-/Cl- antiports through the cell membrane, and amiloride acts on the former, DIDS on the latter to lower pHi. The cellular thermosensitivity to clinically achievable brain hyperthermia at 42 degrees C was enhanced by 0.5 mM amiloride (Na+/H+ antiport inhibitor). T0 values (T0 = the heating period required to reduce experimental survival rate by 1/e) at 42 degrees C without and with amiloride was 192 and 81 min, respectively. The addition of DIDS (HCO3-/Cl- antiport inhibitor) further enhanced. T0 value was 25 min. Fluorophotometric measurement of pHi was employed using the pH sensitive dye, bis(carboxyethyl)carboxyfluorescein, which is trapped in viable cells. The average pHi in control C6 glioma cells in pH 7.2 media was 7.21. In the untreated cells heated at 42 degrees C for 1 hour, the pHi was 7.12. The pHi of the cells heated in the presence of amiloride was decreased to 6.83. The pHi was further lowered to 6.67 by the treatment with amiloride in combination with DIDS for 2 hours. Hyperthermia with amiloride and DIDS may be a more effective treatment for malignant gliomas.
    Journal of Neuro-Oncology 10/1998; 39(3):197-203. · 3.12 Impact Factor
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    ABSTRACT: Hyperthermia has been introduced as a new modality of treatment for glioma. In these experiments, the cytotoxicity of hyperthermia in C6 glioma cells was enhanced by increasing the intracellular acidity with amiloride and/or 4,4-diisothiocyanatostilbene-2,2disulfonic acid (DIDS). Intracellular pH (pHi) is regulated mainly by Nau/Hu and HCOplus3 minus/Clminus antiports through the cell membrane, and amiloride acts on the former, DIDS on the latter to lower pHi. The cellular thermosensitivity to clinically achievable brain hyperthermia at 42 C was enhanced by 0.5 mM amiloride (Nau/Hu antiport inhibitor). T0 values (T0 = the heating period required to reduce experimental survival rate by 1/e) at 42 C without and with amiloride was 192 and 81 min, respectively. The addition of DIDS (HCO3 minus/Clminus antiport inhibitor) further enhanced. T0 value was 25 min. Fluorophotometric measurement of pHi was employed using the pH sensitive dye, bis(carboxyethyl)carboxyfluorescein, which is trapped in viable cells. The average pHi in control C6 glioma cells in pH 7.2 media was 7.21. In the untreated cells heated at 42 C for 1 hour, the pHi was 7.12. The pHi of the cells heated in the presence of amiloride was decreased to 6.83. The pHi was further lowered to 6.67 by the treatment with amiloride in combination with DIDS for 2 hours. Hyperthermia with amiloride and DIDS may be a more effective treatment for malignant gliomas.
    Journal of Neuro-Oncology 08/1998; 39(3):197-203. · 3.12 Impact Factor
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    ABSTRACT: The kinetics of the accumulation of inducible 72-kD heat shock protein (hsp72) and the activation of heat shock transcriptional factor (HSF) after hyperthermia and/or CDDP treatment in two human glioblastoma cell lines, A-172 having the wild-type p53 gene and T98G having the mutated p53 gene were evaluated. Western blot analysis of hsp72, gel-mobility shift assay of HSF, cell survival, and development of thermotolerance were examined. The prominent suppression of heat-induced hsp72 accumulation by CDDP was seen in A-172 cells, but not in T98G cells. This was due to the p53-dependent inhibition of heat-induced HSF activation by CDDP. The interactive hyperthermic enhancement of CDDP cytotoxicity was observed in A-172 cells, but not in T98G cells. In addition, the heat-induced thermotolerance was suppressed by the presence of CDDP in the pretreatment. Suppression of heat-induced hsp72 accumulation by CDDP contributes to an interactive hyperthermic enhancement of CDDP cytotoxicity in the cells bearing the wild-type p53 gene.
    International Journal of Radiation OncologyBiologyPhysics 08/1998; 41(4):915-20. · 4.52 Impact Factor
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    ABSTRACT: We studied the cytotoxic and pharmacological properties of 40 degrees C hyperthermia and CDDP in CDDP-sensitive (IMC-3) and CDDP-resistant (IMC-3-DDP) human maxillary carcinoma cells. Heating at 40 degrees C alone caused almost no cell killing to IMC-3 and IMC-3-DDP cells. In both cell lines, the dose-dependent cytotoxicity of 2-h exposures to CDDP was increased at 40 degrees C in comparison to 37 degrees C. Heating at 40 degrees C also potentiated CDDP cytotoxicity in both IMC-3 and IMC-3-DDP cells with thermal chemoenhancement ratios (CER) of 1.48 and 1.94, respectively. The intracellular CDDP uptake level of IMC-3-DDP at 37 degrees C was significantly reduced compared with IMC-3 cells. At 40 degrees C, however, hyperthermia increased platinum accumulation by factors of 1.4 and 1.8 in IMC-3 and IMC-3-DDP cells, respectively. These findings indicated that CDDP sensitivity was hyperthermically chemopotentiated in CDDP-resistant variants rather than in the control clones. Thus, clinical cancer chemotherapy with CDDP may be improved by an appropriate combination with hyperthermia even at 40 degrees C.
    Cancer Letters 11/1997; 119(1):47-52. · 5.02 Impact Factor
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    ABSTRACT: Modification effects of low hyperthermia (40 degrees C) on cellular chemosensitivity to bleomycin (BLM), and of BLM on thermosensitivity (40 degrees C) were investigated in cultured murine L cells with simultaneous or sequential treatments of these two agents. The heating of L cells at 40 degrees C up to 6 hours resulted in no remarkable lethal damage. Treatment with low hyperthermia followed by BLM for 4 hours showed no more than additive effect. However, a significant chemical (BLM) enhancement effect on the cellular thermosensitivity was observed by the treatment with BLM for 4 hours prior to the low hyperthermia at 40 degrees C. No appreciable thermal enhancement effect on the cellular chemosensitivity to BLM was shown by preheating at 40 degrees C for 3 hours, while post-heating at 40 degrees C showed a significant thermal enhancement effect as well as in the simultaneous treatments. The cell phase response to BLM was levelled in the clinical range of the doses. It is possible that the repair of sublethal damage (SLDR) from treatment with BLM was inhibited by 40 degrees C post-heating and this SLDR was completed at 3 hours of the interval at 37 degrees C between BLM and 40 degrees C heating.
    Journal of experimental & clinical cancer research: CR 07/1997; 16(2):147-52. · 1.50 Impact Factor
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    ABSTRACT: The accumulation of the inducible hsp72 (72-kDa heat shock protein) after hyperthermia and/or cisplatin treatment in human glioblastoma cell line (A-172) was studied by Western blot analysis. The level of hsp72 increased to eight-fold 10 h after hyperthermia alone (44 °C for 20 min, D50) and to three-fold 10 h after cisplatin treatment (5 μg/ml) at 37 °C for 15 min (D50). In contrast, when the cells were simultaneously heated with cisplatin, the accumulation of hsp72 was suppressed. The level of hsp72 increased to about six-fold and two-fold 10 h after hyperthermia (44 °C, 15 min) in the presence of 1 and 10 μg/ ml (D50 or D10) of cisplatin, respectively. In addition, we found both the enhancement of thermosensitivity and the suppression of thermotolerance by the simultaneously combined treatment of hyperthermia and cisplatin. It has been reported that the enhancement of cisplatin cytotoxicity by hyperthermia is due to increase of both cisplatin uptake and DNA damage by hyperthermia. Our results suggest that the interactive cytotoxic enhancement by the combination of hyperthermia and cisplatin may be also due to the suppression of heat-induced hsp72 accumulation by cisplatin.
    Cancer Letters 01/1997; · 5.02 Impact Factor