• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Circumvention of cisplatin resistance in human ovarian carcinoma cells by modulation of cellular protein kinase C acitivity

Research Project

Project/Area Number 05671402
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Obstetrics and gynecology
Research InstitutionJikei University School of Medicine

Principal Investigator

ISONISHI Seiji  Jikei University School of Medicine, Department of obstetrics and Gynecology, Assistant professor, 医学部, 助手 (20184591)

Co-Investigator(Kenkyū-buntansha) KIMURA Eizou  Jikei University School of Medicine, Department of obstetrics and Gynecology, As, 講師 (70161552)
SHIOTSUKA Shigemasa  Jikei University School of Medicine, Department of obstetrics and Gynecology, As, 助手 (40266630)
Project Period (FY) 1992 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1994: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
KeywordsPlatinum / Protein Kinase C / Drug sensitivity / Drug resistance / TNFα / ヌードマウス / プロテインキナーゼC
Research Abstract

On the bases of the report that activation of protein kinase C (PKC) by 12-0-tetradecanoylphorbol-13-acetate (TPA) enhances the cis-Diamminedichloroplatinum (II) (DDP) sensitivity of the human ovarian carcinoma cell line 2008 (Isonishi et al.), we have investigated the cellular mechanism of this sensitization effect and have tried to extend this effect in vivo experiments. Activation of PKC by TPA was found to enhance the sensitivity of 2008 cells to DDP,carboplatin (CBDCA) and (Glycolato-o, o') diammineplatinum (II) (254-S). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of the three drugs to the same extent as for the 2008 cells. TPA produced no significant change in the uptake of [^3H]-cis-dichloro (ethylenediamine)-platinum (II) [^3H]-DEP) or CBDCA.It did not after glutathione content and induced rather than suppressed methallothionein IIA mRNA levels.
In contrast, TPA did not alter the sensitivity to DWA2114R, (-)-(R)-2-aminomethylpyrroli … More dine (1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate, in 2008 cells. Furthermore, it did render the DWA2114R-resistance of 2008/C13*5.25 cells by a factor of 1.7 fold (p<0.05) rather than increase sensitivity. This suggests that TPA sensitizatoin effect was not common to any platnium compounds but was strongly related to their ligands.
Based upon these in vivo data, we have determined the effect of TNFalpha, one of the other PKC activators, on the sntitumor effect of DDP against 2008 tumor xenograft in nude mice. TNFalpha (100mug) alone did not alter the in vivo growth of 2008 xenograft not did it alter DDP induced systemic toxicity. Low dose DDP (7mg/kg) caused a statistically significant reduction in tumor growth. The combination of TNFalpha and low dose DDP resulted in further reduction in tumor growth (p=0.0002) and produced significantly longer survival (p=0.0071). This is strongly indicating that TNFalpha has the potential to enhance the clinical antitumor effect of DDP in patient with ovarian carcinoma without altering systemic toxicity of DDP. Less

Report

(4 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • 1993 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Isonishi,S.,Shiotsuka,S.,Ochiai,K.,Yasuda,M.,and Tanaka,T.,Howell,S.B.: "Depletion of protein kinase C-α(PKCα)by 12-O-tetradecanoyl-phorbol-13-acetate(TPA)enhanced platinum sensitivity in human ovarian carcinoma cells. Proceedings of Am." Assoc. Cancer Res.37(in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi,S.,Shiotsuka,S.,Ochiai,K.,Yasuda,M.,and Terashima,Y.: "Tumor necrosis factor-α(TNF α)enhanced cisplatin(DDP)cytotoxicity to ovarian carcinoma xenografts in nude mice and prolonged their survival. Proceedings of Am." Assoc. Cancer Res.36. 631 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi,S.,Ochiai,K.,Yasuda,M.,Ohkawa,K.,and Terashima,Y.: "Mechanism-related circumvention of cisplatin resistance in human ovarian carcinoma cells by (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)-platinum(II)monohydrate and modulation of its sensitivity by 12-O-tetradecanoylphorbol-13-acetate." Int. J. Oncolo.5. 1309-1314 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi,S.,Hom,D. K.,Eastman,A. and Howell,S. B.: "Enhancement of sensitivity to platinum(II)-containing drugs by 12-O-tetradecanoyl-phobol-13-acetate in a human ovarian carcinoma cell line." Br./J. Cancer.69. 217-221 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 礒西成治: "卵巣癌における細胞内Protein Kinase C活性化による抗癌剤感受性の制御." Oncology & Chemotherapy.10. 97-100 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi,S.,Terashima,Y. Protein kinase C and platinum sensitivity. In: kikuchi,Y. and Terashima,Y. (eds.): "The mechanism of cisplatin resistance and the circumvention" New York : Nova Science Publishers,Inc.,(in press), (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Hom, D.K., Eastman, A.and Howell, S.B.: "Enhancement of sensitivity to platinum (II)-containing drugs by 12-0-tetradecanoyl-phobol-13-acetate in a human ovarian carcinoma cell lin." Br.J.Cancer.69. 217-221 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Ochiai, K., Yasuda, M., Ohkawa, K., and Terashima, Y.: "Mechanism-related circumvention of cisplatin resistance in human ovarian carcinoma cells by (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate and modulation of its sensitivity by 12-0-tetradecanoylphorbol-13-acetate." Int.J.Oncolo.5. 1309-1314 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Shiotsuka, S., Ochiai, K., Yasuda, M., and Terashima, Y.: "Tumor necrosis factor-alpha (TNFalpha) enhanced cisplatin (DDP) cytotoxicity to ovarian carcinoma xenografts in nude muce and prolonged their survival." Proceedings.of Am.Assoc.Cancer Res.36. 631 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Shiotsuka, S., Ochiai, K., Yasuda, M., and Tanaka, T., Howell, S.B.: "Depletion of protein kinase C-alpha (PKCalpha) by 12-0-tetradecanoyl-phorbol-13-acetate (TPA) enhanced platinum sensitivity in human ovarian carcinoma cells." Proceedings.of Am.Assoc.Cancer Res.37(in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Terashima, Y.: Protein kinase C and platinum sensitivity. In : Kikuchi, Y., Terashima, Y.(eds.), The mechanism of cisplatin resistance and the circumvention. New York : Nova Science Publishers, Inc.(in press.), (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Isonishi, S., Shiotsuka, S., Ochiai, K., Yasuda, M., and Tanaka, T., Howell, S. B.: "Depletion of protein kinase C-α (PKC α) by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) enhanced platinum sensitivity in human ovarian carcinoma cells." Proceedings of Am. Assoc. Cancer Res.37(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Isonishi, S., Shiotsuka, S., Ochiai, K., Yasuda, M., and Terashima, Y.: "Tumor necrosis factor-α (TNFα) enhanced cisplatin (DDP) cytotoxicity to ovarian carcinoma xenografts in nude mice and prolonged their survival." Proceedings of Am. Assoc. Cancer Res.36. 631 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Isonishi, S., Ochiai, K., Yasuda, M., Ohkawa, K., and Terashima, Y.: "Mechanism-related circumvention of cisplatin resistance in human ovarian carcinoma cells by (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate and modulation of its sensitivity by 12-O-tetradecanoylphorbol-13-acetate." Int. J. Oncolo.5. 1309-1314 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Isonishi, S., Hom, D. K., Eastman, A. and Howell, S. B.: "Enhancement of sensitivity to platinum (II)-containing drugs by 12-O-tetradecanoyl-phobol-13-acetate in a human ovarian carcinoma cell line." Br./J. Cancer.69. 217-221 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] 磯西成治: "卵巣癌における細胞内Protein Kinase C活性による抗癌剤感受性の制御" Oncology & Chemotherapy.10. 97-100 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Isonishi, S., Terashima, Y.: "Protein kinase C and platinum sensitivity. In: kikuchi, Y. and Terashima, Y. (eds.), The mechanism of cisplatin resistance and the circumvention, New York:" Nova Science Publishers, Inc.,(in press), (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Chkawa,K.,et al.: "Characteristic change in protein kinase C activity and isoforms in AH66 cells during the acquison of multidrug resistant phenotype." Oncol.Reprots. 1. 551-555 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Christen,R.D.,et al.: "Signaling and frug sensitivity." Cancer and Metastasis reviews. 13. 175-189 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Isonishi,S.,et al.: "Mechanism-related circumvention of cisplatin resistance in human oarcinoma cells by (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)-platinum(II)monohydrate and modulation of its sensitivity by 12-o-tetradecanoylphorbol-13-acetate." J.Oncolo.5. 1309-1314 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 大川 清: "Doxorubicin enhances transient expression of P-qlycoprotein and modulates activity and isoform expression of protein kinase C in AH66 rat hepatoma cells." Int.J.Oncol.4. 655-659 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 礒西 成治: "Enhancement of sensitivity to platinum(II)-containing drugs by 12-0-tetradecanoyl-ph or bol-13-acetate in a human ovarian carcinoma cell line." Br.J.Cancer. 69. 217-221 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 礒西 成治: "12-0-tetradecanoyl-phorbol-13-acetate enhances eytotoxicity of multiple platinum drugs" Proceedings of Am.Assoc.Cancer Res.34. 321- (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 木村 英三: "Analysis of the cytotoxic interaction between cisplatin and hyperthermia in a human ovarian carcinoma cell line" Proceedings of Am・Assoc・Cancer Res・. 34. 359- (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 礒西 成治: "卵巣癌における細胞内Protein Kinase C活性化による抗癌剤感受性の制御" ONCOLOGY & CHEMOTHERAPY. 10(印刷中). (1994)

    • Related Report
      1993 Annual Research Report

URL: 

Published: 1993-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi