1995 Fiscal Year Final Research Report Summary
Circumvention of cisplatin resistance in human ovarian carcinoma cells by modulation of cellular protein kinase C acitivity
| Project/Area Number |
05671402
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
ISONISHI Seiji Jikei University School of Medicine, Department of obstetrics and Gynecology, Assistant professor, 医学部, 助手 (20184591)
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| 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)
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| Project Period (FY) |
1992 – 1995
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| Keywords | Platinum / Protein Kinase C / Drug sensitivity / Drug resistance |
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| 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
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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
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[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
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[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
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[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
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[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
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