1998 Fiscal Year Final Research Report Summary
Circumvention of platinum resistance in human ovarian carcinoma cells by modulation of phosphotydil-inositol 4-kinase activity
| Project/Area Number |
08671933
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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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, 産婦人科, 講師 (20184591)
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| Co-Investigator(Kenkyū-buntansha) |
SHIOTSUKA Shigemasa Jikei University School of Medicine Department of obstetrics and Gynecology Assi
OKAMOTO Aikou Jikei University School of Medicine Department of obstetrics and Gynecology Assi
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| Project Period (FY) |
1996 – 1998
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| Keywords | platinum / protein Kinase C / phosphotydilinositol 4-kinase / Drug resistance |
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| Research Abstract |
Based on the previous data we have determined the effect of TNFalpha on the therapeutic index of DDP against 2008 tumor xenografts in nude mice. TNFalpha alone did not alter the in vivo growth of 2008 xenografts. Low-dose DDP(7mg/kg) caused a slight but significant reduction in tumor growth. The combination of TNFalpha and DDP resulted in further reduction in tumor growth to the same degree as seen in regular-dose (RD) DDP (15mg/kg). The combination of TNFalpha and LD DDP prolonged survival of the, wherease LD DDP or RD DDP did not do so. Hence, TNFalpha has the potential to enhance the in vivo cytotoxicity of DDP to ovarian carcinoma cells without altering systemic toxicity of DDP.
Depletion of PKC by TPA enhanced the sensitivity of human ovarian carcinoma 2008 cells to DDP, carboplatin, and (-)-(R)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato)-platinum(II) (DWA). TPA enhanced the sensitivity of the DDP-resistant 2008/C13*5.25 (C13) subline to each of the three drugs to the
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same extent as for the 2008 cells. Since PKCalpha is the only isotype responsive to TPA in these cells, these results suggest that platinum sensitivity can be modulated by PKCalpha. Furthermore, TPA increased accumulation of DDP and DWA in C13 cells by 70 % but not in 2008 cells. TPA decreased cellular glutathione content by 30 % in 2008 cells and 41 % in C13 cells. It did not alter CdCl2 sensitivity in both of these cell lines. These result indicate the maltifactorial sensitization effect of TPA.
Orobol, a potent phosphatidylinositol 4-kinase (PI4K) inhibitor (Umezawa et al. J.Antibiotics 1990), enhanced sensitivity to cisplatin(DDP) in human ovarian carcinoma 2008 cells by a factor of 2.1-fold. Sensitization depends on the lag-time (T) between cell preparation and drug treatment and was maximum 48 hr after cell preparation (T48). The cell population at the G2+M phase of the cell cycle was 4-fold more in T48 than in any other time. PI4K activity in T48 was incresed in response to treatment with orobol by 9-fold. Orobol also produced 2-fold sensitization in DDP-resistant subline. Thus we concluded that orobol did increase the DDP sensitivity in cell-cycle dependent manner via orobol-sensitive pathway, possibly involving PI4K activity and that this signal transduction pathway is also operative in DDP-resistant cells. Less
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[Publications] Isonishi, S., Saitou, M., Hirama, M., Shiotsuka, S., Okamoto, A., Takakura, S.et al.: "Differential regulation of antitumor activity of paclitaxel by orobol and PDGF in human ovarian carcinoma cells." Proceedings Am.Assoc.Cancer Res. 39. 192 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Isonishi, S., Saitou, M., Hirama, M., Shiotsuka, S., Okamoto, A., Takakura, S.et al.: "Differential regulation of antitumor activity of paclitaxel by orobol and PDGF in human ovarian carcinoma cells." 89th annual meeting of Am.Assoc.Cancer Res.(1998)
Description
「研究成果報告書概要(欧文)」より
