1997 Fiscal Year Final Research Report Summary
Overcoming cisplatin-resistance in ovarian cancer through induction of apoptosis by anticancer agents
| Project/Area Number |
07671786
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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 | Tottori University (School of Medicine) |
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Principal Investigator |
MINAGAWA Yukihisa Tottori Univ.Dept.Obstet.Gynecol., Assistant Professor, 医学部・附属病院, 講師 (70190692)
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| Co-Investigator(Kenkyū-buntansha) |
KIGAWA Junzo Tottori Univ.Dept.Obstet.Gynecol., Assistant Professor, 医学部, 講師 (00177784)
TERAKAWA Naoki Tottori Univ.Dept.Obstet.Gynecol., Professor, 医学部, 教授 (90163906)
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| Project Period (FY) |
1995 – 1997
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| Keywords | apoptosis / topoisomerase / cicplatin-resistance / ovarian cancer |
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| Research Abstract |
The aim of the present study was to clarify the relation between quantitative and/or qualitative changes of DNA topoisomerase (Topo) and the ability of apoptosis induction by anti-cancer agents, and to obtain biological findings for overcome cisplatin-(CDDP) resistant ovarian cancer through induction of apoptosis. 1. In vitro experiments with using CDDP-resistant cancer cell lines 1) Enhanced Topo I activity and increased Topo II a cotent were observed in CDDP-resistant cancer cell lines compared to their parent cell lines. 2) During apoptotic process induced by CDDP,a Topo I inhibitor (SN-38), a Topo II inhibitor (VP-16), Topo II a content in CDDP-resistant cell lines increased much more than that in their parent cell lines. In contrast, Topo I content did not changed in all cell lines tested here. p53 protein level did not change during apoptotic process induced by CDDP or SN-38 in both CDDP-resistant and parent cell lines, although it increased much more in parent cell lines compare
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d to CDDP-resistant cell lines after VP-16 exposure. These findings suggest that the quantitative and/or qualitative changes of Topos may relate to the CDDP-resistant phenotype, and Topo II a may play a important role during apoptotic process induced by anti-cancer agents particularly in CDDP-resistant cancer cell lines. Furthermore, p53 independent signaling pathway of apoptotic process might exist in CDDP-resistant cell lines. 2. Analysis of specimens from patients with epithelial ovarian cancer before and after chemotherapy 1) Additional p53 gene mutations and/or increased levels of p53 protein were observed after chemotherapy only in the specimens from non-responders to CAP therapy. 2) The ratio of GSH concentration in each tumors was significantly higher for nonresponders than for responders, increased levels of GST-pi expression after chemotherapy are linked to drug resistance in patients with ovarian cancer. 3) It was suggested that GSH concentration and GST-pi were useful predictors of the effect to a second line chemotherapy, a combination of CDDP and VP-16, in patients with CDDP-refractory tumors. Further study must be awaited to investigate the apoptotic process in CDDP-resistant ovarian cancers, paticulary the process through p53 independent signaling pathway, and multilateral analysis of CDDP-resistant mechanism may be necessary to determine second line chemotherapic regimen before and after the chemotherapy in the same patients with CDDP-refractory ovarian cancer. Less
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