2002 Fiscal Year Final Research Report Summary
Cytopathologic study of intrinsic and acquired drug resistance of human ovarian cancer -the role of YB-1 and cMOAT/MRP2 gene-
| Project/Area Number |
12671612
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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 | Kyushu University |
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Principal Investigator |
HIRAKAWA Toshio Kyushu University Hospital, Lecturer, 医学部附属病院, 講師 (20218770)
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| Co-Investigator(Kenkyū-buntansha) |
SONODA Kenzo Kyushu University Hospital, Assistant Professor, 医学部附属病院, 助手 (30294929)
KOBAYASHI Hiroaki Kyushu University Hospital, Assistant Professor, 医学部附属病院, 助手 (70260700)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Ovarian cancer / Drug resistance / YB-1 / cMOAT1 / MRP2 / MRP1 / MRP3 |
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| Research Abstract |
Purpose: The aim of the first study was to elucidate the association between nuclear YB-1 and cisplatin resistance in human ovarian cancer using cultured cell lines and surgical specimens. Methods: Intracellular YB-1 localization was examined by Western blot analysis for both cisplatin sensitive and resistant human ovarian cancer cell lines. Moreover, 35 pairs of surgical specimens derived from primary and matched recurrent ovarian cancers of the same patient were evaluated for their nuclear YB-1 expression by immunohistochemical staining. Results: Western blot analysis for nuclear and cytoplasmic extracts indicated that cisplatin-resistant cells showed much higher nuclear YB-1 expression than sensitive parental cells. Immunohistochemical analysis showed that 10 paired cases turned from negative nuclear YB-1 in primary lesions to positive nuclear YB-1 in recurrent lesions, whereas only two paired cases showed a reverse turn from positive to negative. Conclusion: The expression of YB-1
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might be a useful predictive marker indicating cisplatin sensitivity and/or a target molecule to treat recurring ovarian cancers by cisplatin-based second-line chemotherapy.
Purpose: The aim of the second study was to characterize patients with unfavorable clinical outcome by the relative mRNA levels of ABC transporter expression in their tumor samples and to examine whether relative mRNA levels of each of the ABC transporter can be a useful predictor of progression-free survival in advanced ovarian carcinoma. Methods: We examined tumor samples taken from 30 patients with primary serous papillary adenocarcinoma of the ovary for the expression of MDR1, MRP1, MRP2, and MRP3 mRNA using real-time reverse transcription-PCR, and we evaluated its correlation with clinical outcome. All 30 patients were divided into three groups according to clinical outcome after debulking surgery and platinum-based chemotherapy: 8 patients were classified into the unfavorable group; 11 were classified into the favorable group; and 11 were classified into intermediate group. Results: The relative mRNA levels of MRP1 and MRP3 were significantly different among the three groups, and the mRNA levels of MRP1 and MRP3 in the unfavorable group were significantly higher than those in the favorable group by multiple comparison. The relative mRNA levels of MRP1 expression were significantly correlated with those of MRP3 expression. In the 30 patients with serous papillary adenocarcinoma, univariate and multivariate analysis demonstrated that the high relative mRNA levels of MRP1 expression were significantly correlated with a short period of progression-free survival. Conclusion: In patients with advanced ovarian serous adenocarcinoma, these results suggest that increased levels of coordinated MRP1 and MRP3 mRNA expression in their tumor samples characterize patients with an unfavorable outcome. Furthermore, a higher level of MRP1 mRNA expression can be a candidate for a useful predictor of a shorter period of progression-free survival. Less
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