| Project/Area Number |
02044119
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Institution | Kagoshima University |
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Principal Investigator |
AKIYAMA Shin-ichi Faculty of medicine, Kagoshima University・Professor, 医学部, 教授 (60117413)
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| Co-Investigator(Kenkyū-buntansha) |
IRA H. Pastan Laboratory of Molecular Biology, National Cancer Institute・Chief, 分子生物門, 部長
MICHAEL M. Gottesman Laboratory of Cell Bioloby, National Cancer Institute・Chielf, 細胞生物部門, 部長
SUMIZAWA Tomoyuki Faculty of Medicine, Kagoshima University. Instructor, 医学部, 助手 (90206582)
FURUKAWA Tatsuhiko Faculty of Medicine, Kagoshima University. Instructor, 医学部, 助手 (40219100)
PASTAN Ira H 国立癌研究所, 分子生物部門(米国), 部長
GODDESMAN Mi 国立癌研究所, 細胞生物部門(米国), 部長
GOTTESMAN Mi 米国国立癌研究所, 細胞生物学部門, 部長
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| Project Period (FY) |
1990 – 1991
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| Project Status |
Completed (Fiscal Year 1991)
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| Budget Amount *help |
¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1991: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1990: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Atypical multidrug-resistant mutants / Adriamycin resistance / Cisplatin resistance / dihydropyridine analogue / PAK-200 / Reversal of multidrug resistance |
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| Research Abstract |
1. Adriamycin resistant mutants.
We have isolated Adriamycin-resistant mutants from human KB carcinoma cells in the presence of cepahranthine that reverses multidrug resistance. These mutants were cross-resistant to daunomycin, actinomycin D, vincristine, vinblastine, etoposide and teniposide.
The accumulation of Adriamycin in the Adriamycin resistant cells was considerably decreased compared to that in the parental KB cells. However, we could not detect any expression of P-glycoprotein in the mutants, and are investigating whether the expression of other membrane protein (s) is changed in the Adriamycin resistant-mutants compared with that in KB cells.
2. Cisplatin resistant mutants.
Cisplatin resistant mutants were isolated from human epidermoid carcinoma KB cells. The mutants were cross-resistant to melpharan, cyclophosphamide, mitomycin C and methotrexate as well as cisplatin analogs. However, they were not cross-resistant to UV light and cadmium. Cisplatin resistant phenotype in these resistant cells were Co-dominant. The accumulation of Cisplatin in the resistant cells was decreased to that in the parental KB cells. We have analysed the membrane proteins in the resistant cells and found that the expression of two proteins was increased. We are now preparing antiserum against these proteins.
3. A newly synthesized dihydropyridine analog, PAK-200.
PAK-200 in combination with Adriamycin completely suppressed the growth of human colorectal carcinoma, COK-36LN, and partially suppressed the growth of multidrug resistant KB-8-5 cells xenografted into nude mice.
The carcium antagonistic activity of PAK-200 was about 1/1000 and 1/10 of those of nicardipine and verapamil, respectively. We have isolated optical isomer of PAK-200 and are checking the biological activity of the isomer.
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