Grant-in-Aid for international Scientific Research
|Allocation Type||Single-year Grants|
|Research Institution||Kagoshima University|
AKIYAMA Shin-ichi Faculty of Medicine, Professor, 医学部, 教授 (60117413)
GOTTESMAN Mi 米国国立癌研究所, 細胞生物部門, 部長
FIJO Antonio T National Cancer Institute, Division of Cancer Treatment, 癌治療部門, 上級研究員
COLE Susan P.C Queen's University, Cancer Research Laboratories, クイーンズ大学・癌研究所, 教授
FURUKAWA Tatsuhiko Faculty of Midicine, Research Associate, 医学部, 助手 (40219100)
GOTTESMANL Michael M National Cancer Institute, Laboratory of Cell Biology
GOTTESMAN M 米国国立癌研究所, 細胞生物部門, 部長
FOJO Antoni 米国国立癌研究所, 癌治療部門, 上級研究員
COLE Susan クイーンズ大学, 癌研究所, 教授
|Project Period (FY)
Completed(Fiscal Year 1996)
|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1996 : ¥1,800,000 (Direct Cost : ¥1,800,000)
|Keywords||MRP / Squamous cell carcinoma / TCC / ATL / PAK-104p / Cisplatin-resistance / GS-X pump / cMOAT|
1. Expression of MRP in tumors.
MRP gene expression was clevated in 8 of 9 (89%) squamous-cell carcinomas of the lung, 17 of 33 bladder tumors (51.5%), 5 of 11 renal pelvic and/or ureter tumors (45.5%), and 14 of 34 ATL (41.2%). Average MRPmRNA expression level of all squamous-cell carcinomas was significantly higher than that of adenocarcinoma of the lung and of colorectal and gastric carcinomas. Low grade urotherial carcinomas (G1 and G2 TCCs) expressed significantly higher levels of MRP mRNA than the high grade G3 TTC.MRP expression was an unfavorable prognostic factor for ATL patients.
2. Reversal of MRP mediated drug resistance.
A pyridine analog, PAK-104P and LTD_4 receptor antagonist, ONO1078, almost completely reversed the resistance to vincristine in C-A120 cells. They competitively inhibited the ATP-dependent [^3H] leukotriene C_4 uptake in membrane vesicles from C-A120. These findings suggested that PAK-104P directly interacts with MRP and inhibits the transporting activity of
3. An active efflux system for heavy metals in cisplatin-resistant human KB cells.
We examined whether factors reportedly related to cisplatin-resistance are really involved in cisplatinresistance in cisplatin-resistant KCP-4 cells and multidrug resistant C-A120 cells. KCP-4 cells were more resistant to heavy metals than C-A120 cells and expressed metallothionein (MT). However MT was not involved cisplatin-resistance in KCP-4 cells. The enhanced DNA-repair activity in KCP-4 cells was partly responsible for the cisplatin-resistance. The GSH level was 4.7 fold higher in KCP-4 cells than in cisplatin-sensitive KB-3-1 cells, but this was not associated with the high cisplatin-resistance in KCP-4 cells. The accumulation of platinum in C-A120 and KCP-4 cells was 68.5 and 20.4% of that in KB-3-1 cells, respectively, while the intracellular levels of antimony potassium tartrate in C-A120 and KCP-4 cells were 13.2 and 9.9% of that in KB-3-1 cells, respectively. These results suggested that the ATP-dependent efflux pump for heavy metals different from MRP is involved in cisplatin-resistance in KCP-4 cells. Less