越智 淳三 岡山大学, 医学部附属病院, 助手 (30214159)
AKEBI Naoki Okayama University Medical School, Department of Urology, Assistant, 医学部附属病院, 助手 (00222555)
小橋 賢二 岡山大学, 医学部・附属病院, 助手 (80225482)
野田 雅俊 岡山大学, 医学部附属病院, 医員
NODA Masatoshi Okayama University Medical School, Department of Urology, Senior Resident
|Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1991 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1990 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1989 : ¥800,000 (Direct Cost : ¥800,000)
A cis-diamminedichloroplatinum(CDDP)-resistant cell line, CL-7/CDDP, has been established by chronic exposure of a parent human bladder cancer cell line, T24(CL-7), to CDDP at progressively increaced concentration for twenty months. CL-7 /CDDP was 2.7-fold more resistant to CDDP than CL-7 as determined by colony formation assay. Biological and biochemical characteristics were examined in CL-7/CDDP to compare with CL-7. There were no differences in doubling time and plating efficiency between the two cell lines, but a small one in the mode of chromosome numbers. Intra-cellular CDDP concentration after CDDP exposure showed no difference between the two cell lines, but CL-7/CDDP showed a higher glutathione(GSH)and metallothionein(MT)level. It is suggested that the mechanism of acquired resistance to CDDP is attributed to intra-cellular detoxication, but not to the efflux.
The sensitivity of CL-7/CDDP for other anticancer drugs were examined by colony formation assay to compare with the par
ent cell line, CL-7. Consequently, these drugs could be classified into 3 groups according to the degree of resistance ; drugs with an equal degree of resistance to that of CDDP(CDDP derivatives, MMC, VP-16), drugs for which the cells showed no resistance(ADM, CTX, IFO, VLB), and drugs whose cytocidal effects were enhanced(5-FU, MTX). The degree of resistance in the CDDP derivatives was the highest in DWA-2114R, decreesing in the following order in CBDCA, NK-121, and 254-S.
An in vivo study was also performed. To determine the anti-tumor effects of anti-cancer drugs in nude mice, CL-7 and CL-7/CDDP cells of 10^7/body each were inoculated subcutaneouly, and the anti-cancer drug was administered intraperitoneally, when estimated tumor weight reached 100mg. Each dose of 2mg/kg, 4mg/kg, or 8mg/kg of CDDP was administered 3 times every 5 days. The inhibition of tumor growth was observed in the CDDP 8mg/kg group with the CL-7 and CL-7/ CDDP tumor, but the resistance to CDDP in the CL-7/CDDP tumor was not clear. Concerning the CL-7/CDDP tumor, the tumor growth was very slow and the dispertion of tumor weight among individual animals was large, which had to be improved.
These results indicated the possibility of non-crosss resistant alternating chemotherapy using these three groups of drugs. Less