[Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines].
The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.
Matsumoto
Y
Y
Dept. of Neurological Surgery, Kagawa Medical School.
Matsumoto
M
M
Minemura
M
M
Takano
H
H
Nagao
S
S
Iglesias
A
A
Fojo
T
T
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000473:pathology
D018528:ATP-Binding Cassette Transporters; D000677:Amsacrine; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; C075423:amsacrine-tetrachloroplatinum dianion complex