Combined in vitro modulation of adriamycin resistance.
In a P-glycoprotein-negative cell line, GLC4-Adr90, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-II (topo-II) activity compared with the parent cell line GLC4. The effect on Adr resistance of buthionine sulfoximine (BSO, GSH synthesis inhibitor), was studied alone or in combination with verapamil (drug-efflux inhibitor), docosahexaenoic acid (membrane lipid domain affector), ethacrynic acid (GST inhibitor), aphidicolin (DNA-polymerase-alpha inhibitor) or novobiocin (NOV, topo-II inhibitor). Cytotoxicity was tested using a microculture tetrazolium assay. In GLC4-Adr90, BSO and NOV increased Adr-induced cytotoxicity 12.9-fold and 1.8-fold respectively. The combination of BSO plus NOV showed an additive effect, decreasing the Adr resistance factor from 75 to 2.7. Combination of modulators of Adr resistance directed at different resistance mechanisms appears promising in vitro.
Meijer
C
C
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Mulder
N H
NH
Timmer-Bosscha
H
H
Peters
W H
WH
de Vries
E G
EG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms; D008562:Membrane Glycoproteins / Q000235:genetics*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics; D010996:Pleural Effusion
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D005978:Glutathione