Combined in vitro modulation of adriamycin resistance

✍ Scribed by C. Meijer; N. H. Mulder; H. Timmer-Bosscha; W. H. M. Petfrs; E. G. E. de Vries

• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: French
• Weight: 605 KB
• Volume: 49
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910490419

✦ Synopsis

In a P-glycoprotein-negative cell line, GLC,-Adr,, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glu- tathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-ll (topo-11) activity compared with the parent cell line GLC,. 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 (DNApolymerase-cu inhibitor) or novobiocin (NOV, topo-ll inhibitor). Cytotoxicity was tested using a microculture tetrazolium assay. In GLC,-Adr,,, 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. 'To whom correspondence and reprint requests should be addressed.