The potential of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide to circumvent three multidrug-resistance phenotypes in vitro.
The effectiveness of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) relative to that of amsacrine, idarubicin, daunorubicin and paclitaxel against three different forms of multidrug resistance (MDR) was determined using two sublines of the CCRF-CEM human leukaemia cell line, the P-glyco-protein-expressing CEM/VLB100 subline and the MRP-expressing CEM/E1000 subline, and two extended-MDR sublines of the HL60 human leukaemia cell line, HL60/E8 and HL60/V8. DACA was effective against P-glycoprotein-mediated MDR and MRP-mediated MDR, whereas the extended-MDR phenotype showed only low levels of resistance (< 2-fold) to DACA. In comparison, idarubicin was ineffective against the MRP and extended-MDR phenotypes. Repeated exposure of the K562 human leukaemia cell line to DACA (55, 546 or 1092 nM for 3 days over 10 weeks) did not result in the development of any significant drug resistance. We conclude that DACA has the potential to treat refractory leukaemia.
Davey
R A
RA
Bill Walsh Cancer Research Laboratories, Clinical Oncology Department, Royal North Shore Hospital, St. Leonards, Australia.
Su
G M
GM
Hargrave
R M
RM
Harvie
R M
RM
Baguley
B C
BC
Davey
M W
MW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000166:Acridines / Q000633:toxicity*; D000677:Amsacrine / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003630:Daunorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000633:toxicity; D007938:Leukemia; D017239:Paclitaxel / Q000633:toxicity; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D000677:Amsacrine; D019328:Buthionine Sulfoximine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D014700:Verapamil; D017239:Paclitaxel; D015255:Idarubicin; D003630:Daunorubicin