The role of methoxymorpholino anthracycline and cyanomorpholino anthracycline in a sensitive small-cell lung-cancer cell line and its multidrug-resistant but P-glycoprotein-negative and cisplatin-resistant counterparts.
The cytotoxic action of two morpholino anthracyclines, methoxymorpholino anthracycline (MRA-MT, FCE 23,762) and cyanomorpholino anthracycline (MRA-CN), was compared with the cytotoxicity of doxorubicin (DOX), the topoisomerase II inhibitor etoposide (VP-16), the topoisomerase I inhibitor camptothecin, methotrexate, and cisplatin in GLC4, a human small-cell lung-cancer cell line, in GLC4-Adr, its P-glycoprotein (Pgp)-negative, multidrug-resistant (MDR; 100-fold DOX-resistant) subline with overexpression of the MDR-associated protein (MRP) and a lowered topoisomerase II activity, and in GLC4-CDDP, its cisplatin-resistant subline. GLC4-Adr was about 2-fold cross-resistant for the morpholino anthracyclines and GLC4-CDDP was, relative to GLC4, more resistant for the morpholino anthracyclines than for DOX. Overall, MRA-CN was about 2.5-fold more cytotoxic than MRA-MT. The cytotoxicity profile of the morpholino anthracyclines in these cell lines mimicked that of camptothecin.
van der Graaf
W T
WT
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Mulder
N H
NH
Meijer
C
C
de Vries
E G
EG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D002945:Cisplatin