Structurally modified anthracyclines retain activity in a cell line with simultaneous typical and atypical multidrug resistance.
Resistance to the classical anthracyclines may be due to one or several mechanisms, most notably p-glycoprotein (pGP) associated multidrug resistance (mdr1, "typical mdr") and altered activity of topoisomerase II (topo II) ("atypical mdr"). Modulators of mdr1 will be of limited value in case of combined forms of resistance. A Friend murine erythroleukemia cell line (F4-6R) carrying both mdrl and topo II mediated anthracycline resistance was used to determine the efficacy of structurally altered anthracyclines against such extended multidrug resistance. Proliferation assays showed that 3'N-morpholinyl substituted anthracyclines were able to retain much of their activity even in this setting. MX2 (KRN8602; 3'-deamino-3'-[4-morpholinyl]-13-deoxo-10-hydroxycarminomycin+ ++), which is 9-alkylated in addition to carrying a 3'N-morpholinyl group, was the most promising agent tested.
Bielack
S S
SS
Department of Pediatric Hematology and Oncology, Pediatric University Hospital Hamburg-Eppendorf, Germany.
Kallenbach
K
K
Looft
G
G
Erttmann
R
R
Winkler
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004250:DNA Topoisomerases, Type II