Growth-inhibitory properties of novel anthracyclines in human leukemic cell lines expressing either Pgp-MDR or at-MDR

• Published in: Investigational new drugs Vol. 12; no. 2; p. 93
• Main Authors: Mariani, M, Capolongo, L, Suarato, A, Bargiotti, A, Mongelli, N, Grandi, M, Beck, W T
• Format: Journal Article
• Language: English
• Published: United States 01.01.1994
• Subjects: Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Cell Division - drug effects; DNA Topoisomerases, Type II - metabolism; Drug Resistance, Multiple - physiology; Humans; Leukemia - drug therapy; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0167-6997
• DOI: 10.1007/BF00874437

The objective of the experiments reported in this paper was the identification of promising anthracycline analogs on the basis of lack of cross-resistance against tumor cells presenting either P-glycoprotein multidrug resistance (Pgp-MDR) or the altered topoisomerase multidrug resistant (at-MDR) phenotype. Differently modified anthracycline analogs known to be active against MDR cells were assayed in vitro against CEM human leukemic cells, and the sublines CEM/VLB100 and CEM/VM-1 exhibiting respectively the Pgp-MDR and the at-MDR phenotype. Two classes of molecules, in which the -NH2 group in C-3' position is substituted with a morpholino, methoxymorpholino (morpholinyl-anthracycline), or an alkylating moiety, present equivalent efficacy in the drug-sensitive and the two drug-resistant sublines. These results indicate that such molecules may exert their cytotoxic effect through a mode of action different from that of "classical" anthracyclines and is not mediated through topoisomerase II inhibition. Both molecules represent novel concepts in the field of new anthracyclines derivatives.