Growth-inhibitory properties of novel anthracyclines in human leukemic cell lines expressing either Pgp-MDR or at-MDR.
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.
Pharmacia-Farmitalia Carlo Erba, R&D/Experimental Oncology Laboratory, Milano, Italy.
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M
Mariani
L
L
Capolongo
A
A
Suarato
A
A
Bargiotti
N
N
Mongelli
M
M
Grandi
W T
WT
Beck
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004250:DNA Topoisomerases, Type II