Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines.
The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.
Harstrick
A
A
Department of Internal Medicine, West German Cancer Center, Essen, Germany.
Vanhoefer
U
U
Schleucher
N
N
Schroeder
J
J
Baumgart
J
J
Scheulen
M E
ME
Wilke
H
H
Seeber
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D016572:Cyclosporine; C046808:N-benzyladriamycin-14-valerate; D014700:Verapamil