Comparison of annamycin to adriamycin in cardiac and MDR tumor cell systems.
Based on the response of a wide variety of tumors to the anthracycline, Adriamycin, numerous studies have been initiated to find an even more effective analog. In this pursuit two of the obstacles that have been necessary to overcome are a unique dose dependent Adriamycin-induced cardiotoxicity reported in patients treated with this chemotherapeutic agent as well as p-gp-mediated multi drug resistance (MDR) which has been found in tumor cells exposed to Adriamycin in vitro and in vivo as well as in human tumor samples. Using an in vitro cardiac cell system and MDR+ and MDR- Friend leukemia cell lines we find that a relatively new anthracycline, Annamycin, has reduced cardiotoxic activity but is more effective in inhibiting the growth of MDR+ cells than Adriamycin. The reduced cardiotoxicity of Annamycin is approximately 10 fold lower than Adriamycin whereas the increased efficacy against the MDR+ Friend leukemia tumor cell line is about 2 fold. The observation that Adriamycin preferentially accumulates in cardiac-muscle (CM) but not in cardiac non-muscle (NM) cells while Annamycin accumulates equally in both, may explain in part the reduced cardiotoxicity of Annamycin. Moreover, the cytosolic accumulation of Annamycin vs the nuclear localization of Adriamycin suggests a different target site for each drug.
Kolonias
D
D
University of Miami, School of Medicine, Department of Cell Biology & Anatomy, Fl. 33136, USA.
Podona
T
T
Savaraj
N
N
Gate
L
L
Cossum
P
P
Lampidis
T J
TJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D006321:Heart / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C080315:annamycin