TY - JOUR
T1 - Hydroxyrubicin, a deaminated derivative of doxorubicin, inhibits mammalian DNA topoisomerase II and partially circumvents multidrug resistance
AU - Solary, Eric
AU - Ling, Vi‐He ‐H
AU - Perez‐Soler, Roman
AU - Priebe, Waldemar
AU - Pommier, Yves
PY - 1994/1/1
Y1 - 1994/1/1
N2 - In vivo effectiveness of doxorubicin remains restricted due to toxicity and drug resistance. Hydroxyrubicin is a synthetic analog of doxorubicin in which the basic amino group at the C‐3′ has been replaced by a hydroxyl group in order to overcome recognition by the multidrug resistant (MDR) P‐ghlcoprotein and limit cardiotoxicity. The present study shows that hydroxyribicin is a less potent intercalator than doxorubicin. Induction of topoisomerase II‐mediated DNA cleavage in the human C‐myc origin by the two drugs was similar, reaching a maximum at 0.5 μM. Results from the NCI Cell Screening program indicate a relatively good correlation between the cytotoxicity of the 2 drugs on 55 cell lines of various origins (r = 0.723). Using a donogenic assay, we observed that hydroxyrubicin was 20‐fold more cytotoxic against the MDR KB‐VI cell line than doxorubicin and was slightly more cytotoxic than doxorubicin in the sensitive KB3.1 cell line. Uptake studies showed that doxorubicin was retained up to I hr in KB3.1 cells and rapidly eliminated from resistant KB‐VI cells. In contrast, hydroxyrubicin was rapidly eliminated from both sensitive KB3.1 and MDR‐positive KB‐VI cells. Both drugs induced protein‐linked DNA single‐strand breaks (SSBs) in both KB3.I and KB‐VI cells, which is consistent with topoisomerase inhibition. However, the kinetics of DNA SSBs induced by both drugs was very different. DNA breaks disappeared quickly in both KB3.1 and KB‐VI cell lines after hydroxyrubicin removal while DNA breaks induced by doxorubicin disappeared very slowly in KB3.1 cells and rapidly in KB‐VI cells. We conclude that removal of the basic amino group at the C‐3′ of doxorubicin modifies drug transport and partially circumvents MDR without changing topoisomerase II inhibition when compared with doxorubicin. © 1994 Wiley‐Liss, Inc.
AB - In vivo effectiveness of doxorubicin remains restricted due to toxicity and drug resistance. Hydroxyrubicin is a synthetic analog of doxorubicin in which the basic amino group at the C‐3′ has been replaced by a hydroxyl group in order to overcome recognition by the multidrug resistant (MDR) P‐ghlcoprotein and limit cardiotoxicity. The present study shows that hydroxyribicin is a less potent intercalator than doxorubicin. Induction of topoisomerase II‐mediated DNA cleavage in the human C‐myc origin by the two drugs was similar, reaching a maximum at 0.5 μM. Results from the NCI Cell Screening program indicate a relatively good correlation between the cytotoxicity of the 2 drugs on 55 cell lines of various origins (r = 0.723). Using a donogenic assay, we observed that hydroxyrubicin was 20‐fold more cytotoxic against the MDR KB‐VI cell line than doxorubicin and was slightly more cytotoxic than doxorubicin in the sensitive KB3.1 cell line. Uptake studies showed that doxorubicin was retained up to I hr in KB3.1 cells and rapidly eliminated from resistant KB‐VI cells. In contrast, hydroxyrubicin was rapidly eliminated from both sensitive KB3.1 and MDR‐positive KB‐VI cells. Both drugs induced protein‐linked DNA single‐strand breaks (SSBs) in both KB3.I and KB‐VI cells, which is consistent with topoisomerase inhibition. However, the kinetics of DNA SSBs induced by both drugs was very different. DNA breaks disappeared quickly in both KB3.1 and KB‐VI cell lines after hydroxyrubicin removal while DNA breaks induced by doxorubicin disappeared very slowly in KB3.1 cells and rapidly in KB‐VI cells. We conclude that removal of the basic amino group at the C‐3′ of doxorubicin modifies drug transport and partially circumvents MDR without changing topoisomerase II inhibition when compared with doxorubicin. © 1994 Wiley‐Liss, Inc.
UR - http://www.scopus.com/inward/record.url?scp=0028235113&partnerID=8YFLogxK
U2 - 10.1002/ijc.2910580115
DO - 10.1002/ijc.2910580115
M3 - Article
C2 - 8014019
AN - SCOPUS:0028235113
SN - 0020-7136
VL - 58
SP - 85
EP - 94
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 1
ER -