Topoisomerase poisoning activity of novel disaccharide anthracyclines.
Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I.
Guano
F
F
Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Pourquier
P
P
Tinelli
S
S
Binaschi
M
M
Bigioni
M
M
Animati
F
F
Manzini
S
S
Zunino
F
F
Kohlhagen
G
G
Pommier
Y
Y
Capranico
G
G
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002240:Carbohydrate Sequence; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D015255:Idarubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D015255:Idarubicin