Amonafide Topoisomerase 억제제

Through a topoisomerase II-mediated reaction, Amonafide treatment produces DNA single-strand breaks (SSB), double-strand breaks (DSB), and DNA-protein cross-links in human myeloid leukemia cells. This compound treatment inhibits colony formation of the leukemic cell lines and the normal human bone marrow GM-CFC in a dose-dependent manner. It does not produce topoisomerase I-mediated DNA cleavage even at 100 μM. The m-AMSA-resistant line is less than 2-fold resistant to this compound [1] This chemical interferes with the DNA breakage-reunion activity of mammalian DNA topoisomerase II resulting in DNA cleavage stimulation. [2] Compared with those of other antitumor drugs, this compound-stimulated cleavage intensity patterns are markedly different. It highly prefers a cytosine, and excludes guanines and thymines instead, at position -1, with lower preference for an adenine at position +1. [3] Topoisomerase II-mediated DNA cleavage induced by this agent is affected only slightly (less than 3-fold) by 1 mM ATP, suggesting that it is an ATP-insensitive topoisomerase II inhibitor in contrast to doxorubicin, etoposide, and mitoxantrone. [4] This compound significantly inhibits the growth of HT-29, HeLa, and PC3 cells with IC50 of 4.67 μM, 2.73 μM, and 6.38 μM, respectively. [5] It is unaffected by P-glycoprotein-mediated efflux, unlike those of the classical topoisomerase II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone). [6]