In Vitro

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. Amonafide treatment inhibits conlony formation of the leukemic cell lines and the normal human bone marrow GM-CFC in a dose-dependent manner. Amonafide does not produce topoisomerase I-mediated DNA cleavage even at 100 μM. The m-AMSA-resistant line is less than 2-fold resistant to Amonafide ^[1] Amonafide 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, Amonafide-stimulated cleavage intensity patterns are markedly different. Amonafide 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 Amonafide is affected only slightly (less than 3-fold) by 1 mM ATP, suggeting that Amonafide is an ATP-insensitive topoisomerase II inhibitor in contrast to doxorubicin, etoposide, and mitoxantrone. ^[4] Amonafide 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] Amonafide is unaffected by P-glycoprotein-mediated efflux, unlike those of the classical topoisomerase II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone). ^[6]

In Vivo

Clinical Trials

A Phase I/II study of Amonafide in men with androgen-independent prostate cancer has been completed.

Features