Title:A “Double-Edged” Scaffold: Antitumor Power within the Antibacterial Quinolone
Volume: 23
Issue: 6
Author(s): Gregory S. Bisacchi and Michael R. Hale
Affiliation:
Keywords:
Quinolone, fluoroquinolone, topoisomerase, gyrase, topo II, topo IV, antitumor, anticancer, cytotoxic,
antibacterial, selectivity, Paul Ehrlich, magic bullet, doxorubicin, etoposide, vosaroxin, quarfloxin, G quadruplex.
Abstract: In the late 1980s, reports emerged describing experimental antibacterial quinolones
having significant potency against eukaryotic Type II topoisomerases (topo II) and
showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies
initiated quinolone anticancer programs to explore the potential of this class in comparison
to conventional human topo II inhibiting antitumor drugs such as doxorubicin and
etoposide. In this review, we present a modern re-evaluation of the anticancer potential of
the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based)
oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted
with the corresponding prokaryotic data, and merged with recent structural biology information which is now
beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible
to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances
in the biological understanding of human topo II isoforms suggest that significant progress might now be
made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely
cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors
could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer
treatment settings, and due to the recent biological and structural advances which can now provide, for the
first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.
