Title:Strategies Targeting DNA Topoisomerase I in Cancer Chemotherapy: Camptothecins, Nanocarriers for Camptothecins, Organic Non-Camptothecin Compounds and Metal Complexes
Volume: 17
Issue: 16
Author(s): Kurtulus Gokduman
Affiliation:
Keywords:
Cancer chemotherapy, topoisomerase I, camptothecin topoisomerase I inhibitors, nano drug delivery systems, organic
non-camptothecin topoisomerase I inhibitors, metal complexes.
Abstract: Topoisomerase I (Topo I) is a nuclear enzyme engaged in adjustment of
DNA topological structure during cell cycle by cleaving and reannealing one of
the two strands of the DNA double helix. Inhibition of this enzyme results in DNA
strand breaks, ultimately leads to apoptosis and cell death; additionally it is in
raised level in solid tumors contrasted with healthy tissues. Consequently, Topo I
has a great potential as a target for the treatment of tumors. Although significant
anti-tumor activity of first Topo I inhibitor, camptothecin (CPT), was observed on
colon, lung, ovarian, breast, liver, pancreas and stomach cancers, CPT and its
clinical derivatives (topotecan and irinotecan) have several restrictions. In addition
to their low water solubility and cell resistance to CPTs, lactone ring opening
causes a reduction in cytotoxic activity and severe side effects in physiological conditions (pH: 7.4,
37°C). Although numerous efficient nano drug delivery systems were developed for CPT and its derivatives
to compensate the handicaps of these compounds, none of them has been approved so far.
On the other hand, organic non-CPT compounds have been searched; indolocarbazoles, indenoisoquinolines
and dibenzonaphthyridines have been applied to clinical development. Especially, indenoisoquinolines
and dibenzonaphthyridines have favorable characteristics compared to CPTs: They are
chemically stable; they have the ability to overcome cell resistance; they stabilize enzyme-DNA
cleavage complexes more persistently. In addition to the approaches based on organic compounds, recently
some metal complexes (e.g., platinum, gold, copper, cobalt, zinc, vanadium, ruthenium) have
also been reported as inhibitors of Topo I. This review will discuss the whole aspects of strategies targeting
Topo I in cancer chemotherapy from past to the recent progresses.
