Strategies Targeting DNA Topoisomerase I in Cancer Chemotherapy: Camptothecins, Nanocarriers for Camptothecins, Organic Non-Camptothecin Compounds and 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.