Topoisomerase inhibitor

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymescite web |url=http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46665 |title=Definition of topoisomerase inhibitor - NCI Dictionary of Cancer Terms |format= |work= |accessdate=] (topoisomerase I and II), which are enzymes that control the changes in DNA structurecite web |url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/nine/14181948.htm |title=Dorlands Medical Dictionary:topoisomerase inhibitor |format= |work= |accessdate=] by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently lead to apoptosis and cell death.

Topoisomerase inhibitors can also function as antibacterial agents.cite journal |author=Mitscher LA |title=Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents |journal=Chem. Rev. |volume=105 |issue=2 |pages=559–92 |year=2005 |month=February |pmid=15700957 |doi=10.1021/cr030101q |url=http://dx.doi.org/10.1021/cr030101q] Quinolones have this function.cite journal |author=Fisher LM, Pan XS |title=Methods to assay inhibitors of DNA gyrase and topoisomerase IV activities |journal=Methods Mol. Med. |volume=142 |issue= |pages=11–23 |year=2008 |pmid=18437302 |doi=10.1007/978-1-59745-246-5_2 |url=http://dx.doi.org/10.1007/978-1-59745-246-5_2]

Classification

Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits.
* Topoisomerase I inhibitors: irinotecan, topotecan, camptothecin and lamellarin D all target type IA topoisomerases.
* Topoisomerase II inhibitors: etoposide

Compounds that target Type II topoisomerase

These inhibitors are split into two main classes: topoisomerase poisons, which target the topoisomerase-DNA complex, and topoisomerase inhibitors, which disrupt catalytic turnover.

Topo II poisons

Examples of topoisomerase poisons include the following:
*eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin. These drugs are anti-cancer therapies.
*bacterial type II topoisomerase inhibitors (gyrase and topo IV): fluoroquinolones. These are antibacterials and include such fluoroquinolones as Ciprofloxacin.

Some of these poisons encourage the forward cleavage reaction (fluoroquinolones), while other poisons prevent the re-ligation of DNA (etoposide and teniposide).

Interestingly, poisons of type IIA topoisomerases can target prokaryotic and eukaryotic enzymes preferentially, making them attractive drug candidates. Ciprofloxin targets prokaryotes in excess of a thousandfold more than it targets eukaryotic topo IIs. The mechanism for this specificity is unknown, but drug-resistant mutants cluster in regions around the active site.

Topo II inhibitors

Examples of topoisomerase inhibitors include ICRF-193.cite journal |author=Robinson HM, Bratlie-Thoresen S, Brown R, Gillespie DA |title=Chk1 is required for G2/M checkpoint response induced by the catalytic topoisomerase II inhibitor ICRF-193 |journal=Cell Cycle |volume=6 |issue=10 |pages=1265–7 |year=2007 |month=May |pmid=17495539 |doi= |url=http://www.landesbioscience.com/journals/cc/abstract.php?id=4225] These inhibitors target the N-terminal ATPase domain of topo II and prevent topo II from turning over. The structure of this compound bound to the ATPase domain was solved by Classen (Proceedings of the National Academy of Science, 2004) showing that the drug binds in a non-competitive manner and locks down the dimerization of the ATPase domain. This is consistent with biochemistry performed by Janet Lindsley's lab (reference needed).

References