Topoisomerase inhibitor

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Topoisomerase inhibitors are chemotherapy agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA structure 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 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

[edit] 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.

[edit] 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 flouroquinolones as Ciprofloxin.

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 prokayrotic and eukaryotic enzymes preferencially, making them attractive drug candidates. Ciprofloxin targets prokaryotes in excess of a thousan fold 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.

[edit] Topo II inhibitors

Examples of topoisomerase inhibitors include ICRF-193. 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).

v • d • e Antibacterials for systemic use: quinolones (J01M)

Fluoroquinolones	Alatrofloxacin^‡ • Ciprofloxacin • Danofloxacin^§ • Difloxacin^§ • Enoxacin • Enrofloxacin^§ • Fleroxacin^‡ • Garenoxacin • Gatifloxacin • Gemifloxacin • Grepafloxacin^‡ • Ibafloxacin^§ • Levofloxacin • Lomefloxacin • Marbofloxacin^§ • Moxifloxacin • Norfloxacin • Ofloxacin • Orbifloxacin^§ • Pazufloxacin • Pefloxacin • Pradofloxacin^§ • Prulifloxacin • Rufloxacin • Sarafloxacin^§ • Sitafloxacin^† • Sparfloxacin • Temafloxacin^‡ • Tosufloxacin • Trovafloxacin^‡

Other quinolones	Cinoxacin • Flumequine^§ • Nalidixic acid • Oxolinic acid • Pipemidic acid • Piromidic acid • Rosoxacin

^†Undergoing clinical trials. ^‡ Withdrawn from market. ^§ Veterinary use medications.

v • d • e Chemotherapeutic agents/Antineoplastic agents (L01)

Alkylating and alkylating-like agents	Nitrogen mustards: (Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Bendamustine, Uramustine) Nitrosoureas:(Carmustine, Fotemustine, Lomustine, Streptozocin) Platinum (alkylating-like): (Carboplatin, Cisplatin, Oxaliplatin, Triplatin tetranitrate, Satraplatin) Alkyl sulfonates:(Busulfan, Treosulfan) Hydrazines:(Procarbazine, Dacarbazine, Temozolomide) Aziridines:(ThioTEPA)

Antimetabolites	Folic acid: (Aminopterin, Methotrexate, Pemetrexed, Raltitrexed) Purine: (Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine) Pyrimidine: (Cytarabine, Decitabine, Fluorouracil/Capecitabine, Floxuridine, Gemcitabine)

Spindle poison/mitotic inhibitor	Taxane: (Docetaxel, Larotaxel, Paclitaxel). Vinca: (Vinblastine, Vincristine, Vindesine, Vinorelbine).

Cytotoxic/antitumor antibiotics	Anthracycline family: (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pixantrone, Valrubicin) streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin) - Hydroxyurea

Topoisomerase inhibitors	Camptotheca: (Camptothecin, Topotecan, Irinotecan, Rubitecan), Podophyllum:(Etoposide, Teniposide)

CI monoclonal antibodies	Receptor tyrosine kinase (Cetuximab, Panitumumab, Trastuzumab) - CD20 (Rituximab, Tositumomab) - other (Alemtuzumab, Bevacizumab, Gemtuzumab)

Photosensitizers	Aminolevulinic acid, Methyl aminolevulinate, Porfimer sodium, Verteporfin

Tyrosine kinase inhibitors	Axitinib, Bosutinib, Cediranib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, Vandetanib

Cyclin-dependent kinase inhibitor	Seliciclib

Other	retinoids (Alitretinoin, Tretinoin), Fusion protein (Aflibercept) - Altretamine, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase (Pegaspargase), Bexarotene, Bortezomib, Celecoxib, Denileukin diftitox, Elesclomol, Estramustine, Irofulven, Ixabepilone, Masoprocol, Mitotane, Oblimersen, Testolactone, Tipifarnib, Trabectedin