Topoisomerase Inhibitors

DNA topoisomerases are enzymes that regulate DNA supercoiling by catalyzing the winding and unwinding of DNA strands.  They cleave the long DNA backbone, so the molecular strands can pass through one another.  Scientists divide DNA topoisomerases into two groups based on the number of strands that they break.  Class I topoisomerases break only one strand of the DNA helix and are important in DNA synthesis.  Class II topoisomerases cut both strands of DNA, using ATP (adenosine triphosphate) for fuel. The uncoiling process involves the relaxation of the coil of both DNA strands.  After the cuts are made and replication or repair is complete, the strands are paired back together and the coil reforms.

The enzymes play a role in fixing DNA damage that occurs as a result of exposure to harmful chemicals or UV rays.  Inhibitors of the topoisomerase enzymes stop DNA replication, RNA transcription, and repair of DNA damage.

Anthracyclines are arguably topoisomerase II inhibitors, although medicinal chemists usually classify them separately.  But inside the cell mechanism involve breaking DNA and stopping cell reproduction in the G2 stage of the cycle.

Topoisomerase I inhibitors include camptothecin, topotecan, and irinotecan.  Topoisomerase II inhibitors include doxorubicin, etoposide, and mitoxantrone.

 




References

Burris HA, Hanauske AR, Johnson RK et al. Activity of topotecan, a new topoisomerase inhibitor, against human tumor colony forming units in vitro. J Natl Cancer Inst. 1992;84:1816-1820

Chen AY, Liu LF. DNA topoisomerases: essential enzymes and lethal targets. Annu Rev Pharmacol Toxicol. 1994;34:191-218.

Fayad W, Fryknäs M, Brnjic S, et al. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters. PLoS ONE. 2009;4(10):e7238.

Pommier Y, Kohn KW. Cell cycle and checkpoints in oncology: new therapeutic targets. Med Sci (Paris.) 2003;19:173-86.

Zhang, H. et al. Human mitochondrial topoisomerase I. Proc Natl Acad Sci U S A. 2001;98:10608-13.

PDF list of topoisomerase inhibitors.

Camptothecin

Brand/Trade Names: Camptosar

Formula: C20H16N2O4

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intravenous

Notes: A natural product, originally derived from tree Camptotheca acuminata.

Doxorubicin

Brand/Trade Names: Adriamycin, Rubex

Formula: C27H29NO11

Mechanism: topoisomerase II inhibitor

Class: antibiotic

Administration: Intravenous

Notes:

Etoposide

Brand/Trade Names: Toposar, VePesid, Etopophos

Formula: C29H32O13

Mechanism: topoisomerase II inhibitor

Class: Plant alkaloid

Administration: Intraveneous

Notes:

Irinotecan

Brand/Trade Names: Camptosar, Onivyde

Formula: C33H38N4O6

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intravenous

Notes:

Mitoxantrone

Brand/Trade Names: Novantrone 

Formula: C22H28N4O6

Mechanism: topoisomerase II inhibitor

Class: antibiotic

Administration: Intravenous

Notes:

Topotecan

Brand/Trade Names: Hycamtin

Formula: C23H23N3O5

Mechanism: topoisomerase 1 inhibitor

Class:

Administration: intravenous

Notes: