Topoisomerase Inhibitors

The development of innovative chemotherapeutic treatments for cancer has caused scientists to look closer at DNA, and at enzymes that promote chemical reactions in the body.

Because DNA is the blueprint for the human body, any damage to a cell’s DNA can result in cancer. DNA is normally a coiled double helix of two strands; it periodically becomes uncoiled in the process of replication during cell division and when the genetic code is transcribed to make new proteins. Two enzymes that play roles in this uncoiling and recoiling process are topoisomerase I and topoisomerase II. They also play a significant role in fixing DNA damage that occurs as a result of exposure to harmful chemicals or UV rays.

There is a distinct difference in the way the two enzymes work. Topoisomerase I cuts a single strand of the DNA double helix while topoisomerase II cuts 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.

Scientists have investigated the topoisomerase enzymes as targets for the generation of new cancer treatments because when they are inhibited in a cell, the cell dies. Inhibitors of the topoisomerase enzymes have the ability to kill cells undergoing DNA replication, stop the reading of the DNA for protein production, and stop repair of DNA damage. Since cancer cells divide much more rapidly than normal cells, the cancer cells will be killed disproportionately by the topoisomerase inhibitors, though some normal cells with topoisomerase activity will also be killed.

Topoisomerase I and II inhibitors work by binding to the topoisomerase enzyme molecule. This blocks the ability of the topoisomerase to bind the DNA back together after it has been cut, thereby making the enzyme nonfunctional.

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

Topoisomerase inhibitors have found success in the real world. Studies have looked at the cancer-killing efficiency of irinotecan, which is a derivative of camptothecin that is FDA approved for use in colorectal cancer. Results show that it has a 13% to 32% response rate when used by itself or in combination with other chemotherapy drugs. That means that 13 to 32% of cancer patients it was used in have had their tumor shrink or disappear completely.


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.


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.


Brand/Trade Names: Camptosar

Formula: C20H16N2O4

Mechanism: Top

Class: Plant alkaloid

Administration: Intraveneous

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


Brand/Trade Names: Adriamycin, Rubex

Formula: C27H29NO11


Class: antibiotic.

Administration: Intraveneous



Brand/Trade Names: Toposar, VePesid, Etopophos

Formula: C29H32O13

Mechanism: topoisomerase II inhibitor

Class: Plant alkaloid

Administration: Intraveneous



Brand/Trade Names: Camptosar, Onivyde

Formula: C33H38N4O6

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intraveneous



Brand/Trade Names: Novantrone 

Formula: C22H28N4O6


Mechanism: topoisomerase inhibitor

Class: antibiotic

Administration: Intraveneous



Brand/Trade Names: Hycamtin

Formula: C23H23N3O5

Mechanism: topoisomerase 1 inhibitor


Administration: intravenous