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.

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

Manufacturers: Pharmacia and Upjohn Company, Biesterfeld Spezialchemie GmbH, Emcure Pharmaceuticals, Jiangsu Yutian Pharmaceutical Co., Jiwan Pharmaceutical Technology Co.

Formula: C20H16N2O4

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intravenous

Notes: A natural product, originally derived from tree Camptotheca acuminata.  Approved by the FDA in 2012.  Used in treatment of colon cancer and rectal cancer.

Doxorubicin

Brand/Trade Names: Adriamycin, Rubex

Formula: C27H29NO11

Mechanism: topoisomerase II inhibitor

Class: antibiotic

Administration: Intravenous

Notes: Approved by the FDA in 1974.  Used to treat acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, .stomach cancer, Hodgkin’s lymphoma, neuroblastoma, non-Hodgkin lymphoma, ovarian cancer, small cell lung cancer, soft tissue and bone sarcomas, thyroid cancer, bladder cancer, Wilms tumor.

Etoposide

Brand/Trade Names: Toposar, VePesid, Etopophos

Manufacturers: Teva Pharmaceuticals, Biotechnica Pharma Global, ChemWerth, Cipla, Jiangsu Hengrui Medicine Co., Ltd.

Formula: C29H32O13

Mechanism: topoisomerase II inhibitor

Class: Plant alkaloid

Administration: Intravenous

Notes:  Approved by the FDA in 1983.  Approved for treatment of small cell lung cancer and testicular cancer,

Irinotecan

Brand/Trade Names: Camptosar, Onivyde

Manufacturers:  Olon spA Biesterfeld Spezialchemie GmbH, Emcure Pharmaceuticals, Jiangsu Yutian Pharmaceutical Co.,  Jiwan Pharmaceutical Technology Co.

Formula: C33H38N4O6

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intravenous

Notes:  Approved by the FDA in 1996.  Approved for treatment of colorectal cancer.

Mitoxantrone

Brand/Trade Names: Novantrone

Manufacturers: Pfizer Manufacturing Deutschland GmbH, Chongqing Carelife Pharmaceutical Co., Cipla  Hanways Chempharm Co., Limited  Hubei Haosun Pharmaceutical Co.

Formula: C22H28N4O6

Mechanism: topoisomerase II inhibitor

Class: antibiotic

Administration: Intravenous

Notes:  Approved by the FDA in 1987.  Used for treatment of acute myeloid leukemia, lymphoma, prostate cancer, and breast cancer.

Sacituzumab govitecan-hziy

Brand/Trade Names: Trodelvy

Manufacturers: Immunomedics, Inc. 

Formula: C76H104N12O24S

Mechanism: topoisomerase 1 inhibitor

Class: Conjugate of MAB and topoisomerase inhibitor.  Also included on page on antibody-drug conjugates.

Administration: Intravenous

Notes:  Approved by the FDA in 2020.  Used for treatment of breast cancer.

Teniposide

Brand/Trade Names: Vumon, VM-26

Manufacturer: Olon Spa

Formula: C32H32O13S

Mechanism: topoisomerase II inhibitor

Class: plant alkaloid

Administration: Intravenous

Notes:  Approved by the FDA in 1992.  Used for treatment of acute lymphoblastic leukemia.

Topotecan

Brand/Trade Names: Hycamtin

Manufacturers: Novartis Pharmaceuticals, Bachem AG, ChemWerth, Cipla, Emcure Pharmaceuticals

Formula: C23H23N3O5

Mechanism: topoisomerase 1 inhibitor

Class:

Administration: Intravenous

Notes:  Approved by the FDA in 1996. Used for treatment of cervical cancer, ovarian cancer, and small cell lung cancer.