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

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: First 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

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

Formula: C₃₃H₃₈N₄O₆

Mechanism: topoisomerase I inhibitor

Class: Plant alkaloid

Administration: Intravenous

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

Mitoxantrone

Brand/Trade Names: Novantrone

Formula: C₂₂H₂₈N₄O₆

Mechanism: topoisomerase II inhibitor

Class: antibiotic

Administration: Intravenous

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

Sacituzumab govitecan-hziy

Brand/Trade Names: Trodelvy

Formula: C₇₆H₁₀₄N₁₂O₂₄S

Mechanism: topoisomerase 1 inhibitor

Class:

Administration: intravenous

Notes:  First approved by the FDA in 2020.

Topotecan

Brand/Trade Names: Hycamtin

Formula: C₂₃H₂₃N₃O₅

Mechanism: topoisomerase 1 inhibitor

Class:

Administration: intravenous

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