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.
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.