Topoisomerase inhibitors

Topoisomerase I inhibitors

• Topotecan
• Irinotecan

Topoisomerase II inhibitors (podophyllotoxin derivatives)

• Etoposide:Glycoside of podophyllotoxin; is extracted from the root of Podophyllum peltatum
• Teniposide: Glycoside of podophyllotoxin

Topoisomerases are a class of nuclear enzymes that are involved in the regulation of DNA supercoiling. They belong to the isomerases. Topoisomerases control and maintain the spatial arrangement (topology) of the DNA double strands during replication.

Type I topoisomerases relax the DNA, transform a superhelical DNA into a relaxed DNA by reversibly cleaving one strand of duplex DNA. This creates the prerequisite for reading, i.e. transcription of the DNA. After successful DNA replication, the DNA gap is closed again. Type I topisomerase always reversibly cleaves only one strand of DNA. Topoisomerase inhibitors I allow DNA cleavage, stabilise the topoisomerase-DNA complex and prevent the enzyme from closing the cleavage site again. This leads to the breakage of the DNA strand and the cell is driven into apoptosis. Topoisomerase inhibitor I develops the strongest antineoplastic activity in the S phase.

The type II topoisomerases act ATP-dependent. They are able to separate both DNA strands. In the case of etoposide, a semi-synthetic glycosidic podophyllotoxin derivative, the glycoside binds with the DNA and the topoisomerase to form a stable complex that allows the cleavage of the DNA double strand but prevents the re-closure of the resulting DNA gap. The enzyme remains bound to the free end of the DNA. The transcription comes to a standstill. The cell gives the signal for its own cell death (apoptosis) because the arrest of DNA relaxation can no longer be released.

Myelosuppression, nausea, vomiting, alopecia and, among others, severe diarrhoea when taking irinotecan.

Various tumours are characterised by an increased topisomerase activity, which is why topisomerase inhibitors as cytostatic agents show a certain tumour selectivity (e.g. in ovarian carcinoma, small cell lung carcinoma, colorectal carcinoma, etc.).

1. Lima CD et al (1994) Three-dimensional structure of the 67K N-terminal fragment of E. coli DNA topoisomerase I. Nature 367:138-145.
2. Wang JC (1991). DNA topoisomerases: why so many? Journal of Biological Chemistry 266:6659-6662.
3. Yu L et al (1995) Solution structure of the C-terminal single-stranded DNA-binding domain of E. coli topoisomerase I. Biochemistry 34:7622-7628.