Medical Pharmacology Chapter 33-34: Anticancer Drugs
Topoisomerases: The extended length of the human genome involving long polymers with double-stranded DNA molecules winding around each other present a topological challenge both during replication and in preparation for transcription. 11
Resolution of complex geometric: topological requirements utilize a set of enzymes, the topoisomerases.
These enzymes allow for proper nuclear and mitochondrial genomic functionality and stability.11
The reader is directed to reference 11 for details concerning topoisomerase chemical and biophysical characteristics.11
There are six topoisomerases in human cells:10, 11
TOP1MT (mitochondrial topoisomerase; gene located in the cell nucleus); type IB
TOP3α type IA
TOP3β type IA
TOP2α type IIA
TOP2β type IIA
TOP1 and TOP2A represent to topoisomerase genes found associated with cellular proliferation and have been noted as amplified in cancers.11
For example, the elevated expression of the TOP2A gene in cancers is also noted in other genes that promote cellular division such as ERBB2, encoding a component of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.11,13.
ERBB2 associated malignancies represented a target for EGFR inhibitors in, for example, lung adenocarcinomas and breast cancer.
An example of TOP1 gene coamplification is noted with the SRC, oncogene protein kinase).11
Topoisomerases function through forming covalent in reversible cleavage or breaks in the DNA backbone.
This process involves formation of a "topoisomerase cleavage complex" or TOPcc.11
Furthermore, anticancer topoisomerase inhibitors function by "trapping" TOPcc thus inactivating topoisomerases at the point of DNA cleavage.
This mechanism of action extends across the range of topoisomerase inhibitors as these agents fit into DNA breaks sites of the topoisomerase cleavage complex.11
TOP1 is the biological target of the anticancer drugs topotecan and irinotecan, derivatives of the alkaloid camptothecin.
TOP2 inhibitors are classified as DNA intercalators as well as non-intercalators, the epipodophyllotoxin related compounds.10
These agents trap TOP2cc (topoisomerase cleavage complexes); however, DNA intercalators at somewhat higher concentrations inhibit TOP2cc through DNA intercalation, destabilizing TOP2 DNA-binding.
Due to intercalation, these anticancer agents exhibit several effects associated with DNA processing including nucleosome destabilization and helicases and polymerase enzyme inhibition.
Examples of drugs classified as intercalators and non-intercalators include:
Doxorubicin (anthracycline, Adriamycin)
Epirubicin (anthracycline, Ellence)
Idarubicin (anthracycline, Idamycin)
Mitoxantrone (anthracenedione, Novantrone)
Dactinomycin (anthracenedione, Cosmegen)
Etoposide (epipodophyllotoxin, Vepesid)
Teniposide (epipodophyllotoxin, Vumon).10