 |
 |
 |
|
|
Nursing Pharmacology Chapter 33-34: Anticancer Drugs
|
|
|
|
|
|
|
Natural Products:
Topoisomerase Inhibitors:
Overview:
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
Topoisomerase Classification and Actions:
There are six topoisomerases in human cells:10, 11
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.
Topoisomerases
function through forming covalent in reversible cleavage or breaks in the
DNA backbone.
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.
TOP2:10
TOP2
inhibitors are classified as DNA intercalators as well as non-intercalators,
the epipodophyllotoxin related compounds.10
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)
Daunorubicin (anthracycline,Cerubidine)
Epirubicin (anthracycline, Ellence)
Idarubicin (anthracycline, Idamycin)
Mitoxantrone (anthracenedione, Novantrone)
Dactinomycin (anthracenedione, Cosmegen)
Etoposide (epipodophyllotoxin, Vepesid)
Teniposide (epipodophyllotoxin, Vumon).10
|
|
|
|
|
|
|
