Topoisomerase Inhibitors

Question 0

Topoisomerase I inhibitors

Answer 0

MOA: bind DNA topo I interfere w/ nicked DNA ligation. Camptothecins: topotecan, irinotecan

Question 1

Camptothecins

Answer 1

Topotecan

Irinotecan

Question 2

Podophyllotoxins

Answer 2

Etoposide

Teniposide

Question 3

Topoisomerase II inhibitors

Answer 3

MOA: bind DNA topo II interfere w/ nicked DNA ligation
Podophyllotoxins: etoposide, teniposide

Question 4

Topoisomerases vs. Anticancer Abx

Answer 4

Topoisomerases are obtained from plant sources and drug binds only when DNA and topoisomerase are together
Abx are obtained from microbial source and intercalate w/ DNA so it is already there (bound) to DNA and not just when topoisomerase and DNA are together

Question 5

Camptothecins

Answer 5

Limited water solubility
Sodium salt that opens lactone ring makes it more soluble, but it is also more toxic*(hemorrhagic cystitis) and less active

Question 6

Topotecan

Answer 6

Topotecan itself is active
*lactone hydrolysis (dihydroxy acid->major active metabolite)Reversible
Highly plasma protein bound
DDI: inhibitors of BCRP and P-gp and CYP3A4
Toxicity: myelosuppression, diarrhea, mucositis

Question 7

Irinotecan

Answer 7

Prodrug carbamate ester
SN-38 is active metabolite
hepatic carboxyesterase converts to active SN-38
UGT1A128/6 mutation has low enzyme activity leading to toxicity because SN-38 doesn’t get converted to inactive SN-38G
Toxicity: acute and delayed diarrhea (dose limiting), myelosuppression, N/V

Question 8

Epipodphyllotoxin

Answer 8

*lactone hydrolysis (hydroxy acid metabolite) is the major active metabolite
Toxicity: mucositis, myelosuppression
N/V is milder

Question 9

Epipodphyllotoxin lipophilic compounds

Answer 9

Enhanced uptake but poor solubility
Solubility enhancer (cremophor-> hypersensitivity rxn)
Etoposide: PO, IV( phosphate)
Teniposide: IV only. Has a thiol group that makes it more lipophilic than etoposide

Question 10

Mechanism of resistance to Topoisomerase inhibitors

Answer 10

1. Down regulation of target enzyme or receptors (topo I or topo IIa)
2. Down regulation of activation enzymes ( hepatic irinotecan converting enzyme)
3. Cellular efflux (Camptothecins- BCRP, MDRP, P-Gp. Epipodophyllotoxins- P-gp)