PMCOL 344 - Topoisomerase inhibitors.
Exam Questions With Correct Answers
Examples of DNA "cutters" topoisomerases inhibitors - answer✔* camptothecin and
derivatives
* anthracyclines
* podophyllotoxin derivatives
many topoisomerase inhibitors are - answer✔prodrugs
DNA topoisomerases are important in - answer✔DNA replication and RNA transcription
type I topoisomerases - answer✔change the degree of supercoiling of DNA by causing aa
breaks and re-ligation (subtypes IA-IIalpha (top3A), 1A-IIbeta (top3B), 1B (top1) )
type II topoisomerases - answer✔cause ds breaks (subtypes IIalpha (top2A), IIbeta (top2B)
topoisomerases are generally present at elevated levels in - answer✔tumors
resolution of the molecular structures of topoisomerases has - answer✔opened new avenues for
drug development in this area
the targets of the currently marketed cancer chemotherapeutic agents are -
answer✔topoisomerase I, IIalpha, IIbeta
"topoisomerase poisons" - answer✔inhibit the re-ligation step and locks enzyme into a
"cleavage complex" (enhances the rate of cleavage)
competitive inhibition of the ATP binding site occurs in - answer✔only type II topoisomerase--
> prevents ATP-hydrolysis which drives the enzymatic action
examples of type II topoisomerase that blocks the ATP binding site - answer✔- novobiocin
- coumermycin
examples of inhibitors of DNA-topoisomerase binding - answer✔- aclarubicin
- suramin
example of topo IB inhibitors - answer✔camptothecin
how is camptothecin used as a chemotherapeutic - answer✔- forms a stable ternary complex
with the topo I-DNA complex
- causes DNA strand breaks which results in apoptosis
how does camptothecin form a stable ternary complex with the topo I-DNA complex -
answer✔intercalation between the -1 and +1 DNA base pairs in the protein-DNA cleavage
complex, additional hydrophobic and electrostatic interactions stabilizes the binding of the
poison and prevent DNA re-ligation by the topoisomerase
camptothecin had remarkable activity in preclinical trials, but what were some problems -
answer✔- low solubility (did not work as well in humans due to this)
- adverse drug rxns
camptothecin is isolated from - answer✔the bark and stem of Camptotheca aciminata
(Camptotheca, Happy tree), a tree native to China used as a cancer treatment in Traditional
Chinese Medicine
what changes can be made to camptothecin to increase solubility while retaining cytotoxicity -
answer✔substitution of one of the rings with different substituents
irinotecan and topotecan - answer✔semisynthetic analogues of camptothecin
irinotecan used to treat - answer✔colon cancer - FOLFIRI (5-Fluorouracil, Leucovorin,
Irinotecan)
topotecan used in - answer✔ovarian and lung cancer
what is the active metabolite of Irinotecan (CPT-11) - answer✔SN-38
what are the inactive metabolites of Irinotecan (CPT-11) - answer✔- NPC
- APC
- SN-38G
irinotecan is converted to an active metabolite (SN-38) by - answer✔carboxylesterase
SN-38 is how many times more active than irinotecan - answer✔1000 times
how can ppl become resistance to irinotecan - answer✔down regulation of carboxylesterase
SN38 is metabolized to an inactive form via - answer✔glucuronidation by UGT1A1
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