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PMCOL 344 - Topoisomerase Inhibitors Study Set Exam
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PMCOL 344 - TopoisomeraseInhibitors Study Set Exam
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
only what kind of topoisomerase inhibits ATP hydrolysis and DNA release at the last step
- Answer type II
, 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
what happens to the metabolism of irinotecan if a person has a reduced fxn variant of
UGT1A1 (present in 10% of Caucasians) - Answer poor metab of irinotecan --> irinotecan
toxicity, as it cannot be excreted from the body in its SN-38 form
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