4 - Oncology 1 Flashcards
(27 cards)
Camptothecin analogues – MOA, examples
- Inhibit topoisomerase 1
- Examples = irinotecan and topotecan
Main difference between topotecan and irinotecan?
- Topotecan -> water soluble, excreted mostly unchanged by kidney
- Irinotecan -> less water soluble, has to be made into pro-drug, hepatic metabolism and biliary excretion
Topotecan – use, effect of genetic variation on dosing, major SE, when to make dose adjustments
- Used to treat ovarian and small cell lung cancer
- Genetic variation doesn’t affect dosing
- Major SE = neutropenia, diarrhea
- Dose adjustments needed w/ renal impairment b/c mainly excreted unchanged by kidneys
Describe how irinotecan is converted into its active metabolite and its effect
- Pro-drug requires conversion by carboxylesterase (CE) to active metabolite SN-38
- SN-38 inhibits topoisomerase 1 => decreased replication and transcription
Major SE of irinotecan
Neutropenia and severe diarrhea
Describe the mechanism of topoisomerase 1
- Helicase breaks H-bonds between nucleotide bases and unwinds DNA for replication to proceed
- This process creates torsional strain on the unwound portion of the DNA helix
- Eventually, this strain would prevent the DNA strand from unwinding and stop replication
- Topoisomerase 1 produces reversible single-strand breaks in DNA during replication
- These single-strand breaks relieve the torsional strain and allow replication to proceed
Is irinotecan cell cycle specific?
Yes, S phase
Generally, anti-cancer drugs that produce _____ are preferable to those that produce _____
Double strand breaks; single strand breaks
Describe the full metabolism of irinotecan
- Carboxylesterase (actually CES2) converts into active metabolite
- Oxidized by CYP3A4 into 2 inactive metabolites (APC and NPC)
- Active metabolite (SN-38) conjugated w/ UDP-glucuronosyl transferase 1A1 (UGT 1A1) to inactive form
- 13% excreted unchanged
Metabolism of ______ is modulated by genetic variation in UGT1A1 while ______ isn’t
Irinotecan; topotecan
Which UGT1A1 alleles affect activity and what is the effect?
- *6, *27, *28, and *37 = reduced activity
- *36 = increased activity
Describe what happens in UGT1A1 *28 allele
- Gene has VNTR of (TA) in the promoter that is part of the TATA box
- UGT1A1 *28 has 7 repeats of TA sequence that results in lower expression of UGT1A1 gene and low glucuronidation
What affect does the UGT 1A1 *28 allele have on SN-38?
- Reduced clearance of SN-38
- Increasing risk of major SE
- Neutropenia – can lead to life-threatening infection
- Diarrhea – can lead to life-threatening dehydration (*most common cause for d/c of irinotecan)
UGT 1A1 *28 associated w/ _____
Hyperbilirubinemia
UGT 1A1 28/28 has about __% the metabolism of irinotecan as 1/1
50%
What is the clinical outcome of UGT 1A1 28/28?
- Better tumour response
- Neutropenia and diarrhea offset the benefit (neutropenia risk greatly increases w/ each *28 allele)
What affect does cigarette smoke have on irinotecan clearance?
- Cigarette smoke appears to increase the clearance and decrease the AUC of irinotecan and its active metabolite SN-38
- Applies to px that have been long-term smokers, not people that smoked just before tx
- This may happen in part b/c of induced expression of UGT1A1 by polycyclic aromatic hydrocarbons (PAH) from cigarette smoke
- Decreases risk of neutropenia and diarrhea
- But may also increase risk of tx failure
What is the active metabolite of tamoxifen?
Endoxifen
Describe the mechanism of tamoxifen
- Tamoxifen binds to ER-alpha or ER-beta, the receptors dimerize & bind to ERE (estrogen response element; sequence of DNA that binds ER) but tamoxifen causes a different conformational change in the ER-alpha or ER-beta => different proteins to be recruited to the ERE
- In some tissues, this results in a decrease in transcription, in others it results in an increase
Describe tamoxifen metabolism
- Tamoxifen -> 4-hydroxy-tamoxifen (very low activity) by CYP2D6 OR N-desmethyl-tamoxifen by CYP3A4/5
- Both metabolites can then be transformed into endoxifen by the opposite CYP enzyme
- Effect of endoxifen is eliminated by glucuronidation; either N or O
[Endoxifen] dependent on which CYP enzyme?
2D6
Describe the genotypes of CYP 2D6 that produce the 4 metabolizer phenotypes for tamoxifen?
- UM = > 2 copies of normal gene (ie: at least 1 xN)
- EM = 2 WT alleles
- IM = 1 WT and 1 def allele
- PM = 2 def alleles (def = all inactive or decreased activity alleles)
What clinical effect does PM have?
Produces less endoxifen from tamoxifen, so puts them at increased risk of tx failure
What effect do CYP 2D6 inhibitors have on endoxifen concentration?
Effect of potent CYP2D6 inhibitors (paroxetine) on endoxifen formation from tamoxifen is similar to having 2 copies of Vt alleles for CYP2D6 (Vt = *3 – *6; inactive)
