4 - Oncology 1

Question 1

Camptothecin analogues – MOA, examples

Answer 1

• Inhibit topoisomerase 1

- Examples = irinotecan and topotecan

Question 2

Main difference between topotecan and irinotecan?

Answer 2

• Topotecan -> water soluble, excreted mostly unchanged by kidney
• Irinotecan -> less water soluble, has to be made into pro-drug, hepatic metabolism and biliary excretion

Question 3

Topotecan – use, effect of genetic variation on dosing, major SE, when to make dose adjustments

Answer 3

• 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

Question 4

Describe how irinotecan is converted into its active metabolite and its effect

Answer 4

• Pro-drug requires conversion by carboxylesterase (CE) to active metabolite SN-38
• SN-38 inhibits topoisomerase 1 => decreased replication and transcription

Question 5

Major SE of irinotecan

Answer 5

Neutropenia and severe diarrhea

Question 6

Describe the mechanism of topoisomerase 1

Answer 6

• 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

Question 7

Is irinotecan cell cycle specific?

Answer 7

Yes, S phase

Question 8

Generally, anti-cancer drugs that produce _____ are preferable to those that produce _____

Answer 8

Double strand breaks; single strand breaks

Question 9

Describe the full metabolism of irinotecan

Answer 9

• 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

Question 10

Metabolism of ______ is modulated by genetic variation in UGT1A1 while ______ isn’t

Answer 10

Irinotecan; topotecan

Question 11

Which UGT1A1 alleles affect activity and what is the effect?

Answer 11

• *6, *27, *28, and *37 = reduced activity

- *36 = increased activity

Question 12

Describe what happens in UGT1A1 *28 allele

Answer 12

• 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

Question 13

What affect does the UGT 1A1 *28 allele have on SN-38?

Answer 13

• 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)

Question 14

UGT 1A1 *28 associated w/ _____

Answer 14

Hyperbilirubinemia

Question 15

UGT 1A1 28/28 has about __% the metabolism of irinotecan as 1/1

Answer 15

50%

Question 16

What is the clinical outcome of UGT 1A1 28/28?

Answer 16

• Better tumour response

- Neutropenia and diarrhea offset the benefit (neutropenia risk greatly increases w/ each *28 allele)

Question 17

What affect does cigarette smoke have on irinotecan clearance?

Answer 17

• 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

Question 18

What is the active metabolite of tamoxifen?

Answer 18

Endoxifen

Question 19

Describe the mechanism of tamoxifen

Answer 19

• 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

Question 20

Describe tamoxifen metabolism

Answer 20

• 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

Question 21

[Endoxifen] dependent on which CYP enzyme?

Answer 21

2D6

Question 22

Describe the genotypes of CYP 2D6 that produce the 4 metabolizer phenotypes for tamoxifen?

Answer 22

• 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)

Question 23

What clinical effect does PM have?

Answer 23

Produces less endoxifen from tamoxifen, so puts them at increased risk of tx failure

Question 24

What effect do CYP 2D6 inhibitors have on endoxifen concentration?

Answer 24

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)

Question 25

Describe the breast cancer tx recommendations based on CYP 2D6 phenotype

Answer 25

• PM and IM -> consider aromatase inhibitor for post-menopausal; aromatase inhibitor and ovarian function suppression for pre-menopausal; if can’t use aromatase inhibitor, consider higher dose tamoxifen
• UM and EM -> no recommendations

Question 26

What is considered high dose tamoxifen?

Answer 26

40 mg/day

Question 27

Does high dose tamoxifen produce endoxifen levels in IM similar to those in EM w/ normal dose?

Answer 27

No, will still produce lower endoxifen levels