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PED3005 Pharmacogenetics > Response To Chemotherapy > Flashcards

Response To Chemotherapy Flashcards

(49 cards)

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1
Q

Describe constitutional polymorphisms

A

Present since fertilisation and in every cell
Less tolerance for variation

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2
Q

Describe somatic mutations

A

Acquired as we age and only in individual cells
More tolerance for variation

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3
Q

What is the target for ‘older’ cancer drugs

A

Highly proliferation cells
Target DNA synthesis and are not tailored to specific mutations
Response affected by genetics

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4
Q

What is the target for ‘newer’ cancer drugs

A

Cancer cell only e.g genomic translocations, over-expressing oncogenes and phenotypic characteristics

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5
Q

What metabolises 5-FU

A

Dihydropyrimidine dehydrogenase (DPYD)

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6
Q

Describe the mechanism of action for 5-FU

A

Pyrimidine analogue incorporated into DNA and RNA = cell cycle arrest and apoptosis
Inhibits thymidylate synthase

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7
Q

Describe the anabolism of capecitabine

A

20% of the drug

Capecitabine -> 5-FU -> FUrd -> FUMP - > RNA
-> FdUrd -> FdUMP -> DNA

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8
Q

What is the role of FUrd

A

Incorporated into RNA

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9
Q

What is the role of FdURd

A

Suicide inhibitor of TS

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10
Q

Describe the catabolism of capecitabine

A

80% of the drug

Capecitabine -> 5-FU (via DYPD) -> FUH2 -> FUPA -> FBA (inactive)

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11
Q

What variants of DYPD have reduced activity

A

Asp949Val
HAPB3

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12
Q

What variants of DYPD have null activity

A

DYPD*2A - splicing defect
*13 - null allele

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13
Q

Describe the DYPD reduced activity variants

A

Approx 35% population
Intermediated metabolisers (30-70% of normal)
Reduce starting does by 50%

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14
Q

Describe the DYPD null activity variants

A

0.2% of general popualation
Poor metabolisers - increased risk for severe or fatal drug toxicity
No 5-FU dose safe in individuals

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15
Q

Describe the metabolism of 5-FU in DYPD null patients

A

90% excreted in urine compared to <20% in normal
Anti cancer efficacy + off target effects
Plasma half like increased from 13mins -> 3hrs

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16
Q

What metabolises irinotecan

A

UGT1A1

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17
Q

Describe the metabolism of irinotecan

A

Metabolised to SN-38 active form by carboxylesterase
Inactivated via conjugation to UGT1A1 and UGT1A7
= SN-38 glucuronide

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18
Q

Describe the anti-cancer activity of SN-38

A

Mediated by inhibitors of TOPO1

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19
Q

How can there be intestinal and bone marrow toxicity in patients after taking irinotecan

A

If patient has Gilberts syndrome die to reduced/absent UGT activity

UGT1A1*28

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20
Q

Describe the UGT1A1*28 allele

Study These Flashcards
A

Common in Europeans
8-78% are poor metabolisers depending on ethnic background

Additional TA repeat in gene promoter
Affects transcription and protein expression

21
Q

What is the UGT1A1 WT

Study These Flashcards
A

*1 allele
6 TA repeats
8% toxicity

22
Q

What other drug is affected by the UGT1A1*28 allele

23
Q

What metabolises thiopurines e.g 6-MP, azathioprine, 6-TG

Study These Flashcards
A

Thiopurine methyltransferases (TPMT)

24
Q

What is the mechanism of action for thiopurines

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A

Direct incorporation into DNA/RNA
Inhibits de novo purine synthesis
Can cause toxicity

25
Describe how AZA and 6-MP have anti-cancer activity
Azathioprine -> 6-MP -> 6tIMP -> 6-tXMP -> 6tGN 6tGN -> Rac1 inhibition + incorporation into DNA = increased apoptosis
26
Describe how 6-TG has anti-cancer activity
6-TG -> 6-tGN -> Rac1 inhibiton + incorporation into DNA = increased apoptosis
27
What genetic variants are there for TPMT activity
TMPT*1/*1 = WT *1/*X = heterozygous defective *X/*X = homozygous defective
28
What ethnicity has the highest frequency of TPMT polymorphism
European and British
29
How is TPMT activity related to TGN conc in patients
Inversely related
30
What inactivates thiopurines
Thiopurine methyltransferases (TPMT)
31
What are the inactive metabolites of 6-TG and 6-MP
6-TG = 6-methylTG 6-MP = 6-methylMP
32
What would happen is TMPT heterozygous/deficient patients are given a standard dose
Develop haematopoietic bone marrow toxicity Dose adjustment is necessary
33
How can chemotherapy be based on tumour cell genotype and phenotype
Targeted specifically to tumour cells Little to no effect on non-tumour cells
34
Describe chronic myeloid leukaemia CML
Defined by Ph chromosome T(9;22) = encodes a fusion oncoprotein with constitutive ABL kinase activity
35
What drug has improved survival rate in CML patients
Imatinib 5 year = 90% 10 year = 84% Other drugs 5 year = <71% 10 year = < 61%
36
How can tumour cells gain resistance to Imatinib
Acquire somatic mutation in Bcr-Abl kinase domain
37
Describe the Bcr-Abl mutation
Mediated at residue 215 which prevents hydrogen bonding in the ATP-binding pocket = no critical drug binding
38
What drug is used to treat CD33 +tive AML
Gemtuzumab
39
Describe the CD33 SNP in AML that affects Gemtuzumab efficacy
WT = has C = SRSF2 binding = full length D2 = has C->T = SRSF2 binding compromised = loss of exon 2
40
What is a treatment for HER2 amplified cancer
Trastuzamab Monoclonal antibody to HER2
41
What is the role of HER2 in cancers
Over expressed in 20% of breast cancers Drives proliferation Over-expression mediated via gene amplification
42
What is the most common mutation on B-RAF that leads to constitutive activation and unregulated cell proliferation
BRAF V600E
43
What is an inhibitor of the BRAF V600E variant
Vemurafenib
44
What is B-RAF
Serine-threonine kinase In RAS/RAF/MEK/ERK in signalling pathway
45
What is Vemurafenib
Small molecule inhibitor of the V600E variant
46
What is the most common BRAF mutation and what doe sit related in
V600E Constitutive activation and unregulated cell proliferation
47
What drug also is an inhibitor of the V600E variant
Dabrafenib
48
What drug acts on MEK in the MAP-kinase
Trametinib
49
What are new chemotherapy drugs based on
Individual therapy E.g genetics, gene expression and protein expression profiling of tumours

PED3005 Pharmacogenetics (10 decks)

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