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PED3005 Pharmacogenetics > Response To Chemotherapy > Flashcards

Response To Chemotherapy Flashcards

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

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

A

*1 allele
6 TA repeats
8% toxicity

22
Q

What other drug is affected by the UGT1A1*28 allele

A

Cytarabine

23
Q

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

A

Thiopurine methyltransferases (TPMT)

24
Q

What is the mechanism of action for thiopurines

A

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

25
Q

Describe how AZA and 6-MP have anti-cancer activity

A

Azathioprine -> 6-MP -> 6tIMP -> 6-tXMP -> 6tGN

6tGN -> Rac1 inhibition + incorporation into DNA
= increased apoptosis

26
Q

Describe how 6-TG has anti-cancer activity

A

6-TG -> 6-tGN -> Rac1 inhibiton + incorporation into DNA
= increased apoptosis

27
Q

What genetic variants are there for TPMT activity

A

TMPT1/1 = WT
1/X = heterozygous defective
X/X = homozygous defective

28
Q

What ethnicity has the highest frequency of TPMT polymorphism

A

European and British

29
Q

How is TPMT activity related to TGN conc in patients

A

Inversely related

30
Q

What inactivates thiopurines

A

Thiopurine methyltransferases (TPMT)

31
Q

What are the inactive metabolites of 6-TG and 6-MP

A

6-TG = 6-methylTG
6-MP = 6-methylMP

32
Q

What would happen is TMPT heterozygous/deficient patients are given a standard dose

A

Develop haematopoietic bone marrow toxicity
Dose adjustment is necessary

33
Q

How can chemotherapy be based on tumour cell genotype and phenotype

A

Targeted specifically to tumour cells
Little to no effect on non-tumour cells

34
Q

Describe chronic myeloid leukaemia CML

A

Defined by Ph chromosome T(9;22)
= encodes a fusion oncoprotein with constitutive ABL kinase activity

35
Q

What drug has improved survival rate in CML patients

A

Imatinib
5 year = 90%
10 year = 84%

Other drugs
5 year = <71%
10 year = < 61%

36
Q

How can tumour cells gain resistance to Imatinib

A

Acquire somatic mutation in Bcr-Abl kinase domain

37
Q

Describe the Bcr-Abl mutation

A

Mediated at residue 215 which prevents hydrogen bonding in the ATP-binding pocket
= no critical drug binding

38
Q

What drug is used to treat CD33 +tive AML

A

Gemtuzumab

39
Q

Describe the CD33 SNP in AML that affects Gemtuzumab efficacy

A

WT = has C = SRSF2 binding = full length
D2 = has C->T = SRSF2 binding compromised = loss of exon 2

40
Q

What is a treatment for HER2 amplified cancer

A

Trastuzamab
Monoclonal antibody to HER2

41
Q

What is the role of HER2 in cancers

A

Over expressed in 20% of breast cancers
Drives proliferation
Over-expression mediated via gene amplification

42
Q

What is the most common mutation on B-RAF that leads to constitutive activation and unregulated cell proliferation

A

BRAF V600E

43
Q

What is an inhibitor of the BRAF V600E variant

A

Vemurafenib

44
Q

What is B-RAF

A

Serine-threonine kinase
In RAS/RAF/MEK/ERK in signalling pathway

45
Q

What is Vemurafenib

A

Small molecule inhibitor of the V600E variant

46
Q

What is the most common BRAF mutation and what doe sit related in

A

V600E
Constitutive activation and unregulated cell proliferation

47
Q

What drug also is an inhibitor of the V600E variant

A

Dabrafenib

48
Q

What drug acts on MEK in the MAP-kinase

A

Trametinib

49
Q

What are new chemotherapy drugs based on

A

Individual therapy
E.g genetics, gene expression and protein expression profiling of tumours

PED3005 Pharmacogenetics (10 decks)

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