Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Adv Pharmacogenetics PED3005 > Cancer chemotherapy > Flashcards

Cancer chemotherapy Flashcards

1
Q

Constitutional polymorphism are present since when ?

A

fertilisation and in every cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

constitutional polymorphisms are _ tolerant for variation

A

less

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

give 3 examples of constitutional polymorphism

A

Trisomy 13 (Patau syndrome)
Trisomy 18 (Edward syndrome)
Trisomy 21 (Down syndrome)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are somatic mutations ?

A

Acquired as we age and only in individual cells (and their progency)
and they are more tolerant for variation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Older cancer drugs tend to target what….

A

highly proliferating cells for example, targeting DNA synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Why do patients have vary responses to older cancer drugs

A

they are not tailered to specific mutation and response is still affected by genetics

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Newer cancer drugs aim to target

A

the cancer cell only e.g. genomic translocations (BCR-ABL), over-expressing oncogenes (EGFR-TKIs, B-RAF), phenotypic characteristics (surface protein expression)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what metabolises 5-fluorouracil

A

Dihydropyrimidine dehydrogenase (DPYD)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is 5-fluorouracil used to treat and how

A
  • Used for >40 years to treat cancer e.g. colorectal, stomach, breast and pancreatic; targets rapidly dividing cells.
  • pyrimidine analogue is incorporated into DNA/RNA causing cell cycle arrest + apoptosis which inhibits thymidylate synthase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

5-fluorouracil side effects include

A

myelosuppression, diarrhoea and cardiac toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

capecitabine is a _

A

prodrug which is converted into 5-fluorouracil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are the two effects of DPYD constitutional genetic variants

A

reduced activity and null activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are the two DPYD genetic variant which causes reduced activity

A

2846 A>T, Asp949Val
(75% for heterozygotes, 50% for homozygotes)
1236 G>A, HAPB3
(75% for heterozygotes, 50% for homozygotes)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what are the two DPYD genetic variant which causes null activity

A

DYPD*2A - splicing defect
(50% activity for heterozygotes, no activity for homozygotes)
1679 T>G; *13
(50% activity for heterozygotes, no activity for homozygotes)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what % of the general population have reduced DPYD activity

A

35%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what is the phenotype of the reduced DPYD activity and how should dose be change for these people

A

DPYD intermediate metabolizer (Decreased DPD activity (leukocyte DPD activity at 30–70% that of the normal population))

Clinical recommendation: Reduce starting dose by 50%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what percentage of the population has no DPYD activity, what is the phenotype and how should clinical dose be effected

A

0.2%
DPYD poor metaboliser
no fluorouracil dose has been proven to be safe for these individuals

18
Q

what metabolises irinotecan

A
  • Uridine diphosphate (UDP)
  • Glucuronosyltransferase family 1 member A1 (UGT1A1)
19
Q

what is Irinotecan used to treat

A

colorectal and lung cancer

20
Q

how is irinotecan metabolised

A
  • Metabolised to the active form (SN-38) by carboxylesterase
  • Inactivated via conjugation by UGT1A1 and UGT1A7 to SN-38 glucuronide
  • Anticancer activity of SN-38 is mediated via inhibition of topoisomerase I
21
Q

what causes Gilberts syndrome

A

a genetic variants in UGT1A1 that give rise to a phenotype form mild hyperbilirubinemia to life threating jaudice

22
Q

which genertic varinat causes gilbert syndrome

A

UGTA1A*28
Characterised by an additional TA repeat (TA)7 in the gene promoter that affects transcription and protein expression

23
Q

what percentage of the general population are poor irinotecan metabolisers

A

8-78% depending on ethnic background

24
Q

what do patienst who has UGT1A1*28 allele experience when treated with irinotecan

A

heamatological toxicity (nuetropenia)

25
Q

thiopurines are used to

A

direct incorporation into DNA/RNA and inhibits de novo purine synthesis

26
Q

what metabolsies 6-mercaptopurine, azathioprine and 6-thioguanine

A

thiopurine methyltransferase (TPMT)

27
Q

what are the two types of TPMT alleles

A

*1 - wild type
*X - defective

28
Q

Most constitutional TPMT genetic polymorphism affects _ activity and how ?

A

Protein
majority are base substitutional variants

29
Q

how does TPMT phenotype affects 6-TGN levels after azathioprine

A

LOW TPMT: homozygous variant (high 6-TGN)
INT TPMT: heterozygote
HIGH TPMT: wild-type (low 6-TGN)

  • TPMT activity is inversely correlated with 6-TGN levels
30
Q

what occurs when TPMT heterozygote/deficient are given a standard dose of thiopurines

A

more likely to develop haematopoietic bone marrow toxicity therefore need dose adjustment

31
Q

how can genotyping be used in cancer treatment

A

use of novel drugs to target tumour that can be predicted to respond on basis of tumour genotype or phenotype

32
Q

why is Imatinib used

A

a ‘poster child’ of targeted therapy for cancer originally developed to treat chronic myeloid leukaemia

33
Q

how does resistance to imatinib develop

A

somatic mutations
- Mutations of Bcr-Abi kinase domains were found in over 90% of patients with CML who relapsed after an initial response to imatinib

34
Q

what are the key amino acids involved in imatinib resistance

A
  • Resistance mediated by mutation at residue 315 (Thr315Ile) – prevents hydrogen bonding between Imatinib and the 315 residue critical for drug binding.
  • Asp363 (D363) is pivotal for nucleophilic attack on peptide substrate during catalysis
  • Tyr393 (Y393) is the target of phosphorylation that controls Abl activation and inactivation,
  • DFG (Asp-Phe-Gly) motif coordinates fundamental cofactors for catalysis, namely Mg2+ ions.
34
Q

what type of cancer is gemtuzumab used to treat

A

CD33 postive acute myeloid leukeamia

34
Q

what two isoforms effect gemtuzumab efficacy

A
  • CC had higher CD33 intensity and lower amount of CD33 D2 isoforms (exon 2 deletion)
  • TT has lower intensity and higher amounts of isoforms
35
Q

Trastuzamab is used to treat what

A

HER2 amplified breast cancer

36
Q

what type of of cancers have activating mutations in B-RAF and what is the effected pathways

A

melanomas, thyroid, ovarian and colorectal
MAP-kinase pathways

37
Q

waht is the most common mutation BRAF and how does it effect the cell

A

v600E
constitutive activation and unregulated cell proliferation

38
Q

what is B-RAF

A

Serine-threonine kinase in the RAS/RAF/MEK/ERK signaling pathway commonly activated in human cancer

39
Q

What is vemurafenib

A

small molecule inhibitor of the V600E variant

Adv Pharmacogenetics PED3005 (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions