Cancer chemotherapy

Question 1

Constitutional polymorphism are present since when ?

Answer 1

fertilisation and in every cell

Question 2

constitutional polymorphisms are _ tolerant for variation

Answer 2

less

Question 3

give 3 examples of constitutional polymorphism

Answer 3

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

Question 4

What are somatic mutations ?

Answer 4

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

Question 5

Older cancer drugs tend to target what….

Answer 5

highly proliferating cells for example, targeting DNA synthesis

Question 6

Why do patients have vary responses to older cancer drugs

Answer 6

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

Question 7

Newer cancer drugs aim to target

Answer 7

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

Question 8

what metabolises 5-fluorouracil

Answer 8

Dihydropyrimidine dehydrogenase (DPYD)

Question 9

What is 5-fluorouracil used to treat and how

Answer 9

• 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

Question 10

5-fluorouracil side effects include

Answer 10

myelosuppression, diarrhoea and cardiac toxicity

Question 11

capecitabine is a _

Answer 11

prodrug which is converted into 5-fluorouracil

Question 12

what are the two effects of DPYD constitutional genetic variants

Answer 12

reduced activity and null activity

Question 13

what are the two DPYD genetic variant which causes reduced activity

Answer 13

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

Question 14

what are the two DPYD genetic variant which causes null activity

Answer 14

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

Question 15

what % of the general population have reduced DPYD activity

Answer 15

35%

Question 16

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

Answer 16

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

Clinical recommendation: Reduce starting dose by 50%

Question 17

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

Answer 17

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

Question 18

what metabolises irinotecan

Answer 18

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

Question 19

what is Irinotecan used to treat

Answer 19

colorectal and lung cancer

Question 20

how is irinotecan metabolised

Answer 20

• 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

Question 21

what causes Gilberts syndrome

Answer 21

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

Question 22

which genertic varinat causes gilbert syndrome

Answer 22

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

Question 23

what percentage of the general population are poor irinotecan metabolisers

Answer 23

8-78% depending on ethnic background

Question 24

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

Answer 24

heamatological toxicity (nuetropenia)

Question 25

thiopurines are used to

Answer 25

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

Question 26

what metabolsies 6-mercaptopurine, azathioprine and 6-thioguanine

Answer 26

thiopurine methyltransferase (TPMT)

Question 27

what are the two types of TPMT alleles

Answer 27

*1 - wild type *X - defective

Question 28

Most constitutional TPMT genetic polymorphism affects _ activity and how ?

Answer 28

Protein majority are base substitutional variants

Question 29

how does TPMT phenotype affects 6-TGN levels after azathioprine

Answer 29

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

Question 30

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

Answer 30

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

Question 31

how can genotyping be used in cancer treatment

Answer 31

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

Question 32

why is Imatinib used

Answer 32

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

Question 33

how does resistance to imatinib develop

Answer 33

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

Question 34

what are the key amino acids involved in imatinib resistance

Answer 34

- 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.

Question 34

what type of cancer is gemtuzumab used to treat

Answer 34

CD33 postive acute myeloid leukeamia

Question 34

what two isoforms effect gemtuzumab efficacy

Answer 34

- CC had higher CD33 intensity and lower amount of CD33 D2 isoforms (exon 2 deletion) - TT has lower intensity and higher amounts of isoforms

Question 35

Trastuzamab is used to treat what

Answer 35

HER2 amplified breast cancer

Question 36

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

Answer 36

melanomas, thyroid, ovarian and colorectal MAP-kinase pathways

Question 37

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

Answer 37

v600E constitutive activation and unregulated cell proliferation

Question 38

what is B-RAF

Answer 38

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

Question 39

What is vemurafenib

Answer 39

small molecule inhibitor of the V600E variant