Cancer chemotherapy Flashcards
Constitutional polymorphism are present since when ?
fertilisation and in every cell
constitutional polymorphisms are _ tolerant for variation
less
give 3 examples of constitutional polymorphism
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edward syndrome)
Trisomy 21 (Down syndrome)
What are somatic mutations ?
Acquired as we age and only in individual cells (and their progency)
and they are more tolerant for variation
Older cancer drugs tend to target what….
highly proliferating cells for example, targeting DNA synthesis
Why do patients have vary responses to older cancer drugs
they are not tailered to specific mutation and response is still affected by genetics
Newer cancer drugs aim to target
the cancer cell only e.g. genomic translocations (BCR-ABL), over-expressing oncogenes (EGFR-TKIs, B-RAF), phenotypic characteristics (surface protein expression)
what metabolises 5-fluorouracil
Dihydropyrimidine dehydrogenase (DPYD)
What is 5-fluorouracil used to treat and how
- 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
5-fluorouracil side effects include
myelosuppression, diarrhoea and cardiac toxicity
capecitabine is a _
prodrug which is converted into 5-fluorouracil
what are the two effects of DPYD constitutional genetic variants
reduced activity and null activity
what are the two DPYD genetic variant which causes reduced activity
2846 A>T, Asp949Val
(75% for heterozygotes, 50% for homozygotes)
1236 G>A, HAPB3
(75% for heterozygotes, 50% for homozygotes)
what are the two DPYD genetic variant which causes null activity
DYPD*2A - splicing defect
(50% activity for heterozygotes, no activity for homozygotes)
1679 T>G; *13
(50% activity for heterozygotes, no activity for homozygotes)
what % of the general population have reduced DPYD activity
35%
what is the phenotype of the reduced DPYD activity and how should dose be change for these people
DPYD intermediate metabolizer (Decreased DPD activity (leukocyte DPD activity at 30–70% that of the normal population))
Clinical recommendation: Reduce starting dose by 50%
what percentage of the population has no DPYD activity, what is the phenotype and how should clinical dose be effected
0.2%
DPYD poor metaboliser
no fluorouracil dose has been proven to be safe for these individuals
what metabolises irinotecan
- Uridine diphosphate (UDP)
- Glucuronosyltransferase family 1 member A1 (UGT1A1)
what is Irinotecan used to treat
colorectal and lung cancer
how is irinotecan metabolised
- 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
what causes Gilberts syndrome
a genetic variants in UGT1A1 that give rise to a phenotype form mild hyperbilirubinemia to life threating jaudice
which genertic varinat causes gilbert syndrome
UGTA1A*28
Characterised by an additional TA repeat (TA)7 in the gene promoter that affects transcription and protein expression
what percentage of the general population are poor irinotecan metabolisers
8-78% depending on ethnic background
what do patienst who has UGT1A1*28 allele experience when treated with irinotecan
heamatological toxicity (nuetropenia)
thiopurines are used to
direct incorporation into DNA/RNA and inhibits de novo purine synthesis
what metabolsies 6-mercaptopurine, azathioprine and 6-thioguanine
thiopurine methyltransferase (TPMT)
what are the two types of TPMT alleles
*1 - wild type
*X - defective
Most constitutional TPMT genetic polymorphism affects _ activity and how ?
Protein
majority are base substitutional variants
how does TPMT phenotype affects 6-TGN levels after azathioprine
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
what occurs when TPMT heterozygote/deficient are given a standard dose of thiopurines
more likely to develop haematopoietic bone marrow toxicity therefore need dose adjustment
how can genotyping be used in cancer treatment
use of novel drugs to target tumour that can be predicted to respond on basis of tumour genotype or phenotype
why is Imatinib used
a ‘poster child’ of targeted therapy for cancer originally developed to treat chronic myeloid leukaemia
how does resistance to imatinib develop
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
what are the key amino acids involved in imatinib resistance
- 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.
what type of cancer is gemtuzumab used to treat
CD33 postive acute myeloid leukeamia
what two isoforms effect gemtuzumab efficacy
- CC had higher CD33 intensity and lower amount of CD33 D2 isoforms (exon 2 deletion)
- TT has lower intensity and higher amounts of isoforms
Trastuzamab is used to treat what
HER2 amplified breast cancer
what type of of cancers have activating mutations in B-RAF and what is the effected pathways
melanomas, thyroid, ovarian and colorectal
MAP-kinase pathways
waht is the most common mutation BRAF and how does it effect the cell
v600E
constitutive activation and unregulated cell proliferation
what is B-RAF
Serine-threonine kinase in the RAS/RAF/MEK/ERK signaling pathway commonly activated in human cancer
What is vemurafenib
small molecule inhibitor of the V600E variant
