Response To Chemotherapy Flashcards
Describe constitutional polymorphisms
Present since fertilisation and in every cell
Less tolerance for variation
Describe somatic mutations
Acquired as we age and only in individual cells
More tolerance for variation
What is the target for ‘older’ cancer drugs
Highly proliferation cells
Target DNA synthesis and are not tailored to specific mutations
Response affected by genetics
What is the target for ‘newer’ cancer drugs
Cancer cell only e.g genomic translocations, over-expressing oncogenes and phenotypic characteristics
What metabolises 5-FU
Dihydropyrimidine dehydrogenase (DPYD)
Describe the mechanism of action for 5-FU
Pyrimidine analogue incorporated into DNA and RNA = cell cycle arrest and apoptosis
Inhibits thymidylate synthase
Describe the anabolism of capecitabine
20% of the drug
Capecitabine -> 5-FU -> FUrd -> FUMP - > RNA
-> FdUrd -> FdUMP -> DNA
What is the role of FUrd
Incorporated into RNA
What is the role of FdURd
Suicide inhibitor of TS
Describe the catabolism of capecitabine
80% of the drug
Capecitabine -> 5-FU (via DYPD) -> FUH2 -> FUPA -> FBA (inactive)
What variants of DYPD have reduced activity
Asp949Val
HAPB3
What variants of DYPD have null activity
DYPD*2A - splicing defect
*13 - null allele
Describe the DYPD reduced activity variants
Approx 35% population
Intermediated metabolisers (30-70% of normal)
Reduce starting does by 50%
Describe the DYPD null activity variants
0.2% of general popualation
Poor metabolisers - increased risk for severe or fatal drug toxicity
No 5-FU dose safe in individuals
Describe the metabolism of 5-FU in DYPD null patients
90% excreted in urine compared to <20% in normal
Anti cancer efficacy + off target effects
Plasma half like increased from 13mins -> 3hrs
What metabolises irinotecan
UGT1A1
Describe the metabolism of irinotecan
Metabolised to SN-38 active form by carboxylesterase
Inactivated via conjugation to UGT1A1 and UGT1A7
= SN-38 glucuronide
Describe the anti-cancer activity of SN-38
Mediated by inhibitors of TOPO1
How can there be intestinal and bone marrow toxicity in patients after taking irinotecan
If patient has Gilberts syndrome die to reduced/absent UGT activity
UGT1A1*28
Describe the UGT1A1*28 allele
Common in Europeans
8-78% are poor metabolisers depending on ethnic background
Additional TA repeat in gene promoter
Affects transcription and protein expression
What is the UGT1A1 WT
*1 allele
6 TA repeats
8% toxicity
What other drug is affected by the UGT1A1*28 allele
Cytarabine
What metabolises thiopurines e.g 6-MP, azathioprine, 6-TG
Thiopurine methyltransferases (TPMT)
What is the mechanism of action for thiopurines
Direct incorporation into DNA/RNA
Inhibits de novo purine synthesis
Can cause toxicity
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
Describe how 6-TG has anti-cancer activity
6-TG -> 6-tGN -> Rac1 inhibiton + incorporation into DNA
= increased apoptosis
What genetic variants are there for TPMT activity
TMPT1/1 = WT
1/X = heterozygous defective
X/X = homozygous defective
What ethnicity has the highest frequency of TPMT polymorphism
European and British
How is TPMT activity related to TGN conc in patients
Inversely related
What inactivates thiopurines
Thiopurine methyltransferases (TPMT)
What are the inactive metabolites of 6-TG and 6-MP
6-TG = 6-methylTG
6-MP = 6-methylMP
What would happen is TMPT heterozygous/deficient patients are given a standard dose
Develop haematopoietic bone marrow toxicity
Dose adjustment is necessary
How can chemotherapy be based on tumour cell genotype and phenotype
Targeted specifically to tumour cells
Little to no effect on non-tumour cells
Describe chronic myeloid leukaemia CML
Defined by Ph chromosome T(9;22)
= encodes a fusion oncoprotein with constitutive ABL kinase activity
What drug has improved survival rate in CML patients
Imatinib
5 year = 90%
10 year = 84%
Other drugs
5 year = <71%
10 year = < 61%
How can tumour cells gain resistance to Imatinib
Acquire somatic mutation in Bcr-Abl kinase domain
Describe the Bcr-Abl mutation
Mediated at residue 215 which prevents hydrogen bonding in the ATP-binding pocket
= no critical drug binding
What drug is used to treat CD33 +tive AML
Gemtuzumab
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
What is a treatment for HER2 amplified cancer
Trastuzamab
Monoclonal antibody to HER2
What is the role of HER2 in cancers
Over expressed in 20% of breast cancers
Drives proliferation
Over-expression mediated via gene amplification
What is the most common mutation on B-RAF that leads to constitutive activation and unregulated cell proliferation
BRAF V600E
What is an inhibitor of the BRAF V600E variant
Vemurafenib
What is B-RAF
Serine-threonine kinase
In RAS/RAF/MEK/ERK in signalling pathway
What is Vemurafenib
Small molecule inhibitor of the V600E variant
What is the most common BRAF mutation and what doe sit related in
V600E
Constitutive activation and unregulated cell proliferation
What drug also is an inhibitor of the V600E variant
Dabrafenib
What drug acts on MEK in the MAP-kinase
Trametinib
What are new chemotherapy drugs based on
Individual therapy
E.g genetics, gene expression and protein expression profiling of tumours
