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Cancer Pharmacology > Haematological Malignancies (2) > Flashcards

Haematological Malignancies (2) Flashcards

1
Q

what is the normal WBC count?

A

~11

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2
Q

How does Chronic myeloid leukaemia occur?

A

c-ABL located on chromosome 9 is translocated to breakpoints on chromosome 22 in clustered relatively small region (BCR)

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3
Q

What does BCR-Abl induce?

A

Stronger tyrosine kinase activity

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4
Q

How do leukaemic cells induce cell division and proliferation?

A

Intregins are expressed on leukaemic cells -> Binds to stromal cells -> Stops normal cell division -> Integrins detach but leukaemic cells are still attached to stromal cells -> cell division and proliferation

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5
Q

What is the tyrosine kinase activity in BCR-Abl important for?

A

To be able to transform cells

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6
Q

What drug targets Abl and BCR-Abl?

A

Imatinib

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7
Q

What else does Imatinib target?

A

Tel-Abl
PDGFR
KIT

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8
Q

How does Imatinib work in CML?

A

It binds to the ATP binding pocket
BCR-Abl require the binding pocket to convert ATP to ADP and therefore phosphorylate the tyrosine kinase motif to activate BCR-Abl

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9
Q

How many people who have bone marrow transplants die due to treatment?

A

~20-30%

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10
Q

How long can symptoms of CML take? And why?

A

5 years due to the removal of the bone marrow

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11
Q

What is the survival rate at 10 years using imatinib?

A

83.3%

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12
Q

What factors can you monitor to see if a patient is improving with imatinib?

A 
Blood count (haematological)
Philadelphia chromosome (cytogenetic) 
BCR-Abl1 level (molecular level)
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13
Q

What is a complete response?

A

If you cannot detect any BCR-Abl

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14
Q

How do you predict if someone has a complete response and their life expectancy wont change?

A

Their blood count is restored
The philadelphia chromosome has been removed
BCR-Abl has been removed

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15
Q

What is a long term side effect of imatinib?

A

Fluid accumulation in the lungs (take take 3 years to present) - causes breathlessness

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16
Q

What are the side effects of imatinib?

A 
Hemorrhage 
Edema 
Nausea and vomiting 
Low blood count
Fever 
Diarrhea 
Skin rash 
Muscle cramps and bone pain 
Vascular obstruction 
Pleural effusion 
Pulmonary hypertension
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17
Q

What are the issue with imatinib?

A

Toxicity
Sub-optimal response
Disease re-emergence

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18
Q

Due to the issues with imatinib, what have been developed?

A

Second generation drugs

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19
Q

Give some examples of second generation drugs

A

Nilotinib
Dasatinib
Ponatinib

20
Q

How does resistance typically occur to imatinib?

A

due to mutations in the ATP binding site which imatinib binds to

21
Q

What is the best second generation drug and why?

A

Ponatinib

T315 mutations in CML - this drug is still able to bind

22
Q

Name a rare subset of AML

A

Acute promyelocytic leukaemia (APL)

23
Q

How many patients die at presentation of APL?

A

30%

24
Q

What is one of the main issue with APL?

A

Commonly get brain bleeds

25
Q

How is APL characterised?

A

By blood coagulation abnormalities

26
Q

What chromosomes are associated with APL?

A

Chromosome 15 and 17

27
Q

What gene is on chromosome 15?

A

PML

28
Q

what gene is on chromosome 17?

A

RARalpha

29
Q

What chromosome is formed in APL patients?

A

PML-RARalpha

30
Q

What does chemotherapy do to APL patients?

A

Increased bleeding and increases risk of early death

31
Q

What is the treatment for APL patients?

A

Vitamin A analogue, retinoic acid

32
Q

What is RARalpha?

A

A nucleur hormone receptor

33
Q

What does RARalpha form a heterodimer with?

A

Retinoid X Receptor (RXR)

34
Q

What does RARalpha/RXR bind?

A

Retinoic acid response elements (RAREs) in the promoter region of genes, including those regulating myeloid differentiation

35
Q

What silences genes?

A 
DNA methyltransferases 
Histone deacetylases (HDAC)
36
Q

What increases gene activity?

A

Histone acetyltransferases (HAT)

37
Q

What normally happens in the absence of retinoic acid?

A

RARalpha-RXR heterodimer recruits corepressors, including HDACs -> silence target gene expression

38
Q

What normally happens in the presence of retinoic acid?

A

RARalpha binds to retinoic acid -> conformational change in the RARalpha/RXR heterodimer -> release of the nucleur co-repressors and recruit coactivators -> increase gene expression

39
Q

What happens in PML-RARalpha?

A

It cannot response to physiological conditions of retinoic acid -> represses gene transcription -> causes t to stay as a primitive cell

40
Q

What are the effects of PML-RARalpha?

A

Alters the epigenetic landscape through histone deacetylation
Affects transcription of genes controlled by other nuclear factors
Stimulates the transcription of hypoxia-induced factors (pro-angiogenesis)
suppresses PML-nuclear body and p53 responses

41
Q

What is the effect of pharmacological all trans retinoic acid (ATRA) on APL?

A

Overcomes the suppressive effects of protein PML-RARalpha
Recruits histone demethylase
May involve proteolytic degradation of PML-RARalpha
Differentiation of leukaemic cells into mature granulocytes -> growth of normal bone marrow

42
Q

What is ATRA effective with?

A

chemotherapy

43
Q

What is the clinical outcome of APL?

A

90% remission and a high rate of cure with combined ATRA and reduced intensity chemotherapy

44
Q

What chemotherapy is used with ATRA?

A

Arsenic trioxide

45
Q

How does arsenic trioxide work?

A

Increases ROS -> Disulphide links in PML or PML-RARalpha and binding to arsenic -> forms nuclear matrix associated nuclear bodies by disulphide-linked multimers -> Sumoylation and degradation of PML-RARalpha
Can induce molecular remission

46
Q

What is the survival rate of ATRA and Arsenic trioxide?

A

97% at 5 years

47
Q

What are Bispecific T cell engager antibodies?

A

They have dual specificity for tumour antigen and CD3

Functionally replace the MHCI/peptide/TCR complex

Cancer Pharmacology (13 decks)

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