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Principles of Medical Research > CML and Imatinib > Flashcards

CML and Imatinib Flashcards

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USMLE® Step 1 flashcards
1
Q

observational studies can only

A

identify patterns and suggest hypotheses

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2
Q

Imatinib ‘the wonder drug’

A

a type of biological therapy called a tyrosine kinase inhibitor. TK are proteins that cells use to signal to each other to grow (chemical messengers). Imatinib targets diff TK, depending on the types of cacncer

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3
Q

what has imatinib been used for

A

leukemia and rare stomach cancers

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4
Q

what does iamtinib target

A

tyrosine kinases- chemical messengers which cause growth

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5
Q

chronic myelogenous leukemia (CML)

A

a cancer of WBC. Characterised by and increase dan unrelated growth of myeloid cells in the bone marrow and accumulation of these in the blood

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6
Q

chronic phase of CML

A

3- years

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7
Q

chronic phase is followed by acute/blast phase which is

A

bad news

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8
Q

treatment of CML use to involve

A

arsenic

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9
Q

story starts in 1960

A

-genetic basis of cancer is not clear
-oncogenes are yet to be identified
-no such thing as TK
In 1960 investigators did not think that tumours were caused by genetic mutations

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10
Q

Nobel and Hungerford 1960

A

Noticed a small version of one of the small chromosomes, they thought it was props a Y. Only CML patients had it- cause or effect

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11
Q

Nowel and Hungerford ypothesis

A

a change in chromosomal structure causes CML

- The Philadelphia chromosome

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12
Q

the philadelphia chromosome

A

hypothesised to caused CML- when the ABL gene usually found on chr9 transacted to chr22

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13
Q

Janet Rowley 1973

A
  • see in 9 CML patients
  • not in other leukemias
  • first specific cancer translocation

hypothesis: translation causes CML

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14
Q

Link between CML and Ableson

A

Human ABLE gene normally on Chr9. Several groups showed theABL is transacted to chr22 to make the philadelphia chromosome

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15
Q

how does a drug get approved

A

1) idea
2) basic research
3) clinical trials- phase 1/11/111- once a disease target is identified, drugs are designed and tested.
4) regulatory approval- human trials are completed. FDA approval

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16
Q

what continues after drug approval

A

safety and efficacy evaluation

17
Q

process, simple

A

CML- observation- hypothesis- cure

18
Q

the Imatinib legacy

A
  • not all cancers are caused by transloacations- some are
  • CML approached lucked out single kinase
  • rational drug design can work
19
Q

Nowell, 1976

A

most neoplasms arise form a single cel origin and tumour progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublimes.

20
Q

tumour cell populations are

A

more genetically unstable than normal cells.

21
Q

patients may require

A

individual therapy.

22
Q

BCR-ABL codes for

A

a fusion protein - this is quite imprecise

23
Q

how would you find out the exact sequence of the fusion prteins

A

identify cDNA and sequence it- about this time ABL shown to be a TK

24
Q

what does the fusion protein do

A

insert plasmid containing BCR-ABL into cells

  • check to see if the cells are actually making it
  • see if it acts as a tyrosine kinase
25
Q

what should be diff between the control cells and BCR-ABL cells

A

BCR-ABL should divide much more quickly

- then tested in animals e.g. mice

26
Q

Dasatinib

A

Imatinib does not hit stem cells. If one stops imatinib CML comes back.
Dasatinib is active agains some resistant mutation- personalised medicine

27
Q

Ciba-Geigy

A

worked on developing a range of TK inhibitors

28
Q

Ciba-Geigy hypothesis

A

a TKI would cure CML

29
Q

how can you tell that imatinib is clearing BCR-ABL +ve cells in

A

do a clinical trial

30
Q

clinical trials- preclinical studies

A

-safety in primates

31
Q

phase 1

A
  • very small scale
  • toxicity- tolerate does and pharmacokinetics
  • can be healthy people or CML sufferers
  • dose is evaluated slowly escalated
  • side effects noted
32
Q

phase 1 imatinib trial

A

showed compete hematologic response 53/54 patients treated daily with 300mg

33
Q

phase 2

A
  • small scale
  • test for a biological response
  • optimum dose evaluated
  • someime an RCT- not alway
34
Q

phase 2 imatinib trial

A

showed haematological response and cytogenetic response

35
Q

phase 3

A

full RCT

  • huge sample size
  • lasting a long period of time

Principles of Medical Research (31 decks)

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