Anti-Cancer Agents 2 Flashcards Preview

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Flashcards in Anti-Cancer Agents 2 Deck (20)
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1
Q

What are the contraindications for classical chemotherapy agents?

A
  • Very advanced Disease
  • Existing bone marrow depression
  • Presence of active infection
2
Q

What are some limitations of classical chemotherapy agents?

A
  • most target cell proliferation but not invasion and metastasis
  • lack of selectivity - toxic effects on marrow etc.
  • lack of sensitivity
  • total elimination of tumor may not be possible
  • development of resistance
3
Q

How do hormone anti-cancer agents work?

A

they generally attack tumors derived from hormone sensitive tissue and can be hormone-dependent

hormone dependency related to presence of steroid receptors in tumour cells

4
Q

What are the three major ways that hormone related anti-tumor agents work?

A
  1. hormones with opposing actions (i.e- glucocorticoids inhibit lymphocyte proliferation)
  2. hormone antagonists- bind the receptor and block its normal action (i.e. tamoxifen = anti-estrogen, flutamide= anti-androgen)
  3. agents that inhibit synthesis of the relevant hormone (i.e aromatase inhibitors)
5
Q

What is Tamoxifen? Describe how Tamoxifen works

A

it is a selective estrogen receptor modulator (SERM)

it is an antagonist of the estrogen receptor in breast - but a partial agonist at some other sites (uterus and bone) - it competes with natural estrogens for binding to ER - effective in early and advanced Estrogen receptor positive breast cancer in both pre-and post- menopausal women

MOA= enters the cell by passive diffusion, binds to estrogen receptor - (the receptor can still bind the DNA but adapts a conformation that prevents the recruitment of cofactors) this inhibits transcription of estrogen responsive genes -does not readily dissociate interfering with the recylcing of receptors

6
Q

Describe how Tamoxifen has antagonist/agonist activity

A

ER contains 2 transcriptional activation domains (AF1 and AF2)

Tamoxifen blocks the effects of estrogen by competitively binding to the AF2 site thereby altering transactivation activities, but tamoxifen does not inhibit activity of AF1

AF2 is dominant in breast tissue - therefore Tamoxifen works as an antagonist in breast tissue

AF1 is more dominant in uterus and bone - so partial agonist activity of tamoxifen occurs

leads to increased risk of endometrial cancer, DVT and PE

7
Q

What is the precursor to estrogen?

A

Androgens - thereby we can inhibit the conversion of androgen to estrogen to reduce the proliferation of estrogen dependent cancers

8
Q

How do Aromatoase inhibitors work?

A

the aromatase enzyme is responsible for key steps in biosynthesis of estrogens

1) conversion of testosterone to estradiol in the ovary- predominant method for estrogen synthesis in premenopausal women
2) conversion of androstenodione to estrone in adipose tissue - predominant method for estrogen synthesis in postmenopausal women

*so aromatase inhibitors inhibit peripheral aromatization (conversion of androgens to estrogens)

9
Q

What is the consideration for pre-menopausal women with the use of Aromatase inhibitors?

A

-they must be combined with surgical or medical ovarian ablation b/c they have negative effects on working ovaries

10
Q

What are the classes of aromatase inhibitors?

A

1) steroid analogues of androsternodione like exemestane - irreversibly inhibits the aromatase enyzme
2) non-steroidal inhibitors - like anastrozole, letrozole - compete reversibly for the androstenodione binding site on aromatase enzyme.

11
Q

What is the relationship between HER2 and breast cancer?

A

Her2= human epidermal growth factor receptor 2

  • plays a role in transmission of signals that ensure controlled cell growth with regulated rate of division
  • excess HER2 protein leads to sustained activation, growth promoting signals are permanently transmitted to nucleus - results in uncontrolled growth and increased rate of division
  • HER2 overexpression by tumor cells found in 20% of women with breast cancer - approved for treatment of HER2 positive breast, stomach and esophagus cancers
12
Q

What is Trastuzumab? How does Trastuzumab work?

A

it is a monoclonal antibody directed against HER2 - blocks the receptor dimerizaiton - it also works by ADCCwhich flags the tumor for destruction by immune system

  • it inhibits proliferation of cancer cells which overexpress this receptors
13
Q

how do we test for HER2?

A
  1. take patient tumor sample
  2. use FISH - accurate but expensive I believe - so usually we test immunochemistry first
  3. test immuno chemistry - if 0= no therapy, if +1= no therapy, if +2 we use FISH to confirm, if +3 we immediately jump to therapy with herceptin
14
Q

why is Tyrosine Kinase targeted in cancer treatment?

A

many molecular pathways controlling malignant progression depend on expression of receptors or intermediate proteins with tyrosine kinase activity

Tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to tyrosine residues on effector proteins in a cell as a molecular on/off switch in many pathways controlling survival/angiogenesis or proliferation

15
Q

What is the association between Chronic myeloid leukaemia and the philadelphia chromosome?

A

95% of chronic myeloid leukaemia patients are positive for this translocation (philadelphia chromosome) which leads to a constitutively active tyrosine kinase - causing genomic instability and decreased regulation of transcription

16
Q

What is Imatinib? How does it work?

A
  • it is a selective tyrosine kinase inhibitor that targets Bcr/Abl

it is highly specific with few side effects

  • used to treat philedephia chromosome positive chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs)
  • resistance mutation can occur however

MOA= blocks ATP binding to BCR-ABL inhibiting its kinase activity. Substrates required for BCR-ABL function cannot be phosphorylated and subsequent cellular events are abrogated

17
Q

drugs ending in -tinib are what class of drugs?

A

they are tyrosine kinase inhibitors

i.e)

imatinib

Gefitinib

Erlotinib

Sunitinib

18
Q

By what mechanism do we prevent growth of new blood vessels in tumors?

A

Angiogenesis inhibitions - inhibits growth of new blood vessels in tumors and blocks the supply of oxygen and nutrients - prevents metastasis =

we can do this by blocking angiogenesis signalling cascade or by blocking endothelial cell proliferation

19
Q

How do we block angiogensis signalling pathways?

A
  • Small molecule receptor tyrosine kinase inhibitors - blocks VEGFRs
  • neutralising antibodies to grwoth factors - anti-VEGF - ibnds and neutrlizes vascular endothelial growth factor (VEGF) blocking its binding to VEGFR
20
Q

drugs ending in -MAB are what?

what does the xi, zu, mumab represent?

A

MAB= monoclonal antibodies

xi= chimeric (human/foreign)

zu = humanized antibody

mumab= fully human