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IHO Week 4 > Antimitotics, Immune modulators, drugs that interfere with protein function, and differentiating agents > Flashcards

Antimitotics, Immune modulators, drugs that interfere with protein function, and differentiating agents Flashcards

1
Q

What are the three chemical types of antimitotics?

A
  1. vinca alkaloids
  2. taxanes
  3. epilone
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2
Q

What are the three vinca alkaloids we know/

A

vincrinstine, vinblastine, vinorelbine

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3
Q

What are the three taxels we know?

A

Paclitaxel, Cabazitaxel, and Docetaxel

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4
Q

What’s the one epilone we know?

A

ixabepilone

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5
Q

What’s the mechanism of action for the vinca alkaloids?

A

They bind to tubuling at the forming end of microtubules and terminate spindle assembly

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6
Q

How does resistance develop against the vinca alkaloids/

A

decreased accumulation via increased P-glyc (MDR - natural products)
changes in target proteins: mutations to tubulin

note: cross reactivity among vinca alkaloids is not absolute

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7
Q

What are the two general side effects caused by the vinca alkaloids? Which is worse: vinblastine or vincristine?

A

bone marrow supression and neurotoxicity

vinblastine = bone marrow suppression
vincristine = neurotoxicity
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8
Q

How does the neurotoxicity present? Why does it occur?

A

Occurs because microtubules are necessaryf or axonal transport

present with loss of reflexes, constipation, paralytic ileus, orthostatic hypotension, and sensory paresthesias

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9
Q

What neurotoxicity sign is actually used as an indication of sufficient dose for vincristine?

A

suppression of DTRs (but decrease dose it this is followed by severe paresthesias and mild to moderate sensory loss)

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10
Q

What’s the mechanism of action fot he taxanes and how does it differ from that of the vinca alkaloids?

A

They also bind to tubulin, but unlike the vinca alkaloids, they enhance and stabilize the spindle assembly (which means they can’t continue through mitosis)

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11
Q

How does resistance develop for the taxanes?

A

decreased accumulation via increased P glycoprotein expression (MDR)

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12
Q

There is extensive elimination and metabolism of the taxanes via what process?

A

CYP 450 metabolism and hepatobiliary excretion (so liver function is critical)

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13
Q

What’s the main worrisome side effect of the taxanes?

A

hypersensitivity reactions (but also BMS, peripheral neuropathy, N/V, hypotension and arrhythmias)

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14
Q

Why is ixabepilone an excellent option in a patient with breast cancer who has failed anthracycline antibiotics and taxane treatments?

A

It’s not a natural product and therefore doesn’t produce multi-drug resistance unlike the others!

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15
Q

What’s the mechanism of action for ixabepilon?

A

similar to palitaxel - it’s an antibiotic that binds to tubulin and enhances and stabilizes spindle assembly

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16
Q

What is ixabepilone often used in conjunction with?

A

capecitabine (for metastatic breast cancer)

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17
Q

What are the three general classes of drugs that target the immun system for antineoplastic therapy?

A
  1. immunosupressive agents
  2. immune system stimulants
  3. hematopoietic factors (supporting agents)
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18
Q

What are the three general types of immunosuppressive agents?

A
  1. glucocorticoides
  2. antibiotics
  3. antibodies
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19
Q

What are two glucocorticoids used for treatment of cancer?

A

dexatheasone and predisone

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20
Q

What’s the general mechanism of action for the glucocorticoids?

A
  1. interfere with the concentration, distribution and function of leukocytes (increases concentration of neutrophils but decrease everything else basically)
  2. end result is decrease in cytokine release - like IL-2 and TNF-alpha
  3. Decreases size of lymph nodes and spleen
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21
Q

What’s the caveat to using the glucocorticoids? Aka…what’s necessary in the tumor cells for these to work?

A

they need to express the requisit receptors - so they’ll only work in prednisone-sensitive lymphomas

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22
Q

How are the glucocorticoids dosed for cancer treatment in comparison to their other uses?

A

they’re used in much higher doses using a “pulse’ regimen

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23
Q

What are 4 antibiotics that are used for immunosuppression? WHen are they used?

A

cyclosporine and tacrolimus (anti-rejection post bone marrow transplant)

Everolimus and temsirolimus (angiogenesis inhibitors)

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24
Q

What’s the mechanism of action for cyclosporine and tacrolimus?

A

bind to cytoplasmic proteins and inhibit calcineurin, which is necessary for activation of NFAT - a T cell-specific transcription factor involved in the sysntehsis of interleukins (so you get a decrease in IL-2)

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25
Q

What cytoplasmic protein is bound by cyclocporine to inhibit calcineurin? Tacrolimus?

A 
Cyclosporine = cyclophilin
Tacrolimus = FK-binding protein
26
Q

How does everolimus and temsirolimus work as angiogenesis inhibitors?

A

They inhibit mTOR, which is an intracellular signaling molecules that increases cell division and angiogenesis

27
Q

What is the beauty of using antibodies for antineoplastics?

A

they’re designed to target specific aspects of cancer cells and then selectively recruit the immune system to destroy the cacner cells

28
Q

What are some targets that we have designed antibodies for?

A

various CDs: CD20 in NHL and CD52- in B-CLL

surface proteins overexpressed in cancers: HER2, VEGF, EGFR

29
Q

What are the three antibodies we have to target CD20 in NHL?

A

Rituximab
Ibritumomab
Tositumomab

30
Q

Denileukin Diftitux is actually a fusion protein, not an antibody, what are the fused parts?

A

diptheria toxin fused to IL-2

31
Q

What does Denileukin Diftitux inactivate in order to inhibit protein translation? In cells expressing what?

A

EF2 (elongation factor 2)

in cells expressing IL-2 receptors

32
Q

What are the toxicities common to all the antibodies and fusion proteins used to modulate the immune system?

A
  1. influsion reactions
  2. hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis
  3. infections (esp reactive TB)
33
Q

What’s the specific toxicity for Alemtuzumab?

A

cough and chest tightness

34
Q

How does resistance arise to the antibodies and fusion proteins tha tmodulate the immune system?

A

changes in target proteins that prevent the antibody from recognizing its antigen

35
Q

How are the antibodies administered?long or short half lifes?

A

IV - super long half lives

36
Q

What three cytokines do we use as immunostimulants for treating cancer?

A

interleukin 2
interferon alpha
TNF alpha

37
Q

Are the cytokines cytotoxic by themselves?

A

No - they recruit immune cells to do the actual killing

38
Q

IL-2 can be used along or with what?

A

IL-2 stimulated autologous lymphocytes = lymphkine activated killer (LAK) cells

39
Q

What are the severe toxicities of IL-?

A

thrombocytopenia, shock, respiratory distress, coma and fatal hypotension

40
Q

What are the thre emechanisms for anti-tumor activity with INF-alpha?

A
  1. decreases production of FGF - an angiogenic
  2. inhibition of cell division (of both normal and tumor cells unfortunately)
  3. increases class 1 MHC expression on tumor cells so you can have increased activity of the CTLs against the tumor cells
41
Q

How does TNF alpha work?

A

It’s similar to IL-1 in terms of actins: you get fibroblast proliferation, chemokine induction and T and B cell activation

in general, causes a decrease in the rate of proliferation of tumor cells while sparing normal cells

42
Q

How does TNF alpha have to be administered?

A

intra-arterial because of extreme short half life

43
Q

WHat’s the toxicity to worry about for TNF_alpha?

A

severe dose-limiting toxicity is malaise, flue-like symptoms and hemorrhagic necrosis

44
Q

What are 5 tyrosine kinases that we target with drugs that interfere with protein function?

A

BCR-ABL
EGFR
HER2
PDGF-R, VEG-R

45
Q

What are the three drugs that target BCR-ABL for treatment of CML?

A

dasatinib
imatinib
nilotinib

46
Q

In addition to BCR-ABL targeting for dasatinib, and imatinib, and nilotinib…what else can they target?

A

c-kit (in GIST treatment)

47
Q

What two drugs do we have to target HER2 in breast cancer?

A

lapatinib

trastuzumab

48
Q

What are the 5 drugs we have to target EGFR?

A 
Cetuximab
erlotinib
gefitinib
lapatinib
panitumumab
49
Q

What three drugs do we have to target PDGF-R and VEGF-R?

A

pazopanib
sorafenib
sunitinib

50
Q

Why do the signal transduction inhibitors generally have fewer side effects than conventional therapies?

A

They are targeted twoards a specific defect of a particular cancer

51
Q

THe mechanism of the drugs that target EGFR differ slightly. WHat’s the emchanism for cetuximab/panitumumab?

A

they’re monoclonal antibodies directed against EGFR

52
Q

THe mechanism of the drugs that target EGFR differ slightly. What’s the mechanism for erlotinib and gefitinib?

A

they’re competitive antagonists of the ATP-binding site of EGFR

53
Q

THe mechanism of the drugs that target EGFR differ slightly. What’s the mechanism of lapatinib?

A

it’s a competitive antagonist of the ATP-binding site of EGFR and HER2 (so it’s a dual inhibitor)

54
Q

While cetuximab and penitumumab have the side effects that are common to antibodies, what are the unique toxicities?

A

skin: rash, photosensitivity, necrotizing fascitis

lung; interstitial lung disease

55
Q

How does L-asparaginase work as an anti-cancer treatment?

A

Cells need asparagine for protein synthesis. Normally, cells are able to turn aspartate into asparagine with asparagine synthase

In the extracellular space, asparagine is converted back to aspartate with L-asparaginase

Cancer cells sometimes lack asparagine synthase, so if you give L-asparaginase, all the asparagine outside the cell will be converted to aspartate and the cancer cell won’t be able to use it

56
Q

L-asparaginase is often given with methotrexate. In what order?

A

MTX has to be given first - it gives you synergistic cytotoxicity due to synchrony

If you give L-asp first, the methotrexate cytoxocity is reduced because the MTC cell kill is dependent upon synthesis of the enzymes necessary for DNA syntheis like DHFR and thymidylate synthase, or which the cell needs asparagine

57
Q

What’s the mechanism of action for Bortezomib?

A

It’s a reversible inhibitor of the 26S proteosome, which degrades ubiquinated proteins

this means the cancer cells lose protein cellular homeostasis, triggering apoptosis

58
Q

What do many cancers do in terms of HCADs?

A

They overexpress or aberrently recruit HDACs

these HDACs then deacetylate chromatin, resulting in more condensed chromatin structure and decreased transcription - leads to tumor suppressor gene silencing

59
Q

What drug do we use as an HDAC inhibitor to treat cancer?

A

vorinostat

60
Q

What are three differentiating agents we know?

A

tretinoin
arsenic trioxide
bexarotene

IHO Week 4 (15 decks)

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