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The toxic life savers > Topo inhibitors, Anthracyclines, Epipodophyllotoxins, Small molecule inhibitors, bisphosphonates > Flashcards

Topo inhibitors, Anthracyclines, Epipodophyllotoxins, Small molecule inhibitors, bisphosphonates Flashcards

1
Q

What are the topoisomerase I inhibitors?

A
  1. camptothecin
  2. topotecan
  3. irinotecan
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2
Q

What are the topoisomerase II inhibitors? (anthracyclines and anthracenediones)

A
  1. doxorubucin
  2. daunorubicin
  3. idarubicin
  4. epirubicin
  5. mitoxantrone
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3
Q

What are the topoisomerase II inhibitors? (epipodophyllotoxins)

A
  1. etoposide

2. teniposide

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4
Q

What is topoisomerase?

A
  1. nuclear enzymes that relax dsDNA

2. create transient breaks (nicks) to facilitate DNA unwinding for DNA replication and RNA transcription

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5
Q

What is the difference btw. topo I and II?

A
  1. topo I- creates ss nicks at the 3’ end

2. topo II- creates ds nicks at the 5’ end

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6
Q

What is the general mechanism of topo inhibitors?

A
  1. bind and stabilize DNA/topo cleavable complex which prevents ligations
  2. irreversible damage results when advancing replication fork encounters complex
  3. lethal ds breaks= cell death
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7
Q

What is the main mechanism of action of topo I inhibitors?

A
  1. stabilize the cleavable complex which is topo I bound to DNA at ssDNA break site
  2. interfere with: DNA replication, transcription, repair, chromosome condensation/separation
  3. lethal effects caused by interaction btw moving replication fork and drug
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8
Q

Are topo I inhibitors cell cycle specific, and if so, what cell cycle do they have the most effect on?

A

No they are not, but they are most effective in S phase

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9
Q

What is the enzyme and metabolite for metabolism of irinotecan?

A

activation by carboxyesterases–> becomes SN-38

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10
Q

What is the metabolic process for topotecan?

A

non-enzymatic hydrolysis and UGT glucuronidation

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11
Q

What is the mechanism of resistance for topo I inhibitors?

A
  1. alterations in topo I
  2. altered drug accumulation in cells
  3. alteration of cell response to topo I drugs
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12
Q

What are the acthracyclines made from?

A

steptomyces bacterium- anti-tumor antibiotics

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13
Q

What is the MOA of topo II inhibitors?

A
  1. binds topo II and prevents religation of dNA ds breaks
  2. DNA intercalation: inserts- btw base pairs perpendicular to long axis of helix (partial unwinding)
  3. inhibition of DNA helicases: dissociated ds DNA into ss DNA- inhibits strand separation and replication
  4. cell membrane damage
  5. stimulates apoptosis
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14
Q

Doxorubicin binds with high affinity to what portion of the DNA strand?

A

5’- TCA

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15
Q

Most DNA is in which form to protect it from DNA intercalation?

A

chromatin

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16
Q

What particular damage do anthracyclines (doxorubicin) cause to cell membranes?

A

binds phospholipids via iron chelation which alters membrane fluidity and makes cells susceptible to shear stress

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17
Q

From cell membrane damage, which pathway is activated by the anthracyclines?

A

sphingomyelin

formation of ceramide–> activates PKC –> activation of proapoptotic caspases –> apoptosis

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18
Q

What is the main mechanism of carditoxicity created by anthracyclines (doxorubicin)?

A

Creation of free radicals

  • quinone ring metabolized to semiquinone radical
  • formed by one electron reduction
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19
Q

The creation of free radicals by anthracyclines leads to what major cell damage?

A
  1. cell membrane damage
  2. DNA base damage
  3. mitochondrial membrane injury
  4. altered calcium sequestration
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20
Q

What are the mechanisms of resistance of anthracyclines?

A
  1. enhanced drug reflux by MDR1, MRP, BCRP
  2. altered topo II activiy
  3. alteration in ability of cell to undergo apoptosis
  4. loss of MMR genes/MMR deficiency- increased DNA repair
  5. increased cellular glutathione- reduces free radical formation
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21
Q

Doxorubicin cardiotoxicity correlates with AU or peak drug levels? Choose one.

A

peak drug levels

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22
Q

What particular mineral in the body becomes increased intracellularly from use with anthracyclines?

A

Iron

23
Q

Antrhracycles are powerful metal chelators and how does this occur and what damage does it lead to?

A

OH-quinone binds ferric iron (anthracycline- iron complex) leading to:

  1. iron mediated cell membrane damage (via oxidative destruction)
  2. oxidation critical sulfhydryl groups
  3. binding of DNA directly (different than intercalation)
24
Q

Iron plays a role in the formation of what damage within the cell after anthracycline administration?

A

free radical damage

25
Q

What are the 3 major steps for metabolism of the anthrcyclines?

A
  1. enzymatic conversion
  2. one-electron reduction–> free radical formation
  3. two-electron reduction–> forms unstable quinone methide and degrades to aglycone specides or inactive metabolite
26
Q

Which metabolism step for anthracylines (doxorubicin) decreases cytotoxicity but increases cardiotoxicity?

A

enzymatic conversion

  • hepatic aldo-ketoreductase family and carbonyl reductase in heart and liver
  • doxorubicin is converted to doxorubicinol (cardiotoxic)
27
Q

Why does doxorubicin cause a hypersenstivity reaction?

A

due to the release of histamine

28
Q

T/F: Doxorubicin can cause radiation recall?

A

True- it is a radiation sensitizer

29
Q

T/F: Doxorubicin is more toxic to cats than dogs?

A

True

30
Q

What are the oxidative mechanisms secondary to free radical formation that cause cardiotoxicity by doxorubicin?

A
  1. injury to the SR –> Ca release and inhibition of sequestration
  2. inhibition of NADH dehyrogenase
  3. lipid peroxide peroxidation
  4. oxidation of myoglobin
  5. iron delocalization
31
Q

What are the non-oxidative mechanisms secondary to free radical formation that cause cardiotoxicity by doxorubicin?

A
  1. inhibition of mitochondrial cytochrome oxidase
  2. direct oxidation of ryanodine receptor sulfhydryls
  3. down regulation of beta-adrenergic receptors
  4. inhibition of specific cardiac mRNAs for alpha-actin and troponin I
    5 directly toxic to cardiac progenitor cells
32
Q

Why is the heart a very sensitive organ to doxorubicin?

A
  1. low levels of cardiac catalase
  2. leaves glutathione peroxidase as only pathway for hydrogen peroxide detoxification
  3. glutathione peroxidase are very sensitive to free radical attack
  4. heart is rich in iron proteins which are capable of donating their metal to catalzye strong oxidant formation
33
Q

What is the MOA of dexrazoxane?

A
  1. iron chelator that can prevent cardiotoxicity
  2. Topo II inhibitor (therefore is chemotherapy in itself)
  3. requires activation by hydrolysis at physiologic pH within the cardiac myocytes
34
Q

What is doxil?

How is it different from doxo?

A

pegylated encapsulated doxorubicin

  • stays in blood longer, penetrates tumor better
  • limits distribution
  • less BM toxicity and cardiotoxicity
35
Q

What is the most specific toxicity of doxil? Explain the C.S. of this toxicity.

A

Palmar plantar dysthesia (PPDE) –> progressive accumulation of tender nodules, erythematous desquamation on palms and soles of feet

36
Q

Which drug is used to prevent PPDE caused by doxil?

A

Vitamin B6 (pyridoxine)- lowers the risk 4x

37
Q

What is the MOA of mitoxantrone?

A

DNA intercalation which inhibits DNA/RNA synthesis

38
Q

T/F: Mitoxantrone cannot be give intra-cavitary.

A

False

39
Q

T/F: Mitoxantrone is not cardiotoxic.

A

False- less cardiotoxic, but can still oxidize critical sulfhydryl groups on ryanodine receptors in the SR

40
Q

There is a synergism between the platinums and which epipodophyllotoxin?

A

etoposide

41
Q

T/F: Tenoposide and etoposide are radiosenstitizers?

A

True

42
Q

T/F: Tenoposide and etoposide must be dose reduced with hepatic disease only?

A

False- dose reduce with both hepatic and renal disease

43
Q

MOR of imatinib?

A
  1. Mutations in AA in BCR-ABL binding site
  2. Preventing BCR-ABL from achieving inactive conformation that is required for binding
  3. Gene amplification of BCR-ABL
  4. Drug efflux via Pgp or ABCG2
44
Q

Match the TKI to the appropriate targets:

Masitinib                      Kit
Imatinib                       PDGFRa/B
Sunitinib                      BCR-ABL 
Toceranib                    VEGFR1/2
Gefitnib                       B-RAF
Erlotinib                      CSF-1
Vemurafenib              Ret
                                    EGFR (ERBB1)
                                    Lyn
                                    Flt-3
                                    FGFR
A
  1. Masitinib= Kit, PDGFRa/B, Lyn
  2. Imatinib = Kit, PDGFRa/B, BCR-ABL
  3. Sunitinib = Kit, PDGFRa/B, VEGFR1/2, FGFR, CSF-1, Ret,
    Flt-3
  4. Toceranib = Kit, PDGFRa/B, VEGFR1, CSF-1, Ret, Flt-3
  5. Gefitnib = EGFR (ERBB1)
  6. Erlotinib = EGFR
  7. Vemurafenib = BRAF
45
Q

Match the MABs to the appropriate targets:

• Humanized CD20 mouse Ab+yttrium-90
Trastuzumab CD20
Bevacizumab HER2
VEGF
• Chimeric: EGFR
Rituximab
Cetuximab

• Radioimmunotherapy:
Ibritumomab tiuxetan

A

• Humanized
Trastuzumab = HER2
Bevacizumab = VEGF

• Chimeric:
Rituximab = CD20
Cetuximab = EGFR

• Radioimmunotherapy:
Ibritumomab tiuxetan = CD20 mouse Ab + yttrium-90 or indium-111

46
Q

Which drug might be able to reverse Pgp-mediated resistance?

A

tamoxifen

47
Q

Which drug has the following MOA?

synthetic antiestrogenic compound – mixed estrogen angonist/antagonist depending on location
o Selective estrogen receptor modular (SERM) – causes estrogen receptor to release its co-activators and bind co-repressors  blocks estrogen signaling

A

tamoxifen

48
Q

In bisphosphonates, which R group is responsible for:

  1. OH hydroxyapatite (Ca binding)
  2. potency
A
  1. R1: -OH hydroxyapatite (Ca binding)

2. R2: potency

49
Q

What is the MOA of amino bisphosphonates (pamidronate, zoledronate)?

A

Nitrogen-containing bisphosphonates (1) inhibit farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway and (2) decrease prenylation of essential GTP binding proteins (Ras, Rho)

50
Q

What is the main MOA of electrochemotherapy?

List two more MOA.

A
  1. to enhance the effectiveness of cytostatic drugs by increased intracellular drug accumulation, by cell membrane electropermeabilization (electroporation)
  2. tumor antivascular effect which results firstly in vascular lock, i.e., decreased blood flow within the tumor, and consequently the retention of cytostatics within it and secondly in a vascular disrupting action, i.e., direct killing of endothelial cells of small blood vessels leading to secondary tumor cell death
  3. activation of the immune system as ECT elicits an immune response by tumor antigen shedding in the tumor surroundings. The involvement of the immune system is crucial for the complete eradication of the tumor
51
Q

Electroporation causes an increased drug uptake of which two cytostatics, which are hydrophilic drugs with poor membrane permeability?

A

bleomycin and cisplatin

52
Q

What is the MOA of suramin?

A

polysulfonated napthylurea, which at noncytotoxic concentrations in vitro, increases tumor sensitivity to chemotherapy, including doxorubicin

Inhibits binding of growth factors (EGF, PDGF, TGF-B) to receptors

53
Q
  1. Which of the following is true regarding doxorubicin cytotoxicity?
    a. Anthracyclines can cause an overexpression of protein kinase C, which in turn causes decreased phosphorylation of topoisomerase II
    b. It can be cytotoxic without even entering the cell due to its multitude of cellular membrane activity
    c. In the heart, doxorubicin increases both AKT and ERK phosphorylation leading to cell death
    d. Downregulation of the expression of factors such as bcl-2 and bax in many tumors antagonizes the drive to apoptosis initiated by exposure to anthracyclines
A

b. It can be cytotoxic without even entering the cell due to its multitude of cellular membrane activity

Events occurring at the cell surface: doxorubicin alters the fluidity of both tumor cell plasma membranes and cardiac mitochondria; it binds avidly to phospholipids including cardiolipin, causes an up-regualtion of EGFR, inhibits transferrin reductase of the plasma membrane, induces iron-dependent protein oxidation in erythrocyte plasma membranes, and can therefore be cytotoxic without entering the cell

The toxic life savers (4 decks)

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