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The toxic life savers > Antimetabolites, Hydroxyurea, Elspar, HDACs > Flashcards

Antimetabolites, Hydroxyurea, Elspar, HDACs Flashcards

1
Q

T/F: Reduce the dose of hydroxyurea with renal disease?

A

True

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2
Q

T/F: Hydroxyurea does not cross the BBB?

A

False

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3
Q

Which chemotherapy does the following?

  1. inhibits ribonucleotide reductase
  2. inhibits conversion of ribonucleotides to dNTPs which are needed for DNA synthesis and repair
A

hydroxyurea

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4
Q

What cell cycle phase is hydroxyurea specific for?

A

S phase

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5
Q

What is the mechanism of resistance for hydroxyurea?

A

elevation of ribonucleotide reductase activity

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6
Q

Hydroxyurea enhances cytotoxicity of which other chemo drugs?

A

purine and pyrimidine analogs

5-FU- decreases dUMP pools

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7
Q

What is the MOA of L-aspariginase?

A

tumor cells lack asparagine synthetase and cannot synthesize asparagine which leads to decreased protein synthesis and apoptosis

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8
Q

Why do normal cells not die from L-aspariginase?

A

asparagine is not an essential AA and normal cells contain asparagine synthetase and can synthesize asparagine

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9
Q

What cell cycle dose Elspar have maximal effect?

A

G1

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10
Q

What is the MOR to Elspar?

A
  1. Upregulation of asparagine synthetase in tumor cells
  2. Neutralizing antibodies
  3. Defective induction of apoptosis
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11
Q

T/F: Elspar penetrates the BBB?

A

False, but it does deplete asparagine in the CSF

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12
Q

What drugs does Elspar have an interaction with and why?

A
  1. methotrexate- decreased toxicity due to inhibition of protein synthesis and prevention of entry into S-phase
  2. vincristine- increased toxicity due to decreased hepatic clearance
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13
Q

Which chemotherapeutics are drugs that interfere with normal cellular functions, particularly DNA synthesis?

A

antimetabolites

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14
Q

What phase of the cell cycle do antimetabolites work best in?

A

S phase

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15
Q

T/F: Antimetabolites efficacy depends on peak drug levels? Why is this?

A

False- depends on duration above a critical threshold
This means they may be more effective as an infusion with longer duration of exposure, more cells allowed to enter S phase

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16
Q

T/F: Antimetabolites do not directly interact with DNA.

A

True- due to this, they are not carcinogenic

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17
Q

What are the drugs that make up the antimetabolites?

Antifolates or folic acid analogs

A

methotrexate

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18
Q 
What are the drugs that make up the antimetabolites?
pyrimidine analogs (T, C, U)
A

5-FU
Capecitabine
Cystosar
Gemcitabine

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19
Q

What is the mechanism of action of methotrexate?

A

competitive inhibitor of dihydrofolate reductase (DHFR)

prevents formation of reduced folates (active form)

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20
Q

What are reduced folates and how are they reduced?

Why are reduced folates important in DNA synthesis?

A

Folic acid compounds are active as coenzymes only in a reduced form- they are converted from dihydrofolic acid (FH2) to tetrahydrofolic acid (FH4) using NADPH as an electron donor by DHFR

  1. transferring of methyl group to form purines
  2. converting dUMP to dTMP (catalyzed by thymidylate synthase)
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21
Q

What occurs to reduced folates when they cannot convert to their active form after methrotrexate inhibits dihydrofolate reductase?

A
  1. reduced folate is oxidized in this reaction
  2. need DHFR for reduction to its active form
  3. increased dUMPs leads to incorporation of U instead of T into DNA and DNA breaks
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22
Q

Methotrexate is metabolized via what mechanism?

A

polyglutamation

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23
Q

Optimal binding of methotrexate to DHFR depends on the presence or occurrence of what two things?

A

presence of NADPH and polyglutamated forms of methotrexate

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24
Q

What enzyme mediates the polyglutamation of methotrexate?

A

folypolyglutamyl synthetase (FPGS)

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25
Q

What is the primary transport mechanism for methotrexate into the cells?

A

reduced folate carrier system

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26
Q

Which transport system allows trasport of folates, including methotrexate into the CNS?

A

pH sensitive transport

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27
Q

What occurs with the depletion of dTMPs and purines by polyglutamated forms of methotrexate?

A

leads to decreased DNA synthesis–> DNA strand breaks–> S/G2 arrest –> apoptosis

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28
Q

What are the MOR for methotrexate?

A
  1. mutations in RFC or DHFR (methotrexate can’t bind to either)
  2. increased MRP-1 (2,3) and BCRP
  3. defects in polyglutamation
  4. increased DHFR concentrations
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29
Q

Does methotrexate cross the BBB?

A

yes, but only at very high doses

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30
Q

What drug is known to block methotrexate toxicity? Why?

A

L-asparaginase: decreases protein synthesis and prevention of cell entry into S-phase

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31
Q

Which drugs enhance methotrexate toxicity?

A

NSAIDs

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32
Q

Methotrexate inhibits purine synthesis and increases nucleotide formation, which increases activation if given before which two drugs?

A

5-FU

cytosar

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33
Q

Which is more important for methotrexate, drug concentration or duration of cell exposure?

A

duration of cell exposure

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34
Q

The presence of what two things would reduce the toxicity of methotrexate?

A
  1. presence of purine bases/nucleosides and thymidine

2. increased concentration of reduced folates

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35
Q

What is a drug the rescues patients from methotrexate induced cytotoxicity?

A

leucovorin (folinic acid)

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36
Q

What is thymidylate synthase?

A

converts dUMP to dTMP, which is then phosphorylated to thymidine triphosphate for DNA repair and synthesis

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37
Q

The conversion of dUMP to dTMP by thymidylate synthase requires the presence of what cofactor?

A

5, 10 methylene-tetrahydrofolate

38
Q

What is the MOA of thymidylate synthase inhibitors?

A

bind 5, 10 methylene-tetrahydrofolate

39
Q

What are the drugs that make up the direct thymidylate synthase inhibitors?

A

ralitrexed

premetrexed

40
Q

Which chemotherapy drug does the following?

  1. inhibits thymidylate synthase (TS) causing depletion of dTMPs and decreased DNA synthesis
  2. incorporated into DNA which triggers repair and strand breaks and apoptosis
  3. incorporated into RNA leading to rRNA/mRNA inhibition
A

5-FU

41
Q

Which cell cycle does 5-FU directly work in to inhibit TS and DNA synthesis?

What about the cell cycle for RNA inhibition?

A

S phase

cell cycle non-specific

42
Q

When 5-FU is phosphorylated after entering cells it becomes what form when incorporated into DNA vs. RNA vs. inhibiting TS?

A

DNA= 5-dUTP
RNA= 5-FUTP
inhibits TS= 5-FdUMP

43
Q

The metabolism and breakdown of 5-FU is mediated by what?

A

dihydropyrimidine dehyrogenase

44
Q

What is the MOR for 5-FU?

A
  1. decreased activity of activating enzymes
  2. increased nucleotide pool size
  3. overexpression of TS and decreased binding
45
Q

T/F: 5-FU does not cross the BBB.

A

False- it most certainly does

46
Q

5-FU is fatal in what species and due to what major adverse event?

A

cats- fatal neurotoxicty

47
Q

What is the neurotoxic and then fatal dose of 5-FU if ingested by a dog?

A

accidental ingestion of >20 mg/kg

lethal is >40 mg/kg

48
Q

What are the acute, intermediate, and delayed toxicites associated with oral overdose of 5-FU?

A

Acute signs develop 45-60 mins post ingestion = neurotoxicity (seizures, tremors), vomiting, diarrhea

Intermediate toxicity (24 hr post) = elevated liver enzymes

Delayed toxicity (4-7 days) = myelosuppression (pancytopenia)

49
Q

Which drug if administered before 5-FU can increase its toxicity by the following:
increasing the pool of folate cofactor (5, 10 MTHF) that compete with F-FdUMP and TS –> decreasing the dissociation rate–> potentiates TS inhibition?

A

leukovorin

50
Q

Which drug if administered before 5-FU can increase its toxicity by the following:
inhibiting purine synthesis and elevating cellular pools of phosphoribosyl phosphate–> increasing activation of 5-FU?

A

methotrexate

51
Q

Which drugs decrease 5-FU metabolism?

A

dihydropyrimidine dehyrogenase inhibitors

52
Q

T/F: 5-FU is a radiosensitizer?

A

True

53
Q

This drug inhibits orotate phosphoribosyltransferase, which normally activates 5-FU, and therefore decreases its toxicity?

A

Allopurinol

54
Q

Which chemotherapy drug does the following?

  1. incorporated into DNA causing loss of template function and chain elongation which will stall replication forks in active DNA synthesis
  2. activates ATR and chk1
A

Cytosar

55
Q

Which phase of the cell cycle is cytosar most active in?

A

S phase

56
Q

Cytosar is a competitive inhibitor of what enyzyme?

A

DNA polymerase (alpha > beta)

57
Q

How does cytosar enter the cell?

A

carrier mediated process

58
Q

T/F: Cytosar is a prodrug?

A

Yes

59
Q

What is the process of cytosar metabolism in order for it to become active within the cell? Name to 3 major enzymes

A

3 enzymes:
CdR kinase (rate limiting step), dCMP, NDP kinase
phosphorylated to ara-CTP

60
Q

T/F: Cytosar crosses the BBB?

A

True

61
Q

The main process of elimination of cytosar is through what in the liver, tissue, and plasma?

A

deamination

62
Q

What is the MOR of cytosar?

A
  1. decreased kinases
  2. increased deaminases
  3. decreased nucleoside transport into the cell
  4. increased dCTP pools (competes with ara-CTP)
  5. increased expression of antiapoptotic proteins
63
Q

Which drugs can cause increased drug toxicity to cytosar?

A

hydroxyruea

methotrexate

64
Q

Which drugs does cytosar increase toxicity in?

A

topo II inhibitors
alkylating agents
cisplatin

65
Q

Which chemotherapeutic inhibits ribonucelotide reductase leading to decreased DNA synthesis and DNA polymerase leading to inhibition of DNA repair?

A

gemcitabine

66
Q

What cell cycle is gemcitabine most specific for?

A

S phase

Also effective in other phases

67
Q

How is gemcitabine transported into the cell?

A

hENT transporter

*Metabolism is similar to cytosar

68
Q

What is the MOR for gemcitabine?

A
  1. decreased CdR kinase
  2. increased deaminase
  3. increased ribonucleotide reductase
  4. decrease nuceloside transport
69
Q

Why is gemcitabine synergistic with the platinums?

A
  1. inhibits NER which is responsbile for repair of bulky adducts created by platinum-DNA damage
  2. incorporation into DNA induces structural changes in DNA helix and increased adduct formation by platinums
70
Q

Why is gemcitabine a radiosensitizer?

Most pronounced if administered at what timeline before or after RT?

A
  1. Due to inhibition of ribonucleotide reductase and DNA polymerase
  2. RNR inhibition–> depletion of deoxyadenosine triphosphate (dATP) –> decreased DNA repair
  • Most pronounced if administered 24-60 hours prior to RT
  • Occurs at doses well below those used for cytotoxicity
  • Most evident in mismatch repair-deficient cells
71
Q

Why is gemcitabine not commonly used in vet med as a radiosensitizer?

A

Causes fairly severe toxicities in veterinary medicine (local tissue toxicity, narrow therapeutic window)

72
Q 
What are the drugs that make up the antimetabolites?
Purine analogs (A, G)
A

6-MP- guanine
6-TG- guanine
Azathioprine- guanine
Fludarabine- adenine

73
Q

Which purine metabolites have the following MOA?

  1. incorporation of metabolites in DNA and RNA which leads to apoptosis through MMR
  2. inhibits de novo purine synthesis
A

6-MP and azathioprine

74
Q

T/F: 6-MP is not cell cycle specific?

A

False- all antimetabolites are S phase specific, Duh!

75
Q

Which enzymes are responsible for 6-MP and azathioprine elimination from the body?

A

xanthine oxidase and TPMT

76
Q

What species is extra sensitive to 6MP and azathioprine?

A

cats b/c they have lower levels of TPMT

77
Q

Which chemotherapeutic works via incorporation of fraudulent nucleotides into DNA and RNA?

A

6-TG

78
Q

T/F: 6-TG has to be converted to 6-MP to become active?

A

False

79
Q

T/F: Azathioprine has to be converted to 6-MP to become active?

A

True

80
Q

Which chemotherapeutic has the following MOA?

  1. Prodrug of cPrPMEDAP, which is deaminated to yield 9-2-phosphonylmethoxyethyl (PMEG) (a guanine nucleotide analog).
  2. PMEG is dephosphorylated to the active metabolism, PMEGpp.
  3. PMEGpp induces cytotoxicity through inhibition of DNA polymerases alpha, delta, and epsilon–> inhibition of DNA synthesis and repair
A

Tanovea

81
Q

Which chemotherapeutics have the following MOA?

  1. remove acetyl groups from the NH2-terminal tails of histones
  2. upregulate expression of TSG
A

HDAC inhibitors

82
Q

Which chemotherapeutic has the following MOA?

  1. Oxidative cleavage of DNA initiated by hydrogen abstraction
  2. Occurs at thymine bases
  3. Causes both ss and dsDNA breaks; to a lesser extent affects RNA and protein synthesis
  4. Reduction of molecular O2 to superoxide or hydroxyl radicals, catalyzed by the drug-ferrous iron complex
A

Bleomycin

83
Q

Which drug has the following MOA?

  1. oral inhibitor of DNA methyltransferase 1 (DNMT1)
  2. treatment results in global decrease in DNA methylation and apoptosis in a canine T-cell LSA cell line
  3. dose dependent decrease in cell survival due to apoptosis
A

Zebularine

84
Q

What 2 potential problems could arise from the use of decitabine and 5-azacytidine?

A
  1. Could create genome-wide hypomethylation and tumorigenesis due to chromosome rearrangements
  2. Demethylation could also trigger the reactivation of genes promoting a more aggressive or metastatic phenotype
85
Q

T/F: 5-azacytidine is incorporated into both DNA and RNA and decitabine is only incorporated into DNA

A

True

86
Q

What enzyme attaches a methyl group to 5’ position of cytosine pyrimidine ring or number 6 nitrogen of the adenine purine ring?

A

DNMT

87
Q

Which nucleoside analogs are known to incorporate into DNA and inhibit DNMT activity?

A

5-azacytidine and 5-aza-deoxycitidine (decitabine)

88
Q

What are the rabacfosadine dermatopathies?

A

Package label: pruritic and erythemic lesions on the dorsum and exudation, crusting, erythema, and necrosis with epidermal sloughing on the ears, face, ventral neck, and forelimbs; otitis externa; pyoderma; excoriations; alopecia

• Cumulative AE, usually after 3+ treatments

89
Q

% dermatologic toxicity with Tanovea?

A

Originally, 37% when given daily or weekly. Still seems to be 25-34% at 21-day dosing, depending on the study

90
Q

Vorinostat and OSU-HDAC42 (AR42) have been evaluated in a variety of canine tumor cell lines and have what MOA ?

A

found to induce histone acetylation, inhibit tumor cell growth and induce apoptosis

91
Q
  1. Vorinostat and OSU-HDAC42 (AR42) effects which cell lines?
  2. The cell lines died how?
A
  1. Sensitive cell lines: T-cell LSA, MCT, OSA, histiocytic sarcoma
  2. Induction of apoptosis was indicated by caspase 3 cleavage and increases in cytoplasmic nucleosomes and the subG1 cell population
92
Q

Regarding a study looking at VPA and doxorubicin, answer these questions:
1. T/F: VPA enhanced the effects of doxorubicin in canine OSA cell lines, resulting in decreased proliferation and increased apoptosis?

  1. When should VPA be administered in relation to doxo?
  2. Did VPA increase toxicity or doxorubicin AUC, half-life, or clearance?
  3. What % of dogs with pulmonary metastatic OSA achieved durable SD
A
  1. True- Confirmed in xenograft model of canine OSA
  2. Can be administered 48 hr prior to doxorubicin at doses sufficient to enhance histone acetylation in tumor and peripheral blood mononuclear cells
    - 240mg/kg/day
  3. Did NOT increase toxicity or doxorubicin AUC, half-life, or clearance
  4. 33% (1 of 3 dogs) with pulmonary metastatic OSA achieved durable SD

The toxic life savers (4 decks)

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