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5224 > Lecture 4 Antimetabolites > Flashcards

Lecture 4 Antimetabolites Flashcards

1
Q

pyrimidines

A

cytosine
thymine
uracil

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2
Q

purines

A

adenine

guanine

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3
Q

nucleosides

A

ribose = RNA
deoxyribose = DNA
purines change to -osine: adenosine, guanosine
pyrimidines change to - idine: uridine, thymidine, and cytidine

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4
Q

AMP

A

adenosine monophosphate

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5
Q

CDP

A

cytidine diphosphate

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6
Q

dGTP

A

deoxy-guanosine triphosphate

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7
Q

dTTP

A

deoxy-thymidine triphosphate

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8
Q

cAMP

A

3-5 cyclic adenosine monophosphate

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9
Q

nucleotides

A

adding one or more phosphates to the sugar portion of a nucleoside results in a nucleotide

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10
Q

antimetabolite

A

similar in structure to native molecules required for normal biochemical rxns, yet slightly different to interfere with normal function of cells

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11
Q

antimetabolites are analogues of

A

vitamins –> coenzymes

nitrogenous bases, nucleosides, adn nucleotides

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12
Q

antimetabolite general MOA

A
  1. interfere with production of nucleic acids by:
    - inhibiting key enzymes for nucleotide synthesis
    - substituting normal purines or pyrimidines
  2. antimetabolites inhibit DNA and RNA synthesis
  3. antimetabolites inhibit cell growth and proliferation
    - usually cell-cycle S phase dependent
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13
Q

antimetabolite examples

A

folate antagonists
pyrimidine antagonists
purine antagonists

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14
Q

Folate antagonists

A

antifolate
methotrexate (MTX, Trexall)
pemetrexed (Alimta)

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15
Q

Folic acid

A

B9

essential for cell growth and fetal development -> low folic acid can lead to neural tube defects

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16
Q

What is folic acid reduced to

A 
tetrahydrofolate (FH4 active) by
dihydrofolate reductase (DHFR)
17
Q

What is FH4

A

coenzyme for the biosynthesis of purines and in the conversion od dUMP to dTMP

18
Q

Methotrexate

A

MTX, analogue of folic acid
most widely used antifolate in cancer chemotx
activity against wide range of malignancies, including solid tumors and hematologic

19
Q

What does MTX inhibit

A

dihydrofolate reductase (DHFR) -> prevents synthesis of FH4 -> crucial enzyme required for DNA synthesis and therefore exerts its effect on the S phase of the cell cycle.

20
Q

What reverses methotrexate

A

leucovorin (reduced folate)

cells during S phase most sensitive

21
Q

MOA of 5-fluorouracil (5-FU)

A
  1. 5-FU is ribosylated and phosphorylated -> nucleotide analogs
  2. 5-FUTP (instead of UTP) is incorportated into RNA -> inhibition of RNA processing
  3. 5-FdUMP inhibits irreversibly thymidylated syntase -> decrease dTMP -> decrease DNA synthesis
22
Q

Combo leucovorin with 5-FU

A
  • FH4 acts as a coenzyme for TS. In the presence of the fake substrate, it won’t work
  • when given with 5-FU or capecitabine, it allows 5-FU to form a more stable bond to TS
  • inhibition of TS in enhanced
    cytotoxic effects of 5-FU are enhanced
  • Leucovorin allows TS To bind more tightly so when the TS binds 5-FU active metabolite, it allows the 5-FU to be more strongly inhibitory
23
Q

What is TS

A

Thymidylate synthetase

24
Q

MOA of 5-FU

A

LEUCOVORIN IS COENZYME TO TS -> BINDS AND ENHANCES BINDING TO 5-FU -> 5-FU WE WANT TO BIND TO MAKE TS STOP MAKING DNA SYNTHESIS (BLOCKS ENZYME LONGER) -> NO LONGER MAKING dTMP, SO NO DNA SYNTHESIS

25
Q

MOA of capecitabine/Xeloda

A

can be taken orally unlike 5-FU
taken as 5-FU + X + Y
metabolized to 5-FU-X in liver, then metabolized in tumor tissue to 5-FU
highly selective analog

26
Q

Cytarabine

A

analog of cytidine or deoxycytidine (nucleoside analogues)

27
Q

Structure of cytarabine

A 
AraC (cytarabine arabinoside)
difference in sugar
only for leukemias and lymphomas 
effective when combined with idareubicin 
cell cycle S phase specific
28
Q

Cytarabine MOA

A

active metabolite at triphosphate stage –> AraCTP

  1. AraCTP is incorporated into DNA and RNA -> inhibits chain elongation and ligation
  2. AraCTP is a competitive inhibitor of DNA polymerase -> reduce DNA synthesis
29
Q

Gemcitabine

A

analog of cytidine or deoxycytidine

Nucleoside analog

30
Q

Gemcitabine application

A
  • structurally similar to cytarabine
  • Wider anti-tumor activity
  • S and G1/S cell cycle phase specific
31
Q

Gemcitabine MOA

A
  • Gemcitabine is phosphorylated to gemcitbine di (dDdCPD) and tri (dFdCTP) phosphate
    1. dFdCDP inhibits the ribonucleotide reductase -> decreases dCTP pool -> reduces DNA synthesis
    2. dFdCTP inhibits DNA polymerase -> decrease DNA synthesis and induces apoptosis
    3. dFdCTP is incorporated into DNA -> inhibits chain elongation and ligation
32
Q

substrates of ribonucleotide reductase

A

diphosphate forms: ADP, GDP, UDP, and CDP

33
Q

Toxicity of pyrimidine antagonist

A

5-FU: N/V, oral and GI ulceration, bone marrow depression
capecitabine: myelosupression, N/V (less than 5_FU)
Cytarabine: N/V, bone marrow depression, megaloblastosis, leukopenia thrombocytopenia
Gemcitabine

34
Q

Purine Antagonists

A

6-thioguanine
6-mercaptopurine
fludarabine phosphate

35
Q

MOA purine analogs

A

After ribosylation and phosphorylation  DNA incorporation.

DNA incorporation  inhibition of DNA synthesis.

36
Q

MOA 6-TG and 6-MP

A

6-Thioguanine and 6-Mercaptopurine are
analogs of Guanine (=O  -SH).
For childhood acute leukemias.
Triphosphate nucleotides formed from 6-MP and 6-TG  DNA incorporation  inhibition of DNA synthesis.

37
Q

Fludarabine phosphate

A

nucleotide analog

38
Q

MOA fludarabine

A
  • Fludarabine phosphate is first dephosphorylated (extracellular).
  • The intermediate is then phosphorylated (intracelluarly).
  • The triphosphate metabolite inhibits DNA polymerase; incorporated into DNA and RNA; diphosphate metabolite inhibits ribonucleotide reductase -> reduces DNA synthesis.
    For chronic lymphocytic leukemia (CLL)
39
Q

Purine Antagonist Toxicity

A

Thioguanin and Mercaptopurine: well tolerated, bone marrow suppresion at high doses and TPMT deficient pt
Fludarabine: myelosupression, neurotoxicity at high doses

5224 (9 decks)

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