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Oncology > Antimetabolites > Flashcards

Antimetabolites Flashcards

0
Q

Antifolates (2)

A

Methotrexate

Pemetrexed

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1
Q

Pyrimidine antagonists (2)

A

Fluorouracil

Capecitabine

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2
Q

Purine antagonists (2)

A

Mercaptipurine

Thioguanine

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3
Q

DNA polymerase/ DNA chain elongation inhibitors (5)

A

Cytarabine, Gemcitabine

Fludarabine, Cladribine, Clofarabine

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4
Q

Miscellaneous Antimetabolites (2)

A

Pentostatin

Hydroxyurea

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5
Q

THF

A

Tetrahydrofolate-> regenerated from dihydrofolate + dihydrofolate reductase
Active form of folic acid

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6
Q

N5, N10-methylene THF

A

Analog of tetrahydrofolate
*Co-factor to the thymidylate synthase *enzyme: rxn converts *substrate, deoxyuridine monophosphate (dUMP) to deoxythymine monophosphate (dTMP) and dihydrofolate

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7
Q

Nucleotides must be in what form to be inserted into DNA?

A

Triphosphate

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8
Q

Ternary complex

A

Enzyme+ substrate+ Co-factor

Thymidylate synthase+ dUMP+ N5,N10 methylene THF

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9
Q

5-Fluorouracil

Pyrimidine antagonist

A

PRODRUG: 5-fluoro dUMP is active form
5-FdUMP is false substrate that covalently binds to enzyme, thymidylate synthase preventing regeneration of THF. Ternary complex is formed
Toxicity:* stomatitis, esophagitis, GI ulceration, myelosuppression, hand and foot syndrome *

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10
Q

Ribonucleotide reductase

A

Enzyme responsible for 2’ reduction to a deoxyribose sugar

*Enzyme ONLY does 2’ reduction when nucleotide is in DIphosphate form

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11
Q

5-FU is catabalized by…

A 
Dihydropyrimidine Dehydrogenase (DPD)
Enzyme has polymorphisms
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12
Q

Leucovorin + 5-FU

A

Increases binding of 5-FU to thymidylate synthase

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13
Q

Capecitabine

Pyrimidine antagonist

A

PRODRUG of 5-FU: 5-fluoro dUMP is active form
Activating enzyme is *thymidine phosphorylase (removes ribose after removing carbonmate) **enzyme is upregulated in cancer cells
Toxicity: *severe diarrhea *hand and foot syndrome, myelosuppression, n/v

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14
Q

Resistance mechanisms to pyrimidine antagonists

A
  1. Loss or decreased activity of activating enzymes
  2. Increased expression or mutation of thymidylate synthase
  3. High levels of degradation enzymes
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15
Q

Methotrexate

Antifolate

A

MOA: pseudo irreversible inhibition of DHFR directly
Indirect inhibition of thymidylate synthase bc co factor is not regenerated ultimately inhibiting formation of dTMP
Inhibition of GAR transformylase involved in purine synthesis
*Toxicity: myelosuppression, mucositis, ulcerative stomatitis *
Maintain urine pH at 6.5 to keep drug ionized for better excretion. Unionized leads to crystalluria

16
Q

Leucovorin + methotrexate

A

Generates folate co-factors for healthy cells. Rescues normal cells

17
Q

Pemetrexed

Antifolate

A

MOA: inhibition of DHFR, * thymidylate synthase, *GAR transformylase
Toxicity: same as MTX; myelosuppression, mucositis, ulcerative stomatitis *
Supplement w/ B12 and folic acid instead of leucovorin for cell rescue

18
Q

Resistance mechanisms to antifolates

A
  1. Impaired uptake
  2. Enhanced efflux
  3. Altered DHFR
  4. Increased concentration to DHFR
  5. Decreased polyglutamation metabolite (drug will not get trapped in cell)
19
Q

Mercaptopurine, Thioguanine

Purine antagonist

A

MOA inhibit rate limiting enzyme in purine synthesis (amidophosphoribosyl transferase)
PRODRUGS
*activating enzyme: hypoxanthine guanine phosphoribosyl transferase HGPRT
*inactivating enzyme is TPMT (polymorphisms)
*Hypoxanthine oxidase competes w/ TPMT
Drugs can cause tumor lysis syndrome and hyperuricemia

20
Q

Allopurinol

A

Inhibits activity of xanthine oxidase and keeps purine antagonists as xanthine and hypoxanthine. Prevents conversion to uric acid

21
Q

Resistance mechanisms to purine antagonists

A
  1. Deficiency in HGPRT
22
Q

Resistance mechanisms to DNA polymerase/ DNA chain elongation inhibitors

A
  1. Mutations in deoxy cytosine kinase

2. Loss of functional nucleoside transporter proteins

23
Q

Hydroxyurea

Miscellaneous Antimetabolite

A

*MOA: inhibition of ribonucleotide reductase (enzyme converts ribose into deoxyribose when nucleotide is in Diphosphate form *
Broad anti tumor activity bc ALL nucleotides must be converted to deoxy form

Oncology (5 decks)

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