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7361 Hem/Onc Block 1 > Antimetabolites > Flashcards

Antimetabolites Flashcards

1
Q

How do antimetabolites work?

A

inhibit synthesis of nucleotides that make up components of DNA

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2
Q

Most of the antimetabolites cell killings happen occurs during which phase of the cell cycle?

A

S phase

pyrimidines, cytidine, purines, antifolates

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3
Q

4 antimetabolite drug classes:

A
  • pyrimidines (5-FU, capecitabine)
  • cytidine (cytarabine, gemcitabine, azacytidine)
  • purines (mercaptopurine, fludarabine, cladribine)
  • antifolates (MTX, pemetrexed, pralatrexate)
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4
Q

Which antimetabolite is a prodrug that is metabolically converted to 5-FU?

A

capecitabine

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5
Q

Which group in the pyrimidine antimetabolite drugs holds the key to its cytotoxicity?

A

5-fluoro group

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6
Q

What is the active species of 5fluorouracil?

A

5-F-dUMP

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7
Q

How do pyrimidine antimetabolite drugs work?

A

inhibit thymidylate synthase; w/o dTMP DNA will fragment and the cell dies

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8
Q

Breakdown of ternary complex requires what?

A

abstraction of proton by an amine in thymidylate synthase

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9
Q

How does 5-F-dUMP inhibit the regeneration of thymidylate synthase?

A

no hydrogen to abstract in the ternary complex, so it can’t breakdown; thus no cofactor is release and thymidylate synthase is not regenerated

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10
Q

5-FU is inactivated by what enzyme?

A

dihydropyrimidine de-hydrogenase (DPD)

found in liver, intestinal mucosa, tumor cells

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11
Q

Pts deficient in what enzyme are at risk of serious toxicity?

A

DPD

DPD is polymorphic

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12
Q

Pts of what ethnicity are 3x as likely to have DPD deficiency?

A

African Americans

AA women 3x higher incidence than AA men

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13
Q

Addition of what enhances response to 5-FU?

A

leucovorin (exogenous folate; N5 formyl tetrahydrofolate)

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14
Q

What disorder occurs more frequently with capecitabine than 5-FU?

A

hand foot syndrome

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15
Q

Capecitabine inhibits what CYP?

A

2C9

can have significant DDIs with warfarin and phenytoin

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16
Q

How do antifolaxe drugs work?

A

inhibit dihydrofolate reductase (DHFR)

prevents DHFR from being reduced to methylene tetrahydrofolate cofactor

results in feedback inhibition of thymidylate synthase

17
Q

Does methotrexate have good CNS penetration?

A

no - minimal with CSF concentrations being only 3% of systemic

high doses with long infusions or intrathecal dosing required

18
Q

What is used for rescue Tx of MTX toxicity?

A

leucovorin

19
Q

Which cytidine antimetabolite drugs are incorporated into DNA to produce their cytotoxic effects?

A

All of them

cytarabine, gemcitabine, azacitidine

20
Q

What must happen to cytidine antimetabolite drugs for them to have activity?

A

must be biotransformed to their triphosphate derivatives

cytarabine, gemcitabine, azacitidine

21
Q

Loss of what enzyme is the primary mechanism of resistance to cytarabine in AML?

A

deoxycytidine kinase

22
Q

Active triphosphate forms of what two cytidine antimetabolite drugs can be mistakenly incorporated into the growing DNA chain?

A

cytarabine
gemcitabine

inhibits DNA polymerase and blocks further chain elongation

23
Q

What happens to the sugar ring when cytarabine/gemcitabine are incorporated into DNA chain?

A

hinders rotation of attached nucleobase, and interferes with base pairing

24
Q

Intrathecal dosing of what form of cytarabine is used for Tx of lymphomatous meningitis?

A

depot liposomal formulation (DepoCyt)

sustained CSF release

25
Q

How long are cytotoxic drug levels elevated following intrathecal administration of DepoCyt?

A

2 weeks

26
Q

What is the most important antimetabolite drug used in the Tx of acute myeloid leukemia (AML)

A

cytarabine

27
Q

What is the main urinary elimination product of gemcitabine?

A

difluorodeoxyuridine (dFdU)

accumulates in pts with renal dysfunction

28
Q

Which cytidine antimetabolite drug is a potent radio sensitizer and should not be used in radiotherapy?

A

gemcitabine

should not be used with radiotherapy except in close monitored clinical trials

29
Q

The cytidine antimetabolite drugs azacitidine and decitabine covalently bind to what enzyme ?

A

DNA methyltransferase

DNA methyltransferases are a family of enzymes that catalyze the transfer of a methyl group to DNA

30
Q

What do DNA methyltransferases do?

A

catalyze the transfer of a methyl group to DNA

31
Q

3 purine antimetabolite drugs:

A

mercaptopurine
fludarabine
cladribine

32
Q

Which two purine antimetabolite drugs have similar MOA to cytarabine/gemcitabine?

A

fludarabine
cladribine

used to Tx CLL and low grade lymphomas

33
Q

Which purine antimetabolite drug is rapidly converted to a ribonucleotide that inhibits the biosynthesis of adenosine monophosphate (AMP) and guanosine monophosphate (GMP)?

A

mercaptopurine

34
Q

What step does mercaptopurine inhibit?

A

conversion of PRPP to PRA by the enzyme Tase

this is the initial and rate limiting step in de novo biosynthesis of purine nucleotides

35
Q

Conversion of mercaptopurine to ___, the active inhibitor of Tase is accomplished in a single step by the enzyme HGPRT.

A

T-IMP

this is the active form of mercaptopurine; it is a prodrug

36
Q

Poor metabolizers of what are at risk of fatal myelosuppression wit mercaptopurine?

A

TPMT

generate more active metabolite T-IMP

37
Q

What is administered with mercaptopurine to increase its duration and anticancer activity?

A

allopurinol

38
Q

What should be assessed before starting mercaptopurine therapy?

A

TPMT genotype

10-15 fold reduced dose and vigilant WBC monitoring is required in TPMT poor metabolizers

7361 Hem/Onc Block 1 (9 decks)

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