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therapeutics 864 - exam 1 > antimetabolites > Flashcards

antimetabolites Flashcards

1
Q

antimetabolites and antifolates target which phase of cell cycle

A

S

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2
Q

t/f antimetabolites are antitumor agents targeted at the biosynthesis or utilization of DNA and RNA precursors.

A

true, both DNA & RNA precursors

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3
Q

what toxicity is often dose-limiting for antimetabolites

A

myelosuppression

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4
Q

t/f Antimetabolites are typically analogs of naturally occurring metabolites.

A

true

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5
Q

t/f only a few antimetabolites require biotransformation to nucleotide analog (sugar and phosphate) to generate active species

A

false, most drugs require biotransformation

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6
Q

nomenclature review

rank these in order of increasing size
-nucleoside
-nucleobase
-nucleotide

A

base > side > tide (has phosphate & sugar)

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7
Q

Which bases are paired together in DNA?

A. Adenine with Cytosine, Thymine with Guanine
B. Cytosine with Guanine, Adenine with Thymine
C. Adenine with Guanine, Thymine with Cytosine

A

B. Cytosine with Guanine, Adenine with Thymine

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8
Q

why can’t nucleotides enter cells?

A

phosphate group/has a charge

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9
Q

Which two are the purines?

A. Adenine and Cytosine
B. Cytosine and Guanine
C. Adenine and Guanine
D. Thymine and Guanine
E. Thymine and Uracil

A

C. Adenine and Guanine

“Pure As Gold”
“Pyramids CUT”

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10
Q

what 2 drugs (pyrimidine analogs) interfere w pyrimidine nucleotide synthesis

A

5-FU & capecitabine

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11
Q

what 2 drugs (pyrimidine analogs) inhibit DNA polymerase

A

Ara-C (Cytarabine) & gemcitabine

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12
Q

what do all pyrimidine analogs have in common

A

they can all be incorporated into DNA & RNA & interfere w DNA/RNA function & DNA replication

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13
Q

what pyrimidine analog is also a uridine analog

A

5-fluorouracil (5-FU)

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14
Q

what was one of the 1st rationally designed antitumor agents?

A

5-FU

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15
Q

5-FU is a prodrug-ish. what is it converted to via 2 step transformation?

A

fluorodeoxyuridine monophosphate (fDUMP)

also converted to F-UMP & then to F-UTP

F-UTP is incorporated into RNA (instead of uridine) and DNA (instead of thymidine)

The fluorine interferes with RNA processing and function

Interferes with polyadenylation of mRNA (which affects RNA stability)

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16
Q

FdUMP enzyme folate ternary complex:

In the presence of ______, thymidylate synthase synthesizes thymidine monophosphate (TMP) from deoxy Uridine monophosphate (dUMP)

The hydrogen on dUMP is replaced with a _____on TMP. Folate acts as a _____donor.

FdUMP mimics dUMP and binds in the _____site of thymidylate synthase

Forms ternary complex with enzyme and tetrahydrofolate

The reaction can’t go to completion and thymidylate synthase is trapped in the ternary complex

_____can’t be produced, which results in inhibition of DNA synthesis – “thymineless death”

Toxicity can be rescued with ______treatment

A

folates; methyl; methyl

active

TMP

thymidine

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17
Q

what drug can be coadministered with 5-FU to increase efficacy? How does this increase efficacy?

A

leucovorate; folate cofactor that is converted to tetrahydrofolate which increases amt of covalent ternary complex with thymidylate synthase

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18
Q

what are the 2 resistance mechanisms of 5-FU

A

downregulation of activating enzymes that convert 5-FU to FdUMP

upregulation of thymidylate synthase

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19
Q

~___% of pop. has polymorphism that result in deficiency of DPD which breaks down 5-FU. This results in ___increased/decreased___ toxicity with 5-FU

A

5%

increased

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20
Q

what rescues pts from 5-FU overdose

A

thymidine

21
Q

what increases efficacy/drug synergy of 5-FU

A

leucovorate via ^ amt of covalent ternary complex w thymidylate synthase

22
Q

what is the orally active prodrug of 5-FU

A

capecitabine

23
Q

Cytarabine (Ara-C, cytosine Arabinoside) is structurally similar to deoxycytidine except for presence of _____ at sugar 2’ (arabinose instead of deoxyribose)

A

beta-OH

24
Q

Ara-C is converted to _______ intracellularly, which is a competitive inhibitor of DNA polymerase alpha

A

Ara-CTP (prodrug)

25
Q

_______ _________ converts cytarabine to non-toxic uracil arabinoside.

Decreased levels of _____ _____ in the CNS makes Ara-C highly toxic in meningeal leukemia and lymphoma

A

Cytidine deaminase; cytidine deaminase

26
Q

what are the 3 resistance mechanisms for cytarabine (ara-C)

A

downregulation of activating enzymes
upregulation of cytidine deaminase
downregulation of transporter to move drug into cells

27
Q

what happens if a pt taking cytarabine experiences decreased levels of cytidine deaminase?

A

Ara-C becomes highly toxic especially in meningeal leukemia & lymphoma

28
Q

t/f gemcitabine has greater potency than cytarabine

A

true

29
Q

what is given with ara-c to increase efficacy and decrease resistance

A

tetrahydrouridine

30
Q

Which drug is a NUCLEOSIDE analog

A. 5-FU

B. Cytarabine

A

B. Cytarabine

uridine & cytidine are nucleosides

5-FU is nucleobase, but most drugs are nucleoside analogs

31
Q

6-mercaptopurine (6-MP) is a _____analog.

A

purine; thio analog of adenine

32
Q

what is the resistance mechanism associated with 6-MP

A

loss of HGPRT, the activating enzyme

33
Q

t/f 6-MP is not a prodrug

A

false; it is a prodrug. thioinosine monophosphate is active metabolite

34
Q

6-MP is inactivated by _________.

A

thiopurine methyl transferase (TPMT)

35
Q

TPMT polymorphisms occur in ~___% of children in US. this causes a _____increase/decrease_____risk of toxicity, so the dose should be ____increased/decreased___

A

10%; increased risk; decrease dose

36
Q

6-MP is known to interact with what drug? describe the interaction

A

allopurinol

xanthine oxidase breaks down 6-MP and allopurinol is a xanthine oxidase inhibitor. This causes 6-MP to build up in body and increase risk of toxicity

allopurinol does not react with 6-TG which is a thio analog of guanine

37
Q

Which drug primarily interferes with purine biosynthesis?

a. 5-Fluorouracil

b. Capecitabine

c. 6-Mercaptopurine

d. Cytosine arabinoside

A

c. 6-Mercaptopurine

38
Q

folate is an essential vitamin –> B# and essential cofactor for many enzymatic rxns

A

B9

39
Q

folate is reduced to _____ by dihydrofolate reductase (DHFR)

A

tetrahydofolate

40
Q

DHFR inhibition causes folate pools to accumulate as __active/inactive__ dihydrofolate. This causes a major effect which is the inhibition of _____

A

inactive–> unable to be converted to active form (tetrahydrofolate)

thymidine monophosphate (TMP)
>inhibits RNA + protein synthesis
>inhibits purine & pyrimidine base synthesis

41
Q

what drug inhibits DHFR and is considered a folate mimic?

A

methotrexate (MTX)

42
Q

what are the 2 resistance mechanisms of methotrexate?

A

> amplification of DHFR gene or mutation of DHFR to resistant form of the enzyme (can’t be inhibited)

> Decreased polyglutamation results in decreased intracellular MTX accumulation

43
Q

t/f Polyglutamation of intracellular MTX helps retain MTX inside the cell.

A

true

44
Q

Anti-folates all share the following characteristics except:

a. They inhibit DHFR

b. They cause myelosuppression

c. They induce a G2/M cell cycle block

d. The toxic effects are “rescued” by Leucovorin

A

c. They induce a G2/M cell cycle block

45
Q

what is the overdose rescue for MTX?

A

leucovorin; increases intracellular tetrahydrofolate which competes with MTX transport into cells, thus reversing toxic effects of DHFR inhibition

46
Q

What rescues a 5-FU overdose?

A. Leucovorin

B. Cytosine arabinoside

C. Thymidine

D. Methotrexate

A

C. Thymidine

47
Q

What increases the efficacy of 5-FU?

A. Leucovorin

B. Cytosine arabinoside

C. Thymidine

D. Methotrexate

A

A. Leucovorin

48
Q

Which antimetabolite should not be given to patients being treated for gout?

A. Cytosine Arabinoside

B. 6-mercaptopurine

C. Cladribine

D. 5-FU

A

B. 6-mercaptopurine

49
Q

Which anti-metabolite does not directly inhibit DNA/RNA synthesis?

A. 5-fluorouracil

B. Cytosine Arabinoside

C. Nelarabine

D. Methotrexate

A

D. Methotrexate

one step upstream

therapeutics 864 - exam 1 (10 decks)

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