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864 > Antimetabolites - Chemo > Flashcards

Antimetabolites - Chemo Flashcards

1
Q

which of the following drugs targets HER2?
a) sirolimus
b) alectinib
c) vemurafinib
d) tucatinib

A

tucatinib

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2
Q

which of the following drugs targets a kinase that is produced by the formation of the Philadelphia chromosome?
a) alectinib
b) gefitinib
c) imatinib
d) binimetinib

A

imatinib

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3
Q

which compound is not a covalent kinase inhibitor?
a) gefitinib
b) osimertinib
c) afatinib
d) acalabrutinib

A

gefitinib

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4
Q

which type of kinase inhibitor can bind in the ATP binding site and stabilize the inactive confimation of a kinase?
a) type I
b) type II
c) type III
d) type IV

A

type II

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5
Q
A
  • T315I prevents compounds from binding in the BCR-Abl pocket
  • ponatinib is indicated for T315I mutation
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6
Q

DNA replication and transcription require pools of nucleotide building blocks

___ block the production of one or more of these building blocks

A

anti-metabolites

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7
Q

drugs that target DNA replication

S phase drugs

A
  • 5-FU
  • cytarabine
  • 6-mercaptopurine
  • methotrexate
  • irinotecan
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8
Q

antimetabolites overview

  • antitumor agents targeted at biosynthesis or utilization of DNA and RNA ___
  • target intermediary metaboic pathways involved in synthesis of essential molecules in ___ cells
  • complex metabolic pathways involved in DNA synthesis
  • all drugs exhibit toxicities to rapidly proliferating cells
  • ___ is often dose limiting
A
  • precursors
  • proliferating
  • myelosuppression
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9
Q

anti metabolites-overview

  • antimetabolites ate typically analogs of naturally occuring metabolites
  • most of these drugs function as enzyme inhibitors
  • substrate and cofactor mimics

most drugs require ___ to nucleotide analog (sugar and phosphate) ro generate active species

A
  • bioactivation
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10
Q

nucleobase + sugar = ___
nucleobase with sugar and phosphate = ___

A

nucleoside
nucleotide

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11
Q
A

adenine and guanine

Pure As Gold
Pyraminds CUT

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12
Q
A

guanine

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13
Q
A

uracil

In RNA, just a difference of a methyl group between T

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14
Q

T or F: the phosphate group on a nucleotide makes it easy to get into the cell

A

FALSE

drugs need to mimic nucleoside or nucleobase

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15
Q

Pyrimidine Analogs

interfere with pyrimidine nucleotide synthesis
- ___ and ___

inhibition of DNA polymerase
- ___ and ___

alternatively, all of them can be incorporated into DNA and RNA and interfere with DNA/RNA function and DNA replication

A
  • 5-FU, capecitabine
  • Ara-C, Gemcitabine
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16
Q

Uridine Analogs

primarily inhibit ___ synthesis from uracil

A

thymidine

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17
Q

5-Fluorouracil (5-FU)

  • fluorinated ___ analog
  • 5-FU is converted to ___via 2 step transformation
  • 5-FU plasma half life is very ___ , but intra cellular FdUMP and FUTP persist
  • in the presence of ___ , thymidylate synthase syntheizes thymidine monophosphate (TMP) from deoxy uridine monophosphate (dUMP)
  • the hydrogen on dUMP is replaced with a methyl on TMP
  • ___ acts as a methyl donor
A
  • uracil
  • FdUMP
  • short
  • folate
18
Q

FdUMP-Enzyme-Folate Ternary Complex

  • FdUMP mimics dUMP and binds in the active site of ___ synthase
  • forms ternary complex with enzyme and ___
  • reaction cant go to completion ___ synthase is trapped in the ternary complex
  • TMP cant be produced which results in inhibition of DNA synthesis - ___ death
  • toxicity can be rescued with ___ treatment
A
  • thymidylate
  • tetrahydrofolate
  • thymidylate
  • thymineless
  • thymidine
19
Q

5-FU

resistance
- ___ of activating enzymes that convert 5-FU to F-dUMP
- upregulation of ___ synthase

susceptibility
- about 5% of the population has gene polymorphisms that resultin a deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and naturally occuring pyrimidines
- polymorphisms predict ___ toxicity with 5-FU

A
  • downregulation
  • thymidylate
  • increased
20
Q

5-FU additional mechanism

5-FU converted to F-UMP and then F-UTP
___ is incorporated into RNA (instead of uridine) and DNA (instead of thymidine)
- ___ interferes with RNA processing and function
- interferes with polyadenylation of mRNA with affects RNA ___

A
  • F-UTP
  • fluorine
  • stability
21
Q

5-FU

cdrug rescue = ___
- “rescues” from overdose
- doesnt help treat their cancer

drug synergy - ___
- stable ___ cofactor that is converted to tertrahydrofolate in cells
- higher tetrahydrofolate levels ___ effectiveness of 5-FU bc theres more ___ complex that can from with thymidylate synthase

A
  • thymidine
  • leucovorate
  • folate
  • increases, covalent
22
Q

Capecitabine

  • orally active ___ of 5-FU
  • multistep conversion in tissues (includng tumor)
  • thymidine phosphorylase ( ___ levels in tumor) then catalyzes 5’-DFU to 5-FU
  • prodrug strategy generates ___ levels of 5-FU selectively within some tumors
A
  • prodrug
  • higher
  • higher
23
Q

Cytosine Analogs

primarily inhibt DNA ___

A

synthesis

24
Q

Cytarabine (Cytosine Arabinoside Ara-C)

  • Ara-CTP is a competitive inhibitor of ___ alpha
  • Ara-CTP is also incorporated into DNA and inhibits further DNA ___
  • ___ deaminase converts cytarabine to non-toxic uracil arabinoseide.
  • Decreased levels of cytidine deaminase in the CNS makes Ara-C highly ___ in meningeal leukemia/lymphoma

multiple resistance mechanisms:
- ___ of activating mechanisms
- upregulation of ___ deaminase
- downregulation of ___ to move drug into cells

A
  • DNA polymerase
  • synthesis
  • cytidine
  • toxic
  • cytidine
  • downregulation
  • cytidine
  • transporter
25
Q

Gemcitabine (Difluorodeoxycytidine)

structurally similar to deoxycytidine except with 2 fluoro substituents at the 2’ sugar
- increased cell ___ , greater ___ for activating enzyme, and better evasion of DNA repair enzymes gives it greater ___ than cytarabine

A
  • permeability
  • affinity
  • potency
26
Q

which drug is a nucleoside analog?
a) 5-FU
b) Cytarabine

A

cytarabine

27
Q

purine analogs

purine biosynthesis
(1)

A

6-mercaptopurine

28
Q

6-Mercaptopurine (6-MP, Purinethol)

thio analog of ___
- 6-MP inhibits ___ enzymes in de novo purine biosynthesis
- blocks synthesis of ___ nucleotides
- Resistance - loss of ___ , the activating enzyme

A
  • adenine
  • multiple
  • purine
  • HGPRT
29
Q

6-MP metabolism and drug interactions

6-MP inactivated by ___ methyl transferase (TPMT)
- TPMT polymorphism occur in 10% of children
- heterozygotes: 65% of standard dose, homozygotes: 10% of standard dose

drug interaction with ___
- inhibits ___ oxidase which is an enzyme that also breaks down 6-MP
- increased ___
- gout is caused by too much uric acid, a breakdown product of purine metabolism that is usually excreted

A
  • thiopurine
  • allopurinol
  • xanthine
  • toxicity
30
Q

6-thioguanine (6-TG)

  • thio analog of guanine
  • ___ does NOT block the breakdown of 6-TG
  • first converted to inactive 6-thioxanthine by guanine deaminase, then oxidized by xanthine oxidase
A

allopurinol

31
Q

which drug primarily interferes with purine biosynthesis?
a) 5-FU
b) capecitabine
c) 6-MP
d) cytosine arabinose

A

6-MP

32
Q

Antifolates - intro to folate

  • vitamin ___

essential cofactor for many enzymatic reactions
- metabolism of ___ and ___ acids
- dihydrofolate is converted to ___
- acts as a ___ donor by sequestering formaldehyde as 5,10 - methylene tetrahydrofolate

A
  • B9
  • amino, nucleic
  • tetrahydrofolate
  • methyl
33
Q

Folic Acid Cycle

  • enters folate pool as dihydrofolate (FH2)
  • reduction to ___ by dihydrofolate reductase (DHFR)
  • ___ inhibtion reduces FH4 pools, folate pools accumulate as inactive dihydrofolate
  • major effect is the inhibition of ___ monophosephate (TMP) synthesis
  • also inhibits RNA and protein synthesis
  • also inhibits ___ and ___ base synthesis
A
  • tetrahydrofolate
  • DHFR
  • thymidine
  • purine, pyrimidine
34
Q

compounds that bind to DHFR are ___ mimics
example: ___

A

folate
methotrexate

35
Q

methotrexate (MTX)

resistance
- ___ of DHFR gene or ___ of DHFR to resistant form of the enzyme
- decreased polyglutamation results in ___ intracellular MTX accumulation
- polyglutamation of intrancellular MTX helps retain MTX ___ of the cell

A
  • amplification, mutation
  • decrease
  • inside
36
Q

Pralatrexate

  • designed to accumulate preferentially in ___ cells
  • selectively enters cell expressing reduced ___ (RFC-1), a protein that is over expressed on certain cancer cells compared to normal cells
A
  • tumor
  • folate carrier type 1
37
Q

Pemetrexed

  • inhibitor of ___ reductase, __ synthase, and glycinamide ribonucleotide formyltransferase
  • decreased risk of drug ___
A
  • dihydrofolate, thymidylate
  • resistance
38
Q

Leucovorin - Overdose rescue

  • LV is used to rescue normal tissues from ___ toxicity
  • stable folate cofactor that is converted to ___ intracellularly
  • increases intracellular pools of tetrahydrofolate and ___ toxic effects of ___ inhibition
A
  • methotrexate
  • tetrahydrofolate
  • reverses, DHFR
39
Q

Leucovorin - drug interaction

mechanism of leucovorin “rescue” probably multifactorial
- delivers reduced folate intracellularly thus bypassing ___ blockade
- leucovorin and methotrexate share a common ___
- leucovorin ___ with methotrexate transport into cells

  • Reminder! Leucovorin is also used to enhance the activity of ___ and ___
A
  • DHFR
  • transporter
  • competes
  • 5-FU, capecitabine
40
Q

anti-folates all share the following characteristics except:
a) they inhibit DHFR
b) they cause myelosuppression
c) they induce G2/M cell cycle block
d) the toxic effects are “rescued” by leucovorin

A

they induce G2/M cell cycle block

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