Antimetabolites - Chemo

Question 1

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

Answer 1

tucatinib

Question 2

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

Answer 2

imatinib

Question 3

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

Answer 3

gefitinib

Question 4

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

Answer 4

type II

Question 5

Answer 5

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

Question 6

DNA replication and transcription require pools of nucleotide building blocks

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

Answer 6

anti-metabolites

Question 7

drugs that target DNA replication

S phase drugs

Answer 7

• 5-FU
• cytarabine
• 6-mercaptopurine
• methotrexate
• irinotecan

Question 8

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

Answer 8

• precursors
• proliferating
• myelosuppression

Question 9

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

Answer 9

• bioactivation

Question 10

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

Answer 10

nucleoside
nucleotide

Question 11

Answer 11

adenine and guanine

Pure As Gold
Pyraminds CUT

Question 12

Answer 12

guanine

Question 13

Answer 13

uracil

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

Question 14

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

Answer 14

FALSE

drugs need to mimic nucleoside or nucleobase

Question 15

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

Answer 15

• 5-FU, capecitabine
• Ara-C, Gemcitabine

Question 16

Uridine Analogs

primarily inhibit ___ synthesis from uracil

Answer 16

thymidine

Question 17

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

Answer 17

• uracil
• FdUMP
• short
• folate

Question 18

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

Answer 18

• thymidylate
• tetrahydrofolate
• thymidylate
• thymineless
• thymidine

Question 19

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

Answer 19

• downregulation
• thymidylate
• increased

Question 20

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 ___

Answer 20

• F-UTP
• fluorine
• stability

Question 21

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

Answer 21

• thymidine
• leucovorate
• folate
• increases, covalent

Question 22

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

Answer 22

• prodrug
• higher
• higher

Question 23

Cytosine Analogs

primarily inhibt DNA ___

Answer 23

synthesis

Question 24

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

Answer 24

• DNA polymerase
• synthesis
• cytidine
• toxic
• cytidine
• downregulation
• cytidine
• transporter

Question 25

# 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

Answer 25

- permeability - affinity - potency

Question 26

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

Answer 26

cytarabine

Question 27

# purine analogs purine biosynthesis (1)

Answer 27

6-mercaptopurine

Question 28

# 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

Answer 28

- adenine - multiple - purine - HGPRT

Question 29

# 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

Answer 29

- thiopurine - allopurinol - xanthine - toxicity

Question 30

# 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

Answer 30

allopurinol

Question 31

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

Answer 31

6-MP

Question 32

# 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

Answer 32

- B9 - amino, nucleic - tetrahydrofolate - methyl

Question 33

# 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

Answer 33

- tetrahydrofolate - DHFR - thymidine - purine, pyrimidine

Question 34

compounds that bind to DHFR are ___ mimics example: ___

Answer 34

folate methotrexate

Question 35

# 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

Answer 35

- amplification, mutation - decrease - inside

Question 36

# 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

Answer 36

- tumor - folate carrier type 1

Question 37

# Pemetrexed - inhibitor of ___ reductase, __ synthase, and glycinamide ribonucleotide formyltransferase - decreased risk of drug ___

Answer 37

- dihydrofolate, thymidylate - resistance

Question 38

# 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

Answer 38

- methotrexate - tetrahydrofolate - reverses, DHFR

Question 39

# 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 ___

Answer 39

- DHFR - transporter - competes - 5-FU, capecitabine

Question 40

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

Answer 40

they induce G2/M cell cycle block