Antimetabolites Dykhuizen Flashcards
which of the following drugs target Her2? (review)
a. sirolimus
b. alectinib
c. vemurafinib
d. tucatinib
d. tucatinib
Which of the following drugs targets a kinase that is produced by formation of the Philadelphia chromosome? (review)
a. Alectinib
b. Gefitinib
c. Imatinib
d. binimetinib
c. Imatinib
Which compound below is NOT a covalent kinase inhibitor? (review)
A. Gefitinib
B. Osimertinib
C. Afatinib
D. Acalabrutinib
A. Gefitinib
Which type of kinase inhibitor can bind in the ATP binding site and stabilize the inactive confirmation of a kinase? (review)
A. Type I B. Type II C. Type III D. Type IV
B. Type II
A CML patient initially tested positive for the Philadelphia chromosome and has enjoyed a 5-year response to imatinib. Unfortunately, the disease has recurred and now tests positive for a T315I mutation.
-Describe how T315l prevents the efficacy of imatinib.
-What might the next course of BCR-Abl targeted therapy might include? (review)
-The T315l mutation prevents the binding of imatinib to BCR-abl
-Ponatinib is indicated upon identification of the T315l mutation
T or F: anti-metabolites block the production of nucleotide building blocks for DNA replication and transcription
T
what is myelosuppression?
common SE of chemotherapy; it is when bone marrow activity is decreased, resulting in fewer RBCs, WBCs, and platelets
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
B. Cytosine with Guanine, Adenine with Thymine
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
C. Adenine and Guanine
5-FU interferes with __________ synthesis
a. purine
b. pyrimidine
b. pyrimidine
________ analogs primarily inhibit thymidine synthesis from uracil
uridine
in the presence of folates, _______ _______ synthesizes thymidine monophosphate (TMP) from deoxy uridine monophosphate (dUMP)
a. thymine synthase
b. thymidine phosphorylase
c. dihydropyrimidine dehydrogenase (DPD)
d. thymidylate synthase
d. thymidylate synthase
what percent of the population has gene polymorphisms that result in a deficiency of the enzyme DPD which breaks down 5-FU, as well as naturally occurring pyrimidines?
~5%
drug rescue agent used for 5-FU overdose
thymidine
drug synergy agent used with 5-FU
leucovorate
cytarabine is converted to ________ intracellularly
Ara-CTP
Ara-CTP is a competitive inhibitor of which enzyme? (slide 28)
DNA polymerase alpha
which enzyme converts cytarabine to non-toxic uracil arabinoside?
a. cytosine deaminase
b. cytidine deaminase
c. DNA polymerase alpha
d. thymidine phosphorylase
b. cytidine deaminase
________ levels of cytidine deaminase in the CNS makes Ara-C highly toxic in meningeal leukemia and lymphoma
a. increased
b. decreased
b. decreased
drug synergy agent with cytarabine
a. leucovorate
b. tetrahydrouridine
c. thymidine
b. tetrahydrouridine
tetrahydrouridine is an inhibitor of what enzyme?
cytidine deaminase (CDA)
Which drug is a NUCLEOSIDE analog
A. 5-FU
B. Cytarabine
B. Cytarabine
6-mercaptopurine is a thiol analog of
a. adenine
b. guanine
c. cytosine
d. thymine
a. adenine
function of 6-mercaptopurine
blocks synthesis of purine nucleotides
6-MP is converted to its active metabolite by what enzyme?
HGPRT
when does 6-MP resistance occur?
with the loss of HGPRT, the activating enzyme
6-MP is inactivated by which enzyme?
a. xanthine oxidase
b. thiopurine methyl transferase (TPMT)
c. dihydrofolate reductase (DHFR)
d. HGPRT
b. thiopurine methyl transferase (TPMT)
TPMT polymorphisms occur in ~____% of children in the US
~10%
what drug does 6-MP have a major drug interaction with?
allopurinol
Which drug primarily interferes with purine biosynthesis?
a. 5-Fluorouracil
b. Capecitabine
c. 6-Mercaptopurine
d. Cytosine arabinoside
c. 6-Mercaptopurine
______ inhibition reduces FH4 pools, folate pools accumulate as inactive dihydrofolate
a. CDA
b. DHFR
c. thymidylate synthase
d. thymidine phosphorylase
b. DHFR (dihydrofolate reductase)
folic acid enters the folate pool as _________; reduction to tetrahydrofolate is done by _______ _______ (enzyme)
dihydrofolate; dihydrofolate reductase
major effect of DHFR inhibition
inhibition of thymidine monophosphate (TMP) synthesis (also inhibits synthesis of RNA, protein, purine and pyrimidine bases)
methotrexate is an inhibitor of which enzyme?
DHFR (dihydrofolate reductase)
compounds that bind to and inhibit DHFR are _____ mimics
folate
how does polyglutamation relate to methotrexate (MTX) resistance?
decreased polyglutamation results in dec intracellular MTX accumulation and resistance; polyglutamation of intracellular MTX helps keep it inside the cell
drug for methotrexate toxicity
leucovorin
how does leucovorin “rescue” normal tissues from methotrexate toxicity? (3 things)
-stable folate cofactor that is converted to tetrahydrofolate intracellularly
-increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition
-competes with methotrexate for transporters
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
c. They induce a G2/M cell cycle block
(they cause an S phase block)
