antimetabolites Flashcards
(49 cards)
antimetabolites and antifolates target which phase of cell cycle
S
t/f antimetabolites are antitumor agents targeted at the biosynthesis or utilization of DNA and RNA precursors.
true, both DNA & RNA precursors
what toxicity is often dose-limiting for antimetabolites
myelosuppression
t/f Antimetabolites are typically analogs of naturally occurring metabolites.
true
t/f only a few antimetabolites require biotransformation to nucleotide analog (sugar and phosphate) to generate active species
false, most drugs require biotransformation
nomenclature review
rank these in order of increasing size
-nucleoside
-nucleobase
-nucleotide
base > side > tide (has phosphate & sugar)
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
why can’t nucleotides enter cells?
phosphate group/has a charge
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
“Pure As Gold”
“Pyramids CUT”
what 2 drugs (pyrimidine analogs) interfere w pyrimidine nucleotide synthesis
5-FU & capecitabine
what 2 drugs (pyrimidine analogs) inhibit DNA polymerase
Ara-C (Cytarabine) & gemcitabine
what do all pyrimidine analogs have in common
they can all be incorporated into DNA & RNA & interfere w DNA/RNA function & DNA replication
what pyrimidine analog is also a uridine analog
5-fluorouracil (5-FU)
what was one of the 1st rationally designed antitumor agents?
5-FU
5-FU is a prodrug-ish. what is it converted to via 2 step transformation?
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)
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
folates; methyl; methyl
active
TMP
thymidine
what drug can be coadministered with 5-FU to increase efficacy? How does this increase efficacy?
leucovorate; folate cofactor that is converted to tetrahydrofolate which increases amt of covalent ternary complex with thymidylate synthase
what are the 2 resistance mechanisms of 5-FU
downregulation of activating enzymes that convert 5-FU to FdUMP
upregulation of thymidylate synthase
~___% of pop. has polymorphism that result in deficiency of DPD which breaks down 5-FU. This results in ___increased/decreased___ toxicity with 5-FU
5%
increased
what rescues pts from 5-FU overdose
thymidine
what increases efficacy/drug synergy of 5-FU
leucovorate via ^ amt of covalent ternary complex w thymidylate synthase
what is the orally active prodrug of 5-FU
capecitabine
Cytarabine (Ara-C, cytosine Arabinoside) is structurally similar to deoxycytidine except for presence of _____ at sugar 2’ (arabinose instead of deoxyribose)
beta-OH
Ara-C is converted to _______ intracellularly, which is a competitive inhibitor of DNA polymerase alpha
Ara-CTP (prodrug)
