Therapeutics Exam 1 (Wendt and Dykhous) PT. 2 Flashcards
Uridine Analogs:
FdUMP mimics _____ and will bind to the active site of _________
mimics dUMP (hint the F is the fluorouracil that is screws everything up for DNA)
active site of: thymidylate synthase
Uridine Analogs:
FdUMP will form a ternary complex with _____ and ______
enzyme (synthase) and reduced folate cofactor (aka the methyl donor!!)
Uridine Analogs:
when FdUMP is in the ternary complex – the reaction cannot go to completion because why?
the F present (is usually an H) prevents the reaction to completing and letting the enzyme detach – enzyme is trapped!
Uridine Analogs:
5-FU leads to _____ depletion and leads to the inhibition of DNA synthesis (via a “_______ death”)
TMP depletion
thymineless death
Uridine Analogs:
5-FU is also converted to F-UTP and will affect _______
RNA processin and function
5-FU resistance can occur by what 2 mechanisms?
downregulation of activating enzymes
upregulation of thymidylate synthase
Thymidine and 5-FU drug interaction:
5-FU THEN thymidine = “_____” cytotoxic effect
Thymidine then 5-FU = “______” cytotoxic effect
then thymidine: is rescuing
thymidine 1st = enhances effect (giving this first will cause the cell to down regulate thymidine synthase!!)
the drug _____ can be given with 5-FU and increase the efficacy by increasing the stability of the synthase complex
Leucovorate
Leucovorate is a stable _____ cofactor and gets converted to _______ intracellularly
folate; tetrahydrofolate
______ breaks down 5-FU (~5% of the population has a polymorphism and has a deficiency of this enzyme)
*deficiency of this enzyme can lead to a life threatening 5-FU
DPD (dihydropyrimidine dehydrogenase)
who is FUdR (fluroreoxyuridine) different than 5-FU
FUdR is the deoxyribonucleoSIDE of 5-FU (aka FUdR has a sugar)
Capecitabine is a orally active prodrug of _____
5-FU
benefit of Capectiabine being a prodrug of 5-FU
longer 1/2 life!/can build up in tissues more
prodrug strategy generates higher levels of 5-FU selectively w/in some tumors
Cytosine analogs:
primarily inhibit _______
DNA synthesis
what bases are pyrimidines?
C & T
what drugs are cytosine analogs?
Cytosine arabinoside…
Gemcitabine
Cytosine arabinoside
is so structurally similar to deoxycytidine but the _______ makes it wack
B-OH at sugar 2’ (sugar is inverted somewhere)
Cytosine arabinoside
gets converted to _____ intracellularly and then acts as a competitive inhibitor to _________
Ara-CTP
DNA polymerase alpha
(Ara-CTP will also get incorporated into DNA and make it wack)
_________ will convert cytosine arabinoside to non-toxic uracil arbinoside
cytidine deaminase
Cytosine arabinoside:
cytidine deaminase is low in the ______ therefore this drug is good to use for these types of cancer: ______ and ______
CNS!!!
meningeal leukemia and lymphoma (aka cancers in lining of brain and spinal cord)
resistance mechanisms to cytosine arabinoside?
downregulation of deoxycytidine kinase (? - apparently an activating enzyme..)
upregulation of cytidine deaminase
downregulation of transport to move drug into cells
Gemcitabine:
gets phosphorylated to ____ and ____ intracellularly
______ will inhibit ribonucleotide reductase (inhibits DNA synthesis)
___ gets incorporated in DNA and halts further chain elongation
dFdCDP; dFdCTP
dFdCDP
dFdCTP
what drugs are used to stop purine biosynthesis
6-mercaptopurine
6-thioguanine
what drugs are used to stop DNA and RNA incorporation of purine analogs
fludarabine
Nelarabine
Cladribine
6-Mercaptopurine: (6-MP)
is a thio analog of _____
adenine
6-Mercaptopurine: (6-MP)
will inhibit MULTIPLE enzymes in the de novo ________ pathyway
purine biosynthesis (aka blocks synthesis of purine nucleotides – all of them not just Adenine)
6-Mercaptopurine: (6-MP)
gets converted to _____ (the active metabolite) by _____
converted to: TIMP (thiosine monophosphate)
by: HGPRT
6-Mercaptopurine: (6-MP)
is inactivated by ______
TPMT!!!
6-Mercaptopurine: (6-MP)
TPMT polymorphism occur in about ~10% of kids — these can result in _____ toxicity
heterozygotes need about _____ of standard dose
homozygotes need about _____ of standard dose
hematologic;
65%
10%
6-Mercaptopurine: (6-MP)
is also broken down by ________ (not just TPMT)
xanthine oxidase
what drug can increase the risk of 6-Mercaptopurine: (6-MP) toxicity
allopurinol (xanthine oxidase inhibitor)
6-Thioguanine: (6-TG)
is very similar to 6-MP but the main difference is _________
allopurinol (canthine oxidase inihibitor) DOES NOT block breakdown of 6-TG
*6-TG and 6-MP both get activated by HGPRT and get inactivated by TPMT
Arabino adenosine analogs will interfere with _____ and _______ aka inhibit DNA replication and transcription
*what drugs are arabino adenosine analogs
interfere with DNA polymerase and ribnucleotide reductase
fludarabine; Nelarabine; (Cladribine - has an extra MOA but still an adenosine analog..)
which Arabino adenosine analogs is used to treat blood cancers because phosphorylation keeps it in the bloodstream
fludarabine (it has sugar and phosphate!! - charge)
Cladribine will inhibit __________ and for some reason that enzyme is critical for ___ cells
inhibit adenosine deaminase (converts adenosine to inosine…?)
critical for B cells! – aka useful for leukemias
Folate is vitamin B___
9
Folate enters “folate pool” as ______ which is (active or inactive)
FH2 (dihydrofolate) — inactive
Dihydroflate (FH2) gets converted to tetrahydrofolate by ______
DHFR (dihyrdofolate reductase)
Folate Cycle:
inhibit _____ will reduce FH4 pools and folate pools accumulate as the inactive dihydrofolate —–>
____ and _____ synthesis decreases
DHFR;
TMP and purine nucleotide synthesis decreases!!
What compounds will bind and inhibit DHFR
Methotrexate
Pralatrexate
Pemetrexed
(they all similar structures to folic acid)
resistance to MTX (methotrexate) can happen how?
DHFR gene is amplified or mutation in DHFR gene leads to resistance
decrease polyglutamylation = decreased intracellular MTX accumulation
MTX can have increased accumulation in cells if ______ occurs
polyglutamylation
what is the “extra benefit” of pralatrexate
*compared to MTX just inhibiting DHFR
it is designed to accumulate in tumor cells — selectively enters tumor cells that are expressing RFC-1 (reduced folate carrier type)
RFC-1 is typically overexpressed on tumor cells over normal cells
what is the “extra benefit” of Pemetrexed
*compared to MTX just inhibiting DHFR
also inhibits thymidylate synthase
glycinamide ribonucloetide formyltransferase
aka less susceptible to drug resistance
how is Leucovorin used when in conjuction with MTX?
used to rescue normal tissues bc it is a stable folate cofactor
hydroxyurea MOA?
decreases production of deoxyribonucleotides BY inhibiting ribonucleotide reductase
hydroxyurea MOA?
DNA synthesis is inhibited in the ___ Phase
S
MOA of Actinomycin?
binds DNA and inhibits transcription by RNA polymerase
Aromatic drugs — slips into DNA and intercolates stuff
MOA of Actinomycin?
DNA synthesis is inhibited in the ___ Phase
any phase! non cell cycle specific (unlike other antimetabolites)
most antimetabolites affect the _____ phase in the cell cycle
S
Topoisomerases provide a mechanism to reduce ______ and provide access to _________
reduce: localized supercoiling
access: to double stranded DNA
Topoisomerase I:
will cut ______ DNA and relax the remaining strand and ______
cut ONE strand of double stranded DNA;
and reanneal
Topoisomerase I inhibitors:
mechanism?
the inhibitor has a strong nucleophile spot – will bind to topo I when it is attached to DNA
prevents Topo I from religating the cut DNA
most cells in ____ phase are sensitive to Topo I inhibitors
S
most topoisomeraise inhibitors will have a polycyclic _____ motif for intercalation — these will preferentially stack with _____
aromatic; guanine
Drug resistance possibilities with Topo I inhibitors
PGP overexpression
MRP overexpression (multidrug resistant protein)
GLUTATHIONE S-TRANSFERASE overexpression\
Topo downregulation or mutation to inhibit binding
what drugs are Topo I inhibitors
topotecan
irontecan
(the camptothecins)
Topo I inhibitors:
Camptothecin - natural product: low solubility/unpredictable toxicity
Topotecan: water soluble analog of camptothecin
Irinotecan: is a prodrug made into _____
Sn-38 *** related to genetic testing!!!
why do genes affected irinotecan?
active metab of irinotecan = SN-38;
SN38 is metabolized by UGT1A1
toxicity of irinotecan can happen if low expression of UGT1A1
Topo II is able to relieve ______ and ______
torsional strain; untangle DNA
two forms of Topo II:
Top2A and Top2B: which is most targeted? and why?
Top2A:
is required for decatenation of cells during mitosis
Anthracyclines: inhibit ______
Topo II
what drugs are Anthracyclines:
Doxorubicin
Dauomycin
Epirubicin
Idarubicin
how do Anthracyclines work?
multiple mechanisms:
intercalator
FREE RADICAL causes DNA damage
Inhibit Topo II***
issue with Anthracyclines?
free radical damage –> cardiotoxicity
Topo II inhibitors - Anthracyclines:
which one is most widely used?
doxorubicin
Topo II inhibitors - Anthracyclines:
which one has a dark red color/known as red death/red devil
doxorubicin
Topo II inhibitors - Anthracyclines:
which one has less cardiotoxicity than doxorubicin and faster elimination
epirubicin
Topo II inhibitors - Anthracyclines:
which one has increased fat solubility and cellular uptake
Idarubicin
which drug can be given with anthracyclines to decrease cardiotoxicity and how does it work
Dexrazoxane;
binds to iron/blocks iron-oxygen toxicities;
cardiotoxicity of doxorubicin and daunomycin believed to be caused by iron catalyzed free radical formation!!!
Mitoxantrone works how?
similar to anthracyclines but NOT an anthracycline — will intercalate and inhibit topo II buuut NO FREE RADICAL TOXICITY = less cardiotoxicity!!!!!
how do Topo II inhibitors - Epipodophyllotoxins work?
inhibit religation of double stranded breaks induced by Topo II but DO NOT INTERCALATE
what drugs are Topo II inhibitors - Epipodophyllotoxins
Etoposide and Teniposide
what cell phase are they effective?
Anthracyclines:
Epipodophyllotoxins:
Anthra: non cell cycle specific
Epipop: G2 block
drug resistance problems with Topo II inhibitors?
PGP overexpression
MRP overexpression (multidrug resistant protein)
GLUTATHIONE S-TRANSFERASE overexpression - ONLY anthracyclines
increased DNA damage repair
Topo II downregulation or mutation to inhibit binding
how does bleomycin work?
has charged side chain and will intercalate with DNA and then imidazole part does Fe+/O2 species generate DNA free radical
radical leads to DNA single strand/double strand breaks
bleomycin:
______ is dose limiting and cumulative
and myleosuppression is minimal!!
pulmonary toxicity
bleomycin:
gets inactivated by _________ which is in high concentrations for everywhere but _______
by aminohydrolase
skin and lungs (why pulmonary toxicity and rash ADEs)
*resistant cancers will have elevated aminohydrolase
what are the two major general microtubule inhibitor drug classes
Microtubule destabilizer
and
microtubule stabilizer
microtubule stabilizers will make microtubules “_____”
and
microtubule destabilizers will _______
stabilzers “frozen”
destabilizers “won’t form”