exam 1 lecture 4 Flashcards
Which of the following drugs targets a kinase that is produced by
formation of the Philadelphia chromosome?
a) Alectinib
b) Gefitinib
c) Imatinib
d) binimetinib
imatinib
Which compound below is not a covalent kinase inhibitor?
A. Gefitinib
B. Osimertinib
C. Afatinib
D. Acalabrutinib
Gefitinib
Describe how T315I prevents the efficacy of imatinib?
T315I mutation prevents binding of imatinib to BCR-abl
What drug is indicated upon identification of T315I mutation
Ponatinib
Which drugstarget DNA replication (S-cell cycle)
5-fluorouracil
Cytarabine
6-mercaptopurine
methotrexate
Irinotecan
What do antimetabolites target?
They target intermediary metabolic pathways involved in synthesis of essential molecules in proliferating cells
What is dose limiting to antimetabolites
It targets rapidly proliferating cells (myelosuppression)
What are antimetabolites analogs of? WHat do they mimic?
Naturally occuring metabolites.
cofactor mimics and substrate mimics
What is adenine paired with? WHat are the pyramidines? WHich ones have two hydrogen bonds?
Adenine with thyamine.
Pyramidines are CUT
Adenine and thyamine both have 2 bonds.
What are some pyramidine analogs that interfere with pyramidine nucleotides synthesis?
5-FU and capecitabine
What are some pyramidine analogs that inhibit DNA polymerase
Gemcitabine and Ara-C
WHat are some uridine analogs? How do they work?
5-fluorouracil.
Primarily inhibit thymidine synthesis from uracil
WHat type of analog is 5-flurouracil? WHat is it converted to?
it is a fluorinated uracil analog
5-FU is converted to fDUMP via a two step transformation
What happens to dUMP in the presence of folates
Thymidylate synthase synthesizes thymidine monophosphate (TMP) from dUMP
How is the ternary complex formed? WHat does this entail?
fDUMP mimics DUMP and binds active site of thymidylate synthase.
forms ternary complex with enzyme and tetrahydrofolate
this makes reaction unable to proceed to completion and thymidylate synthase is trapped in ternary complex
TMP can not be produced, results in inhibition of DNA synthesis.
how to rescue fdump-enzyme-folate toxicity
thymidine treatment
source of resistance to 5-FU
Downregulation of activating enzymes that convert 5-FU to fDUMP
upregulation of thymidylate synthase
describe the susceptability of 5-FU in the population
5% of the population has a gene polymorphism resulting in the deficiency of enzyme DPD. Which breaks down 5-FU. Results in increased toxicity with 5-FU
5-FU drug rescue during overdose
Thymidine
What drug increases the efficacy of 5-FU
leucovorate
what is leucovorate converted to in the cell?
folate
How does higher tetrahydrofolate affect the efficacy of 5-FU
increases
Name a cytosine analog
Cytarabine
What happens to cytarabine in the cell
Converted to Ara-CTP intracellularly
What is Ara-CTP
Ara-CTP is a competitive inhibitor of DNA polymerase a
Ara-CTP is also incorporated into DNA and inhibits further DNA synthesis
What does cytidine deaminase do? What happens if there is decreased levels of cytidine deaminase in CNS?
Converts cytarabine to non toxic uracil arabinoside.
decreased levels of cytidine deaminase in CNS makes Ara-C highly toxic in leukemia and lymphoma
What are some resistance mechanisms of cytarabine
Downregulation of activating enzymes
upregulation of cytidine deaminase
downregulation of transporter
cytarabine is deactivated by
cytidine deaminase
What is given with cytarabine to increase efficacy and decrease resistance (synergy)
Tetrahydrouridine
Name a purine analog
6-mercaptopurine
6-mercaptopurine is an analog of?
adenine
what does 6-mercaptopurine block the synthesis of?
Purine nucleotides
Resistance of 6-mercaptopurine is caused by
HGPRT
What is 6-mercaptopurine inactivated by
TPMT
What percent of children have TPMY in US
10%
Drug interaction of 6-mercaptopurine
6-MP has a drug interaction with allopurinol
Describe the interaction between allopurinol and 6-MP
allopurinol is a xanthine oxidase inhibitor.
Xanthine oxidase breaks down 6-MP. Those taking allopurinol are at risk for 6-mp toxicity
what are folates essential for?
It is an essential cofactor for many enzymatic reactions.
Describe the MOA of folic acid and how DHFR comes into play.
Folic acid enters the folate pool as dihydrofolate (FH2)
reduction to tetrahydrofolate happens by DHFR
What does DHFR inhibition do? What drugs target DHFR?
DHFR inhibition reduces FH4 pools.
The major effect is the inhibition of TMP synthesis
Antifolates target DHFR
cpds that bind to and inhibit DHFR are
folate mimics 1) folic acid
2) methotrexate
WHat causes resistance to methotrexate?
amplification of DHFR gene or mutation of DHFR to resistant form of enzyme
decreased polyglutamation results in decreased intracellulat mtx accumulation
What is overdose rescue for methotrexate? How does it work?
Leucovorin
it increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition
Leucovorin enhances which substances
5-FU and capcitabine
what rescues 5-fu toxic effects
thymidine
What are alkylating agents? What do they result in?
Alkylating agents generate reactive electrophilic intermediates that react with nucleophilic groups. They result in attachment of alkyl to DNA and protein
What is the most common site of alkylation
alkylation of purine bases in DNA (most commonly guanine)
What do we mean when we say alkylating agents are bifunctional
They produce intra and inter strand linkages
Are alkylating agents cell cycle specific?
No
Repair of cross links in normal cell vs cancer cell
Repair of crosslink in cancer is not good
are alkylating agents potent nucleophiles or electrophiles
electrophiles
side effects of alkylation
some rapidly proliferating cells are sensitive to effects of DNA alkylation and cross linking (bone marrow, gut mucosa)
measurable incidence of 2nd malignancy in long term survivors. Usually in bone marrow.
(myelosuppression, N/V, carcinogenic)
side effects of all alkylators
(myelosuppression, N/V, carcinogenic)
What are two strategies to decrease reactivity of nitrogen mustard gas
- decrease nucleophilicity of nitrogen by adding aryl group
- prodrug strategy
describe the prodrug strategy to decrease reactivity of mustard gas and the role PM plays in this
PM- Phosphoramide mustard- is a metabolite that crosslinks DNA
hydroxylated metabolite must be converted to PM into tumor cell because PM is highly polar and does not readily diffuse into cell and has short half life.
PM is inactivated by
aldehyde dehydrogenase
Most useful and commonly used alkylating agent
cyclophosphamide
side effects of cyclophosphamide
mild bone marrow toxicity
hemorrhagic cystitis
why does cyclophosphamide have mild bone marroe toxicity
sparing to marrow stem cell because of high ADH levels in these cell types
why does cyclophosphamide have hemorrhagic cycstitis (toxic to bladder)
acrolein is toxic to bladder mucosa
acrolein accumulates in urine and damages bladder mucosa
how to block hemorrhagic cystitis
use mesna
how does mesna work
mesna contains charged sulfonate group so it does not penetrate cells. mesna accumulates in the urine
what inactivates cyclophosphamide
aldehyde dehydrogenase
