Antimetabolites Flashcards
Are most antimetabolites cell cycle specific or non-specific?
Most antimetabolites are cell cycle SPECIFIC and interfere with DNA SYNTHESIS
Are antimetabolites carcinogenic? Why?
Don’t interact with DNA so not carcinogenic
Pharmacokinetics: For many antimetabolites, does efficacy depend on duration above a critical threshold or a peak concentration? So, do effect depend on schedule of administration or not?
For many antimetabolites, efficacy depends on duration above CRITICAL THRESHOLD, so effects do depend on the SCHEDULE of administration
- What are the two groups of antimetabolites?
2. What are the drugs in each group?
- Nucleoside analogs and Antifolates
- Nucleoside analogs: PURINE (6-thioguanine, 2-chlorodeoxyadenosine) or PYRIMADINE (5-FU, cytosine arabinoside, gemcitabine) analogs
Antifolates - methotrexate
MOA Antifolate
MOA Nucleoside analog
MOA Antifolate: prevent formation of reduced folates (which are needed for DNA synthesis)
MOA Nucleoside analog:
- inhibit formation of normal nucleotides or
- interact w DNA preventing extension of new strand
Methotrexate.
Analog of _______ and a ______ inhibitor of ______ ______ – > prevents formation of reduced folate – > inhibits DNA synthesis and cell death dt lack of dTMPs and/or purines
Methotrexate.
Analog of FOLIC ACID and a COMPETITIVE inhibitor of DIHYDROFOLATE REDUCTASE (DHFR) – > prevents formation of reduced folate – > inhibits DNA synthesis and cell death dt lack of dTMPs and/or purines
______ prevents formation of reduced folates which are necessary for:
- Transfer of methyl groups to form _____
- Conversion of _____ to _____, catalyzed by _________
- Reduced folate is oxidized in this reaction – > its regeneration is dependent on _____ for reduction to its active form
METHOTREXATE prevents formation of reduced folates which are necessary for:
- Transfer of methyl groups to form PURINES
- Conversion of dUMP to dTMP, catalyzed by DHFR
- Reduced folate is oxidized in this reaction – > its regeneration is dependent on DHFR for reduction to its active form
Methotrexate is metabolized w/in the cell by what process? what is the effect?
polyglutamation…this leads to addition of glutamic acid residues to this drug…preventing efflux of mtx out of cell
Optimal binding of MTX to DHFR depends on the concentration of what?
NADPH
Name 8 MTX toxicities;
- Myelosuppression
- Oral mucositis
- GI epithelial denudation
- Renal tubular obstruction (precipitates) & injury
- Hepatotoxicity
- Pneumonitis
- HS reactions
- Neurotoxicity
Toxicity of MTX may be reversed by these 3 things
- administration of thymine,
- exogenous purines,
- or reduced folate (leucovorin) - reduces normal tissue toxicity
This antineoplastic blocks both toxicity AND antitumor acitivty of MTX
LSPAR
Pretreatment with this common drug may decrease renal clearance and increase MTX toxicity
NSAIDS
Pretreatment wtih MTX will increase ___ and ____ nucleotide formation (two chemo drugs)
5-FU and cytosar
Name 3 mechanisms of MTX resistance
- Mutations in the reduced folate carrier system
- Low levels of TS activity (MTX is analog of folic acid, and competitively inhibits DHFR which prevents reduced folate….leads to inhibition of DNA synthesis and cell death dt lack of dTMPs and/or purines…dUMP to dTMP is catalyzed by thymidylate synthase
- Increased production of DHFR
Does MTX penetrate BBB?
How is MTX excreted? Significance?
Yes, achieves cytotoxic concentration in CNS
MTX excreted in kidneys. Reduce dose in proportion to creatinine clearance
5-FU and oral capecitabine resemble what type of bases
PYRIMIDINES (uracil, thymidine)
How does 5-FU work? ie, what happens after it penetrates cells?
5-FU penetrates cells,
– > metabolized to NUCELOSIDE forms w addition of ribose or deoxyribose
– > catalyzed to enzymes that normally act on U or T
Phosphorylation – > active FLUORINATED nucleotides = 5-FUTP and 5-FdUMP
What are the two active fluorinated nucleotides produced after phosphorylation of 5-FU
5-FUTP
5-FdUMP
What is the fate of the fluorinated nucleotide 5-FUTP (from 5-FU)
5-FU – > 5-FUTP and 5-FdUMP
5-FUTP – > is incorrectly incorporated into RNA RNA RNA (instead of U)
leads to inhibition of nuclear processing of rRNA/mRNA and may cause other errors of base pairing during transcription
What is the fate of the fluorinated nucleotide 5-FdUMP (from 5-FU),
- in particular which enzyme does it inhibit?
- is the reaction reversible or irreversible?
- what does this deplete?
5-FU – > 5-FUTP and 5-FdUMP
5-FdUMP – > irreversible inhibitor of THYMIDYLATE SYNTHASE (normally converts dUMP – > dTMP) – > leads to depletion of dTMP and thus DNA synthesis
5-FdUMP (a metabolite of 5-FU) is an irreversible inhibitor of thymidylate synthase.
Thymidylate synthase is dependent on which cofactor?
TS is dependent on cofactor 5,10-methylenetetrahydrofolate
**All 3 (5-FdUMP, TS, cofactor) combine to form a covalent ternary complex. Dissociation rate of complex is DECREASED if there is EXCESS cofactor (this is why giving leucovorin to patients w 5FU will decrease toxicity)
5-FU is catabolized to _____ in the liver and excreted as CO2, urea, F-beta-alanine
Patients with ____ deficiency (enzyme that eliminates 5FU) have increased toxicity
- 5FU catabolized to DHFU in liver
2. Patients w DPD deficiency (which eliminates 5FU) have increased toxicity)
5FU can be cell cycle specific or NON-specific. Give an example of each
- In cells where toxicity is d/t interruption of DNA synthesis – > should have SPECIFICITY for cells in S-phase
- When major mechanism is incorporation of 5-FUTP into RNA – > should be cell cycle non-specific
Name 5 specific (odd) toxicities of 5FU
- skin rashes
- conjunctivitis
- ataxia (dt effects on cerebellum)
- cardiotoxicity
- palmar-plantar erythrodysthesia (more common w CRI)
