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)
Capecitabine (oral fluoropyrimidine derivative)
Absorbed unchanged from GIT and metabolized in liver by ________ to form _______. Then converted to 5’DFUR by ______ (located mainly in liver and tumor). Finally, _____ converts 5’DFUR to 5FU
Capecitabine.
Absorbed unchanged from GIT and metabolized in liver by Carboxylesterase__ to form __5’DFCR. Then converted to 5’DFUR by __Cytidine Deaminase_ (located mainly in liver and tumor). Finally, Thymidine Phosphorylase (TP) converts 5’DFUR to 5FU
Thymidylate synthase inhibitors (give 2 examples) inhibit TS by binding ______ — > depletes dTMPs (which are normally required for DNA synthesis)
Thymidylate synthase inhibitors [Raltitrexed (Tomudex) and Premetrexed Disodium (Alimta)] inhibit TS by binding 5,10-methyenetetrahydrofolate — > depletes dTMPs (which are normally required for DNA synthesis)
Cytosine arabinoside is a nucleoside analog similar to _________
Cytosine arabinoside is a nucleoside analog similar to __deoxycytidine (b-hydroxyl group on 2-position of sugar instead of deoxyribose)___
What is the active form of cytosar (ara-C)
Active form of Ara-C is Ara-CTP - converted to triphosphate in tumor cells
What enzyme degrades Ara-C (cytosar)?
What is the product and by what process?
What enzyme degrades Ara-C (cytosar)?
Cytidine deaminase
What is the product and by what process?
Ara-U (uracil arabinoside), deamination
What is the effect of methotrexate/cytosar interaction
MTX increases ara-CTP formation
What is the effect of fludarabine and hydroxyurea on cytosar?
Like MTX, both increase ara-CTP formation
both inhibit ribonucleotide reductase, decrease CTP pools and increase ara-CTP formatino
Is there synergism between Cytosar and cisplatin?
Only if Ara-C is given BEFORE cisplatin
How does Ara-C (cytosar) enhance alkylator activity?
Inhibits repair of DNA-alkylator adducts
cytoxan, cisplatin, purine analogs, MTX, etoposide
Name 2 mechanisms of resistance for Cytosar
- Decreased activity of CdR kinase (deoxycytidine kinase) (responsible for ara-C to ara-CTP)
- Cells w expanded pool of dCTP that competes w active metabolite ara-C
Toxicity Ara C (8)
- Myelosuppression
- GI epithelial ulceration
- oral mucositis possible
- ileus possible
- Noncardiogenic pulmonary edema
- Cerebellar and cerebral edema (high dose)
- intrahepatic cholestasis
- pancreatits
Ara-C MOA:
Penetrates cells by carrier-mediated mechanism (that deoxyC uses)
Inside cell is phosphorylated by kinases to ____ — > a competitive inhibitor of ___ _______ (enzyme needed for DNA synthesis) — > then cells die if in _______
Ara-C MOA:
Penetrates cells by carrier-mediated mechanism (that deoxyC uses)
Inside cell is phosphorylated by kinases to Ara-CTP — > a competitive inhibitor of _DNA__ _Polymerase__ (enzyme needed for DNA synthesis) — > then cells die if in _S-Phase__
Which one(S) is/are radiosensitizers?
Ara-C
Gemzar
MTX
Gemzar
Gemcitabine = ______ analog, similar to ara-C but also has activity against solid tumors!
Gemcitabine = CYTOSINE analog, similar to ara-C but also has activity against solid tumors!
Gemcitabine MOA
(similar to Ara-C)
1. Requires intracellular activation via phosphorylation to _______ – > incorporated into ____ and inhibits ___ synthesis
- Gemzar can also inhibit ____ _____ – > can affect DNA synthesis by preventing de novo biosynthesis of deoxyribonucloside triphosphate precursors; this is how it has radiosensitizing properties! (by depleting ________ _______ pools)
- Gemzar can stimulate deoxycytidine kinase and inhibit cytidine deaminase
Gemcitabine MOA
(similar to Ara-C)
1. Requires intracellular activation via phosphorylation to dFdCTP – > incorporated into DNA and inhibits _DNA__ synthesis
- Gemzar can also inhibit Ribonucleotide Reductase – > can affect DNA synthesis by preventing de novo biosynthesis of deoxyribonucloside triphosphate precursors; this is how it has radiosensitizing properties! (by depleting _deoxyadenosine__ _triphosphate__ pools)
- Gemzar can stimulate deoxycytidine kinase and inhibit cytidine deaminase
Is Gemzar cell cycle phase specific?
Unlike ara-C, killing effects are NOT limited to S phase
______(enzyme) phosphorylates gemzar intracellularly to produce dFdCMP (difluorodeoxycytidine monophosphate) – > then converted to the diphosphate (__________) and triphosphate (___________) forms.
CdR kinase(enzyme) phosphorylates gemzar intracellularly to produce dFdCMP (difluorodeoxycytidine monophosphate) – > then converted to the diphosphate (__dFdCDP__) and triphosphate (__dFdCTP__) forms.
Gemzar –(CdR kinase)– > dFdCMP —> di and triphosphate forms (dFdCDP and dFdCTP)
What does the diphosphate inhibit? Consequence?
What does the triphosphate inhibit? Consequence?
Gemzar:
- dFdCDP inhibits ribonucleotide reductase, depleting deoxyribonucleoside pools needed for DNA synthesis
- dFdCTP inhibits DNA sythesis, leading to strand termination once incorporated into DNA
4 mechanisms of Gemzar resistance
- Overexpression of ribonucelotide reductase
- increased tumor levels of CdR kinase
- Induction of cytidine deaminase and high concentrations of heat shock proteins
- Inhibition of nuceloside transporters can prevent influx of gemzar through cell membrane (absence of transporters associated w reduced survival of patients w pancreatic cancer)
Name 3 guanine analogs
Guanine analogs:
Azathioprine
6-mercaptopurine (6-MP)
6-thioguanine (6-TG)
Name 3 adenosine analogs
Adenosine analogs:
Cladribine
Fludarabine
Pentostatin
What is allopurinol used for?
What is the MOA?
This has no antineoplastic activity
Allopurinol used for leuk/LSA patients to prevent hyperuricemia and uric acid nephropathy
Allopurinol limits conversion of xanthine to xanthine and hypoxanthine to uric acid by INHIBITING XANTHINE OXIDASE
What is the active metabolite of Allopurinol?
OXIPURINOL is active metabolite of Allopurinol
Cladribine MOA (3)
Incorporated into DNA as false nucleotide
Inhibits DNA polymerase and ribonucleotide reductase
Cladribine activates caspases – > apoptosis
A rash forms when cladribine is used with which drug?
cladribine + allopurinol = rash
Name 2 toxicities of cladribine
Immunosuppression – > infections
RASH
fludarabine is resistant to which process?
fludarabine resistant to DEAMINATION
fludarabine mechanism of cytotoxicity
- inhibition of DNA polymerization
2. termination of DNA and RNA replication
Nucleoside analogs are deaminated by which enzyme?
Adenosine deaminase - rate limiting step for nucleoside analogs
fludarabine: dephosphorylated to ______ – > transported into cells and converted to active triphosphate derivative
fludarabine: dephosphorylated to 2-fluoro-ara-A – > transported into cells and converted to active triphosphate derivative
How does Hydroxyurea cause radiosensitization?
Synchronization in G1-S phase
By depleting deoxynucleotide pools, HU inhibits DNA repair that typically follows RT damage
How is HU excreted? Precautions?
Renal excretion. Dose reduce in failure.
Mechanism of resistance for HU?
Upregulation of ribonucleotide reductase
What three enzymes are inhibited by HU?
DNA polymerases
Thymidylate synthase
Thymidine kinase
How does HU affect Ara-C?
- HU increases metabolism of AraC to active metabolite (and enhances effects of other antimetabolites)
MOA Hydroxyurea
HU:
Inhibits ribonucleotide reductase by inactivation of tyrosyl free radical on M-2 subunit
Is hydroxyurea cell cycle phase specific or not?
HU selectively kills cells in S phase. Cells most rapidly synthesizing DNA are most sensitive.
Cytotoxicity of HU is enhanced by what type of drugs?
iron chelating agents enhance cytotoxicity
What is the relationship between Lspar and methotrexate?
How is the cell cycle involved?
Asparaginase blocks methotrexate action, “rescues” from methotrexate toxicity
♣ Inhibition of PS, prevention of entry into S phase of cell cycle
