Lecture 3: Antimetabolites Flashcards
Antimetabolites
Mimic natural metabolites
Interfere with biosynthetic pathways-block enzymes
Inhibits critical step in nucleic acid synthesis:
Anti-folate
Pyrimidine analogues
Purine analogues
Most are CELL CYCLE SPECIFIC: max cytotoxicity in S-phase
Toxicity reflected in proliferating cells: GIT, Bone marrow, Hair loss
Not carcinogenic bc low dose given for a long time rather than hi dose
Methotrexate(MTX)
Folate analogue-INSIDE CELLS folate and MTX converted to polyglutamates
No dTMP formed since MTX(and pG-MTX) blocks FH4 formation and also polyglutamated-MTX(pG-MTX) blocks dUMP->dTMP
Most widely used antimetabolites
Breast cancer protocol CMF-M=methotrexate
Childhood acute lymphoblastic leukemia
Osteogenic sarcoma[HDMTX(hi dose MTX)+ Leucovorin rescue]
SFX: oral and GIT ulcerations, Myelosuppression, pulmonary infiltrate and fibrosis
Leucovorin
Used to rescue normal tissue from MTX toxicity
Mech: dihydrofolate reductase(DHFR)-independent conversion to FH4**(MTX blocks this normally)
Selectivity: Hi dose of MTX can enter tumour cells, but lower doses of MTX and Leucovorin are actively pumped out
Hi doses of MTX, low MTX and Leucovorin can enter all normal cells(since they have less transporters to pump them out therefore effective for saving normal tissue
Possible mechanism of MTX resistance
Reduce uptake via folate transporters
Increased MTX efflux
Via ABC family transporters (MRPs1-4 or ABCG2
Altered target enzyme
Reduction in polyglutamation
Folylpolyglutamate synthetase
Increase thymidine uptake(SALVAGE PATHWAY)
Pyrimidine Analogues
Antimetabolites which mimic the structure of metabolic pyrimidines
Fluorouracil: nucleoBASE analogue-”fluors” are base of houses
Cytosine arabinoside: nucleoSIDE analogue
Gemcitabine: nucleoSIDE analogue-gems are side pieces
5-fluorouracil(5-FU)
nucleobase:SLOW
Mech: inhib DNA synthesis(inhibit thymidylate synthase), slows growing tumors, suicide substrate
See diagram
Capecitabine
Prodrug of 5-FU
Oral administration, has largely replaced 5-FU, especially in GIT cancer
ENZYMES: Carboxylesterase(liver), Cyd deaminase(liver & tumour), dThdPase(tumour)-ONLY TUMOURS WILL METAB capecitabine
Specific thymidylate synthase inhibitors
Raltitrexed
Product of TS substrate binding pocket
Transport into cell via folate transporter
Fully active after polyglutamylation
Potent inhibitor of TS IC50=9nM in vitro, competes with N5N10methylene THF
Result: Inhibits DNA synthesis, deplete dTMP, S-phase specific
Used in colorectal cancer
Cytidine Analogs-pyrimidine nucleoside analogs
Cytarabine(araC) and Gemcitabine(dFdC)= BOTH PRODRUGS
S-phase specific
Clinical resistance to araC(Cytarabine)
Decrease uptake via nucleoside transporter
Increase activity of cytidine deaminase-araU path(RNA synthesis)
Decrease activity of dCK-first step
Change in activity of DNA polymerase
Cytarabine(araC)
Acute myeloid leukemia(AML) Long, intravenous infusions Rapid deamination and clearance S-phase specificity Myelosuppression***-dose limiting
Gemcitabine(dFdC)
Same activation path as araC dFdCTP incorporated into DNA Inhibition of DNA polymerization dFdCDP inhibits ribonucleotide reductase Irreversible inhibition Diphosphate form binds to active site Activity in solid tumors Pancreas, lung, breast SFX: Myelosuppression***
Purine Analogues
Fludarabine:
Nucleotide analogue
Used mainly in chronic lymphocytic leukemia(CLL)
Inhibits various enzymes:
DNA polymerase, ribonucleotide reductase
DNA ligase, partially inhibits RNA polymerase
Prevents elongation of DNA strands through direct incorporation into DNA as a false nucleotide
Active against both diving and resting cell-most cytotoxic during S-Phase
Purine analogues: Nucleobases
Converted into fraudulent nucleotides
Incorporated into DNA
Inhibits various enzymes
Used mainly for acute lymphoblastic leukemia
EX. Azathioprine: block DNA and RNA synthesis
