Prevent DNA synthesis / Inhibitors of DNA synthesizing enzymes
II. INHIBITORS OF DNA SYNTHESIZING ENZYMES:
CLADRIBINE, CYTARABINE (ARA-C), FLUDARABINE, GEMCITABINE
-
with the exception of HYDROXYUREA, all of these drugs are structurally related to nucleotide bases (i.e., CHEMICALLY, these are antimetabolites)
- MECHANISTICALLY, the difference between these drugs and the antimetabolites discussed earlier (MTX, PREMETREXED, PRALATREXATE, 5-FU, CAPECITABINE, 6-MP, 6TG) is that these drugs do not inhibit nucleotide synthesis pathways
Types
- Antimetabolites:
- PYRIMIDINES: CYTARABINE, GEMCITABINE (converted into compounds that compete with/mimic CDP and CTP)
- PURINE: CLADRIBINE, FLUDARABINE (converted into compounds that compete with/mimic ADP and ATP)
- incorporated into DNA where they block DNA polymerases (α = DNA synthesis and β = DNA repair)
- also inhibit ribonucleotide reductase
- HYDROXYUREA
- inhibits ribonucleotide reductase
- synchronizes cells in a radiation-sensitive phase of the cell cycle (G1)
- also used to treat sickle cell anemia, where it increases production of fetal hemoglobin γ, interfering with the polymerization of HbS, and therefore decreasing painful crises in patients with severe sickle cell disease
- the mechanism whereby it increases fetal hemoglobin γ is unknown