DNA polymerase alpha, DNA polymerase beta, DNA polymerase epsilon (POLA, POLB, POLE)

Fludarabine is an antimetabolite nucleoside analog that is rapidly converted intracellularly into its active triphosphate metabolite (F-ara-ATP). F-ara-ATP acts as a potent inhibitor of several chromosomal DNA polymerases, specifically DNA polymerase alpha (POLA1; the primary enzyme for initiating DNA replication), DNA polymerase epsilon (POLE; responsible for leading strand synthesis during DNA replication), and to a lesser degree, DNA polymerase beta (POLB; primarily active in base-excision DNA repair). F-ara-ATP competitively inhibits these enzymes by mimicking natural nucleotides, and once incorporated into DNA, causes chain termination, blocks further elongation, and can induce DNA strand breaks. The inhibition of DNA synthesis leads predominantly to S-phase arrest and triggers apoptosis (programmed cell death), making these polymerases critical targets in the therapeutic action of fludarabine against hematologic malignancies such as chronic lymphocytic leukemia and indolent lymphomas. Fludarabine also inhibits other related enzymes, including ribonucleotide reductase and DNA primase, further contributing to its cytotoxic effects.

Other names

DNA pol alphaDNA pol betaDNA pol epsilonDNA polymerase αDNA polymerase βDNA polymerase ε

Competitive inhibition of DNA synthesis by incorporation of nucleoside analog triphosphates (e.g., fludarabine triphosphate, F-ara-ATP); Chain termination after incorporation into DNA; Inhibition of enzymatic activity of DNA polymerase alpha and epsilon (S-phase arrest); weaker inhibition of beta (primarily repair polymerase); Induction of apoptosis via DNA damage