Fludarabine moa

Fludarabine is the 5’-phosphate of 2-fl uoroadenine arabinoside, a purine nucleotide analog. It is useful in the treatment of chronic lymphocytic leukemia and may replace chlorambucil, the current drug of choice. Fludarabine is also eff ective against hairy cell leukemia and indolent non-Hodgkin lymphoma. Fludarabine is a prodrug, the phosphate being removed in the plasma to form 2-F-araA, which is taken up into cells and again phosphorylated (initially by deoxycytidine kinase). Although the exact cytotoxic mechanism is uncertain, the triphosphate is incorporated into both DNA and RNA. This decreases their synthesis in the S phase and affects their function. Resistance is associated with reduced uptake into cells, lack of deoxycytidine kinase, and decreased affinity for DNA polymerase as well as other mechanisms. Fludarabine is administered IV rather than orally, because intestinal bacteria split off the sugar to yield the very toxic metabolite, fluoroadenine. Urinary excretion accounts for partial elimination. In addition to nausea, vomiting, and diarrhea, myelosuppression is the dose-limiting toxicity. Fever, edema, and severe neurologic toxicity also occur. At high doses, progressive encephalopathy, blindness, and death have been reported.