Inhibition of RNA transcription: a biochemical mechanism of action againstchronic lymphocytic leukemia cells by fludarabine

Fludarabine is a nucleotide analog effective in the clinical treatment of c hronic lymphocytic leukemia (CLL) and other indolent lymphocytic malignanci es. Although the incorporation of fludarabine into DNA is a key event in ca using cytotoxicity in proliferating leukemia cells, the precise mechanisms by which fludarabine kills CLL cells remain unclear because of the quiescen t nature of this malignancy. The present study demonstrated that inhibition of RNA transcription correlated significantly with the cytotoxic action of fludarabine in CLL cells. In contrast, suppression of the low level of DNA synthesis did not affect the survival of the leukemia cells. In addition, inhibition of fludarabine incorporation into cellular DNA through repair sy nthesis in CLL cells did not alter the cytotoxicity of this drug. Rather, i nhibition of RNA synthesis by fludarabine led to a specific diminishment of certain cellular proteins from CLL cells. The combination of fludarabine w ith another RNA synthesis inhibitor, actinomycin D, or with the protein syn thesis inhibitor, puromycin, substantially enhanced the cytotoxic activity against CLL cells. These results suggest that termination of mRNA transcrip tion and the consequent depletion of proteins required for cell survival ma y be a novel biochemical mechanism of action of fludarabine in CLL cells. T hus, inhibition of RNA/protein synthesis may provide a new therapeutic stra tegy for the treatment of CLL patients.