Cytotoxic combination of loxoribine with fludarabine and mafosfamide on freshly isolated B-chronic lymphocytic leukemia cells

Fludarabine has shown a definite clinical activity in B-cell chronic lympho cytic leukemia (B-CLL). Recently it has been demonstrated that loxoribine, a guanine ribonucleotide derivative, is able to increase the cytotoxicity o f fludarabine in B-CLL cells, in vitro. We have here extended these finding s by testing the activity of loxoribine in combination with fludarabine and mafosfamide. As we have previously demonstrated, loxoribine enhances the a ctivity of fludarabine at all concentrations, while only lower doses of maf osfamide seem to be positively affected by loxoribine. The combination of f ludarabine and mafosfamide is synergistic on CLL cells, and the cytotoxic a ctivity is increased by the addition of loxoribine. We have also evaluated the pro-apoptotic activity of each drug, both alone and in combination; the se results are concordant with the cytotoxicity data, thus demonstrating th at, even though loxoribine is more active in combination with fludarabine t han with mafosfamide, the efficacy of the triple combination is higher than that obtained with any other agent alone or in double combination.