loxoribine and fludarabine

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

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Cyclophosphamide; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Female; Guanosine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Tumor Cells, Cultured; Vidarabine

Purine analogues like fludarabine have been shown to be superior to conventional therapy for B-cell chronic lymphocytic leukemia (B-CLL). In order to improve the activity of fludarabine, we tested its combination with loxoribine, a guanine ribonucleotide derivative, known to enhance the sensitivity of B-CLL cells to cytotoxic drugs. B-CLL cells from 6 patients were studied; co-incubation with loxoribine 100 microM increased the activity of fludarabine by 12% to 48%, as demonstrated by XTT colorimetric assay; while 1000 microM loxoribine exerted a protective effect. Accordingly, fludarabine-induced apoptosis was enhanced by the addition of loxoribine 1000 microM (39% increase). These results indicate that the combination of loxoribine and fludarabine could be of interest in B-CLL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Drug Interactions; Drug Screening Assays, Antitumor; Female; Guanosine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Tumor Cells, Cultured; Vidarabine