Antitumor activity of fludarabine against human multiple myeloma in vitro and in vivo

Abstract Fludarabine, a nucleoside analogue, plays a major role in the treatment of B‐cell lymphocytic leukemia, hairy cell leukemia, and indolent lymphomas. There is a controversy about antitumor activity of fludarabine in multiple myeloma (MM). The aim of this study was to evaluate the activity of fludarabine against human myeloma cells both in vivo and in vitro . We demonstrated that myeloma cell line RPMI8226 was efficiently inhibited by fludarabine, concomitantly with decreased phosphorylation of Akt, down‐regulation of the inhibitor of apoptosis proteins (IAP) family, including XIAP and survivin, and induction of apoptosis related to activation of caspase cascade. Contrary to dexamethasone, the effect of fludarabine on RPMI8226 cells was independent of interleukin‐6. Fludarabine also induced cytotoxicity in dexamethasone‐sensitive (MM.1S) and ‐resistant (MM.1R) cells at 48 h with IC 50 of 13.48 μg/mL and 33.79 μg/mL, respectively. In contrast, U266 cells were resistant to fludarabine. Moreover, RPMI8226 myeloma xenograft model was established using severe combined immunodeficient mice. The tumors treated with fludarabine at 40 mg/kg increased less than 5‐fold in 25 d comparing with approximately 10‐fold in the control tumors, demonstrating the antitumor activity of fludarabine in vivo . These results suggest that fludarabine may be an important therapeutic option for MM patients who are resistant to dexamethasone.