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 IC50 of 13.48 microg/mL and 33.79 microg/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.