Activity of Bendamustine in Chronic Lymphocytic Leukemia
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Liang, William Siyuan
Chronic lymphocytic leukemia (CLL) is a common leukemia, with a heterogeneous clinical course. When treatment is required, patients usually receive an alkylating agent, such as chlorambucil, or a nucleoside analogue, such as fludarabine, or a combination of the two types of drug. Bendamustine is a promising new agent for CLL and is believed to have the properties of an alkylating agent, with some features of a nucleoside analogue. In the present study, we have compared the activity of bendamustine with chlorambucil and fludarabine in primary CLL cells, to determine whether bendamustine is more typical of an alkylating agent or a nucleoside analogue. In addition, we investigated whether bendamustine retains activity against cells that are resistant to the other agents. Cell viability studies using the MTT assay demonstrated that bendamustine produced a linear dose-response curve and a narrow range of effective drug concentrations, between sensitive- and resistant-cases. This is very similar to that seen with chlorambucil, but not with fludarabine. Using annexin V/7-ADD staining and flow cytometry, we demonstrated that the three drugs induced apoptosis in CLL cells, that they had equivalent antitumor activities and that there appeared to be cross-resistance between the drugs. Finally, using y-H2AX staining to measure DNA double-strand breaks (DSB), we demonstrated that with equivalent drug doses, bendamustine and chlorambucil produced few DSB whereas fludarabine produced a high number of DSB. In summary, our study suggests that bendamustine has equivalent antitumor activity as chlorambucil or fludarabine against CLL cells in vitro, with properties that are more typical of an alkylating agent.
bendamustine, chronic lymphocytic leukemia