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Flavopiridol: where do we stand in chronic lymphocytic leukemia?

Leukemia volume 18, pages 243–246 (2004)Cite this article

The findings presented by Dr Billard and his co-workers in a previous issue of Leukemia (‘Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia’) serve to shed more light on the mechanism of action of flavopiridol in B-CLL.1 In particular, this paper identifies two new mechanisms by which this agent induces apoptosis in B-CLL cells: (1) inhibition of nitric oxide (NO) synthase and (2) cleavage and downregulation of the negative cell-cycle regulator p27kip1. Although flavopiridol was initially described as a cyclin-dependent kinase (CDK) inhibitor, subsequent studies have clearly demonstrated that this agent exerts its antitumor activity in B-CLL cells by inducing programmed cell death. These laboratory findings further our understanding of the mechanism(s) by which flavopiridol reverses the antiapoptotic state of B-CLL cells. In addition, these results support the need for continued clinical studies of this drug in patients with B-CLL.

While B-CLL, the most common type of adult leukemia, responds to chemotherapy, only a proportion of patients achieve a complete response (CR) and treatment remains palliative. In recent years, the purine analog fludarabine and fludarabine-based combination regimens have shown improved efficacy in B-CLL, as measured by CR rates and progression-free survival.2,3,4,5,6,7,8,9 However, overall survival has not improved. This inherent resistance of B-CLL cells to traditional cytotoxic therapy arises from the defective apoptosis of these tumor cells. Unlike acute leukemias, which are characterized by uncontrolled proliferation, B-CLL arises from cellular defects in programmed cell death. Thus, cell-cycle-specific agents and other drugs that act against actively dividing and proliferating cells are ineffective in this disease. In B-CLL antiapoptotic proteins such as Bcl-2, Mcl-1 and X-linked inactivator of apoptosis (XIAP) are overexpressed, and high levels of Mcl-1 are associated with the failure of B-CLL patients to achieve CR to initial therapy with fludarabine.10

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Acknowledgements

We thank John C Byrd for reviewing this manuscript and offering thoughtful suggestions and comments.

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  1. Division of Hematology and Oncology, The Ohio State University, Columbus, OH, USA

    T S Lin & P Porcu

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Lin, T., Porcu, P. Flavopiridol: where do we stand in chronic lymphocytic leukemia?. Leukemia 18, 243–246 (2004). https://doi.org/10.1038/sj.leu.2403237

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