Abstract
Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and patients are left with limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL (“consensus” drugs) with five of these showing low or no activity on lymphocytes from a majority of normal donors, suggesting some degree of specificity for the leukemic cells. To our knowledge, this is the first study to screen a drug library against primary CLL cells to identify candidate agents for anti-cancer therapy. The results presented here offer possibilities for the development of novel drug candidates for therapeutic uses to treat CLL and other diseases.
Highlights
Chronic Lymphocytic Leukemia (CLL), the most common leukemia in the Western world, is characterized by the accumulation of monoclonal CD5+ mature B cells in the peripheral blood (PB), lymph nodes (LN) and bone marrow (BM)
Primary cells collected from six CLL patients and five unaffected donors were screened in parallel against the National Institutes of Health (NIH) Chemical Genomics Center Pharmaceutical Collection (NPC) library compounds
Our assay identified over 100 Food and Drug Administration (FDA) approved compounds with anti-CLL activity including, as expected chemotherapeutic agents used in this disease such as fludarabine, chlorambucil, bendamustine, mitoxantrone and vincristine
Summary
Chronic Lymphocytic Leukemia (CLL), the most common leukemia in the Western world, is characterized by the accumulation of monoclonal CD5+ mature B cells in the peripheral blood (PB), lymph nodes (LN) and bone marrow (BM). The standard of care for CLL is watchful waiting of asymptomatic patients and chemoimmunotherapy for patients with active disease [2]. This clinical approach to CLL is guided by the absence of a curative chemotherapy regimen, the results of clinical trials that have shown no benefit for early chemotherapy in asymptomatic patients, and the relatively long natural history of the disease with a median survival of 11 years [3]. CLL is divided into two main subgroups based on the presence or absence of acquired somatic mutations in the immunoglobulin heavy-chain variable region (IGHV) expressed by the leukemic B cells. High expression of ZAP70 and CD38 are additional markers indicating more rapid disease progression [4]. Risk stratified treatment approaches are pursued for patients with these adverse prognostic markers [5,6]
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