Identification of therapeutic candidates for chronic lymphocytic leukemia from a library of approved drugs.
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.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.
Min
M
Shen
Yaqin
Y
Zhang
Nakhle
N
Saba
Christopher P
CP
Austin
Adrian
A
Wiestner
Douglas S
DS
Auld
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008163:Luminescent Measurements; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries
D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D020169:Caspases