Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study.
New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogenetic abnormalities (p = 0.02). Sensitivity of bone marrow and lymph node cells was highly correlated with that of blood cells. Even though direct killing may not be the only therapeutic effector function in vivo, results from this head-to-head comparison may help to identify drugs of particular interest for intensified clinical development.
Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address: sandra.eketorp-sylvan@karolinska.se.
Sandra Eketorp
SE
Sylvan
Department of Microbiology, Tumor and Cell Biology and Center for Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden.
Henriette
H
Skribek
Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Stefan
S
Norin
Department of Microbiology, Tumor and Cell Biology and Center for Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden.
Orsolya
O
Muhari
Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Anders
A
Österborg
Department of Microbiology, Tumor and Cell Biology and Center for Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden.
Laszlo
L
Szekely
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents