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Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma

Maria Bach Laursen, Steffen Falgreen, Julie Støve Bødker, Alexander Schmitz, Malene Krag Kjeldsen, Suzette Sørensen, Jakob Madsen, Tarec Christoffer El-Galaly, Martin Bøgsted, Karen Dybkær, Hans Erik Johnsen, Myeloma Stem Cell Network (MSCNET)

Review Article
Experimental Hematology, In Press, Accepted Manuscript, Available online 27 July 2014

Abstract

Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death—one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines (HBCCL) used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures (REGS). The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms.


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