Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.
OBJECTIVE
Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry.


METHODS
A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules.


RESULTS
ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders.


CONCLUSIONS
This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.
Schmidmaier
R
R
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, München, Germany. ralf.schmidmaier@med.uni-muenchen.de
Mörsdorf
K
K
Baumann
P
P
Emmerich
B
B
Meinhardt
G
G
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000032:analysis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D053668:Syndecan-1 / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1