ABSTRACT
BACKGROUND/AIMS: 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. CONCLUSION: 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.
Subject(s)
Cell Adhesion Molecules/analysis , Multiple Myeloma/drug therapy , ADP-ribosyl Cyclase 1/analysis , Cell Adhesion , Drug Resistance, Neoplasm , Female , Humans , Integrin alpha4beta1/analysis , Intercellular Adhesion Molecule-1/analysis , Lymphocyte Function-Associated Antigen-1/analysis , Male , Membrane Glycoproteins/analysis , Middle Aged , Multiple Myeloma/chemistry , Multiple Myeloma/pathology , Syndecan-1/analysis , Vascular Cell Adhesion Molecule-1/analysisABSTRACT
Subcutaneous (SC) injections of ceruletide (caerulein diethylammonium hydrate, CER) and the octapeptide of cholecystokinin (CCK-8) reduced the intake of liquid food in male NMRI mice starved for 18 h. The corresponding ED50 values were 2 micrograms/kg for CER and 24 micrograms/kg for CCK-8; hence, on a molar basis, CER was 14 times more potent than CCK-8. Naloxone (0.2 and 1 mg/kg, SC) inhibited eating. (D-Ala)2(MePhe)4-(Met(O)-ol)5-enkephalin (FK 33-824; 0.3 and 1 mg/kg) was only stimulatory. Naloxone enhanced the effect of CER, whereas FK 33-824 antagonized it. It is concluded that concerning the inhibition of food intake, opioid peptides can be antagonists of CCK-like peptides. This is consistent with the current view of the regulation of appetitive behaviour.
Subject(s)
Ceruletide/pharmacology , D-Ala(2),MePhe(4),Met(0)-ol-enkephalin/pharmacology , Feeding Behavior/drug effects , Naloxone/pharmacology , Sincalide/pharmacology , Animals , Drug Interactions , Male , MiceABSTRACT
In a comparative study new antiinflammatory agents, like sodium-(3-[(2,6-dichlorephenyl)-amino5-phenyl)-acetate (diclofenac); d,l-2-(3-phen0xy-phenyl) propionic acid (fenoprofen); 2-(3-benzoxyl-phenly-propionic acid (ketoprofen); cis-5-fluoro-2-methyl-1-(p-methylsulfinyl) benzylideryl-3-indenyl-acetic acid (MK 231, sulindac); 2-(6-methoxy-2-naphthyl)-propionic acid (naproxen/, showed nearly the same antiiflammatory effectiveness as 5-methoxy-2-methyl-1-(4-chlorobenzoyl)-indolyl-(3)-acetic acid (indometacin). In homogenates of inflamed rat paws an antiproteolytic activity of the new antiinflammatory agents was lacking.
