RESISTANCE TO CYTOTOXIC CHEMOTHERAPY-INDUCED BY CD40 LIGAND IN LYMPHOMA-CELLS

The modulation of the cytotoxic effects of an anthracyclin by CD40L wa s investigated in five non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Rail, BJAB, BL36, BL70). Incubation with doxorubicin (DOX) increased in a dose-dependent manner the percentage of apoptosis in NHL cells. C oculture with irradiated L cells expressing CD40L (CD40L L cells), but not CDw32 (CDw32 L cells), significantly reduced (33% to 89%) the per centage of apoptosis in all five cell lines treated with 0.1 to 0.5 mu g/mL of DOX, but in only three cell lines at 1 CL mu g/mL. Interleuki n-10 (IL-10), IL-6, IL-2, or tumor necrosis factor (TNF) induced no ad ditive protective effects with CD40L L cells. In all five cell lines, DOX induced a concentration-dependent increase of the activity of the cysteine-protease caspase 3. Coculture with CD40L L cells, but not wit h CDw32 L cells, inhibited (38% to 100%) the activation of caspase 3 i nduced by 0.1 to 0.5 mu g/mL of DOX in all five NHL cell lines, but in only two cell lines at 1 mu g/mL. Finally, the antiproliferative effe ct of 0.1 to 0.5 mu g/mL concentrations of DOX was also partially abro gated on coculture with CD40L L cells in all five cell lines, but in o nly two cell lines at 1 mu g/mL. Cytokines, either alone or in combina tion with CD40L L cells, did not affect DOX-induced inhibition of prol iferation. These results indicate that CD40L inhibits the apoptosis an d antiproliferative effect induced by DOX and Interferes with caspase 3 activation in B NHL cell lines. (C) 1998 by The American Society of Hematology.