8CL-CAMP CYTOTOXICITY IN BOTH STEROID SENSITIVE AND INSENSITIVE MULTIPLE-MYELOMA CELL-LINES IS MEDIATED BY 8CL-ADENOSINE

We have examined the cytotoxic effects of cyclic adenosine-3',5'-monop hosphate (cAMP) derivatives on multiple myeloma cells lines and determ ined that the 8-Chloro substituted derivative (8Cl-cAMP) is one of the most potent. We report here that 8Cl-cAMP is cytotoxic to both steroi d sensitive and insensitive myeloma cells with a half maximal concentr ation of approximately 3 mu mol/L. 8Cl-cAMP toxicity in myeloma cells is dependent on phosphodiesterase activity in the serum of cell cultur e medium. A metabolite of 8Cl-cAMP, 8-Chloro-adenosine (8Cl-AD), kills myeloma cells as effectively as 8Cl-cAMP. Adenosine deaminase (ADA) c onverts 8Cl-AD into 8Cl-inosine and abrogates the cytotoxic effects of 8Cl-cAMP, 8Cl-AMP, and 8Cl-AD, as does 5-(p-Nitrobenzyl)-6-Thio-Inosi ne (NBTI), an inhibitor of nucleoside uptake. These data suggest that 8Cl-cAMP must be converted to 8Cl-AD and that 8Cl-AD is the compound t hat enters the cell. Contrary to glucocorticoid-mediated cell death in myeloma cells, the pathway of 8Cl-AD-mediated cell death appears to b e independent of interleukin-6 (IL-6) actions. Although the exact mode of action for this agent is currently unknown, its ability to kill st eroid sensitive and insensitive multiple myeloma cells in an IL-6 inde pendent fashion may offer exciting new therapeutic options. (C) 1998 b y The American Society of Hematology.