2',2'-DIFLUORODEOXYCYTIDLINE (GEMCITABINE) INDUCES APOPTOSIS IN MYELOMA CELL-LINES RESISTANT TO STEROIDS AND 2-CHLORODEOXYADENOSINE (2-CDA)

The paucity of effective cytotoxic agents for the treatment of steroid resistant multiple myeloma explains the ongoing search for alternativ e substances for chemotherapy of this disease. In the present study, t he purine antagonist 2-chlorodeoxyadenosine (2-CdA, cladribine) and th e pyrimidine antagonist 2',2'-difluorodeoxycytidine (gemcitabine) were tested on four myeloma cell lines (i.e., U 266, OPM 2, RPMI 8226, IM 9), one plasma cell leukemia cell line (HS Sultan) and a myeloid contr ol cell line (HL 60), all of which are resistant to 10(-6) M dexametha sone. Gemcitabine has been found to be promising in the chemotherapy o f other tumors with low proliferative activity, but its effectiveness against myeloma cells has not been analyzed so far. In our tests, gemc itabine induced a significant degree of apoptosis in all cell lines in vestigated. After incubation for 48 h with 10 mu M gemcitabine, the me dian numbers of apoptotic cells were in the range of 45% in the OPM 2 and 79% in the U 266 cell line. All of tbe investigated cell lines wer e responsive to concentrations of 10 mu M gemcitabine even after an ex posure of only 30 min, three of them (U 266, HS Sultan, IM 9) also res ponded to a concentration of 10 nM. Higher concentrations and longer e xposure times were necessary to suppress the growth of normal hematopo ietic bone marrow progenitor cells. In contrast to gemcitabine, standa rd concentrations of 2-CdA (i.e., 30 and 300 nM) failed to induce a si gnificant degree of apoptosis in the cell lines investigated but inhib ited the growth of myeloid progenitor cells. The results suggest that gemcitabine induces apoptosis in myeloma and plasma cell Leukemia line s resistant to steroids and 2-CdA. The fact that tumor cell apoptosis was achieved at concentrations clinically achievable and tolerable, wh ich at the same time do not inhibit the growth of normal CFU-GM progen itor cells, favors the initiation of phase I trials with this drug for the treatment of multiple myeloma.