gms | German Medical Science

Nitrogen-containing bisphosphonates (N-BP) are effective in preventing osteolytic bone disease in patients with multiple myeloma (MM) and solid tumors. N-BP inhibit the enzyme farnesylpyrophosphate synthase and thus block the prenylation of small GTPases like Ras, Rho and Rac. In vitro studies have demonstrated that N-BP can also directly affect the growth and viability of myeloma cells and several other malignancies as osteosarcoma,breast and prostate cancer. The goal of this study was to investigate potential direct antitumor effects of zoledronate (ZOL), the most active N-BP available, in vivo. ZOL action was tested in the INA-6 SCID model, in which mice were injected intraperitoneally with INA-6 cells, a strictly IL-6 dependent malignant plasma cell line, and subsequently develop plasmacytomas. In several experiments involving more than 50 mice a significant survival benefit of ZOL treated animals compared to the control group (p=0.002) was observed. This effect could be achieved using single doses comparable to those used in patients. Histological examination of plasmacytomas explanted 72 hours after a single injection of 8 µg ZOL revealed wide apoptotic areas in contrast to tumors of untreated animals. Immunohistological examination revealed induction of apoptotic plasma cells already 24 h after ZOL. However, the IL-6 pathway seemed not to be inhibited since two downstream molecules, STAT3 and MAPK p42/44, were phosphorylated. The induction of apoptosis correlated with an accumulation of the unprenylated form of the small GTPase Rap1A, which was virtually absent in tumors of untreated mice. Our findings demonstrate for the first time a direct and specific effect of ZOL in plasmacytomas in vivo and point to a therapeutic potential in malignancies beyond the prevention of osteolytic lesions.