Synergistic cytotoxic effects of zoledronic acid and radiation in human prostate cancer and myeloma cell lines

The clinical use of the potent bisphosphonate zoledronic acid has increased recently, especially for the treatment of bone metastases. Synergistic effects with chemotherapeutic agents (e.g., doxorubicin, paclitaxel) have been shown. It is not known whether similar synergistic effects exist with radiation. IM-9 myeloma cells and C4-2 prostate cancer cells were treated with up to 200 μM concentrations of zoledronic acid, irradiated with single doses of up to 1,000 cGy, or exposed to combinations of both treatments. Cell viability was then determined via yellow dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay and the affected fractions analyzed using the median effect principal, a method developed and validated by Chou and Talalay. A statistically significant synergistic cytotoxic effect of the combination of zoledronic acid and radiation was documented. The extent of the effect was cell type–dependent, with the C4-2 cells showing a greater synergistic effect than the IM-9 cells. The combined use of zoledronic acid and radiotherapy shows enhanced in vitro cytotoxicity for two human prostate and myeloma cancer cell lines over that expected for a simple additive effect from each treatment alone. A clinical trial is under way to test this combination therapy.