There is debate regarding the direct effect of
bisphosphonates against visceral
metastases from solid
tumors, despite their proven efficacy against the skeletal complications of
metastasis. The aim of this study was to determine whether
zoledronic acid showed direct activity against five ovarian cell lines and
tumor-derived cells, and whether addition of
zoledronic acid to
cytotoxic agents increased their cytotoxicity. In this study we used a standardized
ATP-based
tumor chemosensitivity assay (
ATP-TCA) to measure the activity of
alendronate,
clodronate and
zoledronic acid in five ovarian
carcinoma cell lines and human solid
tumors (breast, lung, ovarian, unknown primary
carcinoma, and cutaneous and
uveal melanoma) (n=34). We also tested the combination of
zoledronic acid with
paclitaxel and
cisplatin in
tumor-derived cells. All five cell lines exhibited greater sensitivity to
bisphosphonates than the
tumor-derived cells and in all five the IC50 for
zoledronic acid was less than 4 muM. In the
tumor-derived cells,
zoledronic acid showed concentration-dependent inhibition with a median IC50 for all
tumors tested of 17 muM and evidence of apoptosis (
caspase activation). Simultaneous addition of
zoledronic acid to
cisplatin or
paclitaxel showed no major increase in cytotoxicity. We conclude that the activity of
bisphosphonates was greater in cell lines than in
tumor-derived cells. However, the pattern of activity of
bisphosphonates was the same in cell lines and
tumor derived cells. This study suggests a direct, or possibly an indirect, effect of
zoledronic acid and other
nitrogen-containing
bisphosphonates against neoplastic cells, but simultaneous addition with
cisplatin or
paclitaxel does not substantially increase the activity of the
cytotoxic agent.