gms | German Medical Science

Background: Beside their use as anti-resorptive drug, bisphosphonates are well known to stimulate γ/δT cells and to have direct effects on tumor growth.

Methods: We determined the direct cytotoxic effect of pamidronate and zoledronic acid, the induction of apoptosis and their anti-metastatic potentials. Next, we analyzed how bisphosphonates acts on γ/δT cells propagated with our recently published protocol. The susceptibility of pancreatic carcinoma cells pretreated with bisphosphonates against γ/δT cells was tested in cytotoxicity assays and the subgroup involved in killing was investigated

Results: Zoledronic acid but not pamidronate has a cytotoxic potential even at physiological dosage. Zoledronic acid does not only induce apoptosis by inhibiting the Ras-pathway but has also an anti-metastatic effect. Fresh prepared γ/δT cells consisting mainly out of Vδ2 cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells. gd T cells could be expanded four-fold by use of anti-CD3 and IL-2. However, these γ/δT cells do not respond to bisphosphonates and kill mainly in a Vδ1 dependent manner.

Conclusion: Our results demonstrate that zoledronic acid has a direct apoptotic effect on pancreatic carcinoma cells and has anti-metastatic properties. Tumor cells treated with zoledronic acid are more susceptible against Vγ9Vδ2 T cells, the most abundant population of γ/δT cells in the peripheral blood. Treatment with zoledronic acid for patients with pancreatic carcinoma might be an option.