Eradication of osteosarcoma lung metastasis using intranasal gemcitabine

We sought to determine whether gemcitabine, a new pyrimidine antimetabolite, could inhibit the growth of human osteosarcoma cells (OS) in vitro and in vivo. Four human OS cell lines (MG-63, TE-85, SAOS-2 and SAOS-LM7) were used to assess the activity of the drug in vitro. Gemcitabine caused growth inhibition and cell death in all four cell lines as measured using the MTT and colony-forming assays (IC(50) = 6.5 nM-9 microM and 7-14 nM, respectively). Using our newly developed human SAOS-LM7 OS lung metastasis mouse model, we assessed the in vivo activity of gemcitabine given i.p. and intranasally (i.n.). Mice were treated twice weekly for 3 weeks and then once weekly for 3 weeks using either i.p. or i.n. gemcitabine starting 4 weeks after tumor cell injection. The i.p. injection, at 120 mg/kg, resulted in a decrease in lung weights and the size of the nodules. However, no significant reduction in the number of metastatic nodules was seen (control median: >200 versus gemcitabine median: 150, p = 0.084). In contrast, the number of lung metastases was significantly decreased in mice that received i.n. gemcitabine at 15 (median: 1; range: 0-115, p<0.005) and 12 mg/kg (median: 41; range: 7-163, p = 0.005) when compared with control mice (median: >200). Intranasal therapy is a non-invasive method of drug delivery and has the advantage of targeting the lung, resulting in a higher drug concentration in the tumor area. In our study, i.n. instillation of gemcitabine inhibited the growth of lung metastases at an 8- to 10-fold lower dose than that used i.p. and appeared to be more effective in eradicating OS lung nodules. Because the lung is the most common site of OS metastasis, our data suggest that i.n. gemcitabine may be a novel therapeutic approach in the treatment of OS lung metastases.