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We evaluated the effect of gene therapy in the murine osteosarcoma cell line, LM8, which preferentially metastasizes to the lungs. LM8 cells were transduced with the gene for a herpes simplex virus thymidine kinase (HSV-tk) or Escherichia coli beta-galactosidase (lacZ). We investigated the cytotoxicity of LM8 cells bearing an HSV-tk gene after treatment with ganciclovir (GCV). LM8 cells bearing an HSV-tk gene were more sensitive than non-transduced cells. The remarkable inhibition of tumor growth and pulmonary metastases was confirmed in vivo. Our findings indicated that GCV kills tumor cells transduced with HSV-tk in vitro and in vivo.

When monocytes were cocultured with human osteosarcoma-derived cells (HOS cells), multinucleated giant cell formation of monocytes was induced. Intriguingly, even when a filter was interposed between monocytes and HOS cells, polykaryocytes also appeared. The multinucleated giant cells have characters similar to osteoclast-like cells. These findings indicate that soluble factor(s) secreted from HOS cells play an important role in polykaryocyte formation from monocytes. Twelve cloned cells were established from HSOS-1 cells and their capacities of inducing osteoclasts were investigated. Three cloned cells inducing nos. 4 and 9 had an ability of inducing osteoclasts (multinucleated giant cells, TRAP, calcitonin receptor and c-src mRNAs, osteoresorbing activity), and three cells, including nos. 1 and 5, did not show the ability. HOS cells and the cloned cells expressed several cytokine mRNAs. M-CSF was detected in the culture fluids of HOS cells, which also expressed RANK and RANK/ODF/OPGL mRNAs. Intriguingly, HOS cells secreting a soluble osteoclast inducing factors(s) expressed TNF-alpha converting enzyme mRNA. Furthermore, OCIF/OPG inhibited HOS cell-induced osteoclastogenesis and soluble RANKL could be detected in the culture fluids of HOS cells expressing TACE, suggesting that one of soluble osteoclast-inducing factor(s) is soluble RANKL. When blood monocytes were indirectly cocultured with HSOS-1 cells or cloned no. 9 cells in the presence of OCIF for 14 days, HOS cell-mediated osteoclastogenesis was suppressed, indicating that RANK-RANKL system is involved in the HOS cell-mediated osteoclastogenesis.

Our study focuses on the antineoplasmic action of hyperthermia. In this study, use of a heat-generating cement was exploited for the management of pathological and impending fractures in malignancies. The cement contains magnetic powder in ceramic particles and generates well-regulated heat when a magnetic field is applied externally. Eighteen rabbits were inoculated with blocks of VX2 tumor into one of their tibia. One week after the procedure, 9 rabbits were exposed to a magnetic field (HT group) while the remaining 9 rabbits were not (non-HT group). In rabbits killed between 20 and 42 days after the VX2 inoculation, the circumference of the operated leg was 7.9 +/- 0.3 cm and 10.2 +/- 1.0 cm (mean +/- SE) in HT and non-HT groups, respectively ( P < 0.05). Histological findings revealed the regressive change in tumor tissue of the HT group. By radiographs, pathological fractures and cortical bone destruction were seen in 5 and 8 rabbits in the non-HT group, respectively, but in the HT group these effects were absent in all the rabbits except 1 in which a definite diagnosis has not been made. Our findings demonstrate that controlled hyperthermia therapy using a newly developed bone cement suppresses tumor growth and prevents local bone destruction caused by VX2 tumors.