RETROVIRAL VECTOR-MEDIATED TRANSFER OF AN ANTISENSE CYCLIN G1 CONSTRUCT INHIBITS OSTEOSARCOMA TUMOR-GROWTH IN NUDE-MICE

Metastatic osteosarcoma is a potential target for gene therapy, becaus e conventional therapies are only palliative and metastatic disease is invariably fatal, Overexpression of the cyclin G1 (CYCG1) gene is fre quently observed in human osteosarcoma cells, and its continued expres sion is found to be essential for their survival, Previously, we repor ted that down-regulation of cyclin G1 protein expression induced cytos tatic and cytocidal effects in human MG-63 osteosarcoma cells (Skotzko et al., Cancer Research, 1995), Here, we extend these findings in a t umorigenic MNNG/HOS cell line and report on the effective inhibition o f tumor growth in vivo by an antisense cyclin G1 retroviral vector whe n delivered as concentrated high titer vector supernatants directly in to rapidly growing subcutaneous tumors in athymic nude mice, Histologi c sections from the antisense cyclin G1 vector-treated tumors showed d ecreased mitotic indices and increased stroma formation within the res idual tumors, Furthermore, in situ analysis of the cell-cycle kinetics of residual tumor cells revealed a decrease in the number of cells in S and G2/M phases of the cell cycle concomittant with an accumulation of cells in the G1 phase, Taken together, these studies demonstrate i n vivo efficacy of a high-titer antisense cyclin G1 retroviral vector in an animal model of osteosarcoma.