Genetic changes found in human
osteogenic sarcoma cells, including loss of the p53 and Rb
tumor suppressor elements and overexpression of the
cyclin G1 (CYCG1) proto-oncogene, suggest the potential of gene transfer as a treatment for metastatic disease. In this study, we examined the effects of antisense
cyclin G1, in comparison with antisense
cyclin D1 (CYCD1) and enforced expression of the universal
cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the proliferation of human MG-63
osteosarcoma cells. Retroviral vectors bearing antisense CYCG1 as well as antisense CYCD1 and WAF1/CIP1 (in sense orientation) driven by the Moloney murine leukemia virus long terminal repeat promoter inhibited the growth and/or survival of transduced MG-63 cells in 2-7 day cultures. This represents the first demonstration that
cyclin G1 is essential for the survival and/or growth of human
osteosarcoma cells.
Cytostatic and cytopathic effects were accompanied by a significant increase in the incidence of apoptosis, as determined by immunocytochemical analysis of DNA fragmentation. Furthermore, transduction of MG-63 cells with a retroviral vector bearing the suicide gene,
herpes simplex thymidine kinase (HStk), induced cell death on treatment with
ganciclovir, exhibiting pronounced bystander effects. Taken together, the data affirm the feasibility of modulating inducible cell cycle control
enzymes as a potential gene therapy approach in the clinical management of
osteogenic sarcoma.