The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity

Cyclin-dependent kinase inhibitors are potent suppressors of cell growth an d have been proposed as targets for gene replacement therapy in cancer. Exp ression of either p16(INK4a) or p21(WAFI) protected cells from the cytotoxi c effects of the topoisomerase II inhibitor, etoposide. A lower level of p5 3 was induced in CDK inhibitor-expressing etoposide-exposed cells suggestin g that protection may be due to lower levels of DNA damage in the growth ar rested cells. Exposure of human osteosarcoma cells to either p16(INKa) or p 21(WAF1) prior to and during etoposide therapy protected cells against etop oside-induced cell death. Infection of the cells by p16(INK4a) or Ad-p21(WA F1) following exposure to etoposide resulted in loss of the protective effe ct with evidence of enhanced growth inhibition. The results suggest that th e schedule of administration of DNA damaging etoposide chemotherapy and cel l cycle inhibitory therapy is a major determinant of the resulting cytotoxi city.