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 and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.
Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
N S
NS
Prabhu
K
K
Somasundaram
H
H
Tian
G H
GH
Enders
K
K
Satyamoorthy
M
M
Herlyn
W S
WS
El-Deiry
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005047:Etoposide / Q000627:therapeutic use*; D019942:Genes, p16; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D018844:Cyclin-Dependent Kinases