Adenoviral-mediated wild-type p53 gene expression sensitizes colorectal cancer cells to ionizing radiation.
Wild-type p53 gene transfer into the SW620 colorectal carcinoma cell line was performed using the replication-defective adenovirus Ad5/CMV/p53 to evaluate the effect of wild-type p53 expression on radiation sensitivity. The results indicated that infection with Ad5/CMV/p53 sensitized the cells. The survival at 2 Gy was reduced from 55 to 23%. Flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-labeled cells and in situ TUNEL staining of xenograft tumors demonstrated an increase in labeled cells with combination treatment, indicating increased apoptosis in cells treated with Ad5/CMV/p53 before irradiation. A significant enhancement of tumor growth suppression by this combination strategy was observed in a s. c. tumor animal model compared to p53 gene therapy alone. The delay in regrowth to control tumor size of 1000 mm3 was 2 days for 5 Gy, 15 days for Ad5/CMV/p53, and 37 days for Ad5/CMV/p53 + 5 Gy, indicating synergistic interactions. These data indicate that the delivery of wild-type p53 to cells with p53 mutations increases their radiation sensitivity, and this may be accomplished by adenoviral-mediated gene therapy.
Spitz
F R
FR
Departments of Surgical Oncology, Section of Thoracic Molecular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Nguyen
D
D
Skibber
J M
JM
Meyn
R E
RE
Cristiano
R J
RJ
Roth
J A
JA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53