A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers.
The cytotoxicity of a recombinant adenovirus expressing the wild type tumor suppressor gene p53 (AdWTp53) was studied in two human breast cancer MCF-7 sublines selected for resistance to adriamycin (MCF-Adr) and mitoxantrone (MCF-Mito). Although the levels of wild type p53 protein following infection with AdWTp53 are comparable in all cell lines, the two drug-resistant MCF-7 sublines were 300- and 18-fold more sensitive to killing by AdWTp53 compared with the drug-sensitive parental MCF-7 cell lines. In each cell line, AdWTp53 infection led to cell cycle arrest, and reduction of Cdk2 and cyclin B1-Cdc2 activity. Nucleosomal DNA fragmentation analysis (as a function of apoptosis) following AdWTp53 infection revealed that, while the parental MCF-7 cells failed to undergo apoptosis, both drug-resistant cell lines showed distinct DNA laddering. In MCF-Adr cells, a combination treatment of AdWTp53 and adriamycin was much more toxic than either of the reagents used individually. Finally, exposure of a mixed population of MCF-Adr and CD34+ cells to AdWTp53 selectively prevented MCF-Adr cell colony formation, while there was no inhibition of CFU-GM colony formation from CD34+ cells. These findings suggest that some drug-resistant human breast cancers may be effectively treated with adenovirus expressing wild type p53.
Seth
P
P
Medical Breast Cancer Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. pseth@boxp.nih.gov
Katayose
D
D
Li
Z
Z
Kim
M
M
Wersto
R
R
Craig
C
C
Shanmugam
N
N
Ohri
E
E
Mudahar
B
B
Rakkar
A N
AN
Kodali
P
P
Cowan
K
K
D000256:Adenoviridae; D017209:Apoptosis; D016465:Bone Marrow Purging; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008942:Mitoxantrone / Q000633:toxicity; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008942:Mitoxantrone