Sensitization of cis-platinum by a recombinant adenovirus vector expressing wild-type p53 gene in human ovarian carcinomas.
Mutations of the tumor suppressor wild-type p53 gene have been implicated in the development of resistance to anticancer drugs. We have examined the role of wild-type p53 in resistance to cis-diamminedichloroplatinum (II) (CDDP) in human ovarian cancer cells using a recombinant adenovirus containing human wild-type p53 cDNA (Adwtp53). In this study we used the human ovarian A2780 tumor cells (wtp53), which are sensitive to CDDP and A2780/CP tumor cells (nonfunctional/mutant p53) and are resistant to CDDP. Studies show that introduction of wtp53 protein via adenovirus gene transfer into A2780/CP cells significantly sensitized these cells to CDDP cytotoxicity, indicating wtp53 was involved in resistance to CDDP. We found that introduction of wtp53 protein also resulted in growth arrest of A2780/CP tumor cells whereas the parent A2780 cells were significantly less sensitive to Adwtp53. This synthesis of wtp53 protein induced by Adwtp53 in A2780/CP cells resulted in a significant increase in the expression of Bax protein without significantly effecting the expression of bcl2 protein, and induced a dose-dependent increase in the nucleosomal DNA fragmentation. The presence of CDDP further enhanced this apoptosis, causing a 30-fold sensitization of A2780/CP cells to CDDP. These results indicate that mutation of p53 protein in A2780/CP ovarian tumor cells resulted in the resistance to CDDP and that combination of wtp53 gene and CDDP may result in sensitization of mutant p53-containing tumors to chemogenetherapy.
Song
K
K
Development Therapeutics Department, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Li
Z
Z
Seth
P
P
Cowan
K H
KH
Sinha
B K
BK
D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D002945:Cisplatin