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Sensitization of cis-platinum by a recombinant adenovirus vector expressing wild-type p53 gene in human ovarian
1Development Therapeutics Department, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Abstract:
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.
Insights
Mutations in the wild-type p53 gene can cause resistance to chemotherapy drugs like CDDP. Restoring wild-type p53 in ovarian cancer cells sensitized them to CDDP, suggesting a new combination therapy approach.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in the tumor suppressor wild-type p53 gene are linked to anticancer drug resistance.
- Ovarian cancer cells with nonfunctional p53 (A2780/CP) exhibit resistance to cis-diamminedichloroplatinum (II) (CDDP).
Purpose of the Study:
- To investigate the role of wild-type p53 in CDDP resistance in human ovarian cancer cells.
- To evaluate the potential of gene therapy using wild-type p53 to overcome CDDP resistance.
Main Methods:
- Utilized a recombinant adenovirus carrying human wild-type p53 cDNA (Adwtp53) for gene transfer.
- Employed CDDP-sensitive (A2780) and CDDP-resistant (A2780/CP) human ovarian cancer cell lines.
- Assessed cell viability, growth arrest, apoptosis markers (Bax, bcl2), and DNA fragmentation.
Main Results:
- Introduction of wild-type p53 into A2780/CP cells significantly sensitized them to CDDP cytotoxicity.
- Wild-type p53 induction promoted A2780/CP cell growth arrest and apoptosis, evidenced by increased Bax expression and DNA fragmentation.
- CDDP further enhanced Adwtp53-induced apoptosis, leading to a 30-fold sensitization of A2780/CP cells.
Conclusions:
- Mutation of p53 confers resistance to CDDP in ovarian cancer cells.
- Restoring wild-type p53 function can re-sensitize resistant ovarian cancer cells to CDDP.
- Combination therapy with wild-type p53 gene transfer and CDDP shows promise for treating p53-mutant ovarian tumors.