Chemosensitivity and p53‐dependent apoptosis in epithelial ovarian carcinoma

Abstract

BACKGROUND Although p53 gene mutation frequently is observed in ovarian carcinoma, the function of the p53 gene in chemosensitivity has not been defined conclusively. The objective of the current study was to elucidate the relation between chemotherapy-induced apoptosis through the p53 pathway and chemosensitivity to ovarian carcinoma. METHODS Tumor samples were obtained from 24 patients with epithelial ovarian carcinoma before and after chemotherapy with cisplatin, doxorubicin, and cyclophosphamide. Mutations in the p53 gene were screened by polymerase chain reaction–single-strand conformation polymorphism analysis and determined by cycle sequencing. Expression of the p53, Bax, and bcl-2 proteins and proliferating cell nuclear antigen (PCNA) were determined by immunohistochemical staining. Apoptotic cells were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling method. RESULTS Of the 24 patients, 12 responded to chemotherapy and 12 did not. p53 gene mutation was observed in ten nonresponders and two responders. The incidence of p53 protein expression in tumors with the gene mutation was 58% (7 of 12) and was 17% (2 of 12) in tumors without the gene mutation. A significant reverse correlation between apoptotic index (AI) and labeling index (LI), determined by the percentage of PCNA positive cells, was observed in tumors after chemotherapy. AI was found to increase significantly after chemotherapy in tumors with the wild-type p53 gene (3.84 ± 1.64 vs. 7.13 ± 5.23) but LI did not change in either tumor type. The expression of Bax protein was significantly greater in tumors with the wild-type p53 gene after chemotherapy. bcl-2 protein expression did not relate to p53 gene status before or after chemotherapy. CONCLUSIONS The current study suggests that p53-dependent apoptosis in tumors is strongly related to the chemosensitivity in epithelial ovarian carcinoma. Cancer 1999;86:1307–13. © 1999 American Cancer Society.