p53 gene status and chemosensitivity in ovarian cancer.
Recent studies suggest that drug induced apoptosis relates to the sensitivity. p53 gene, which has a pivotal role in inducing apoptosis, frequently mutates in ovarian cancer. Therefore, p53 gene status and chemosensitivity in epithelial ovarian cancer is discussed. Nonresponders to chemotherapy had mutations of the p53 gene more frequently (83% for nonresponders vs. 16% for responders) in patients with epithelial ovarian cancer undergoing platinum-base chemotherapy. Apoptotic index was significantly greater in tumors with wild-type p53 gene than those without the gene. p53 gene transduction markedly enhanced the sensitivity to cisplatin (CDDP) and CDDP-induced apoptosis, but did not affect the sensitivity to paclitaxel (PTX) nor PTX-induced apoptosis in ovarian cancer cells without p53 gene. The combination treatment with a recombinant adenovirus carrying a wild-type p53 gene (AxCAp53) and CDDP significantly suppressed tumor growth of ovarian cancer cells with and without p53 gene, compared with a single treatment of either AxCAp53 or CDDP in ovarian cancer xenograft. Apoptotic index was significantly higher and proliferating cell nuclear antigen labeling index was relatively lower in an ovarian cancer xenograft without p53 gene receiving combination treatment, compared with a single treatment of either CDDP or AxCAp53, suggesting that the transduction of p53 gene induces apoptosis, but does not enhance the DNA repair system. A significant survival advantage was observed in the combination treatment compared with other treatments in carcinoma peritonitis models. In conclusion, p53 gene status contributes the sensitivity to CDDP in ovarian cancer. Additionally, combination treatment of p53 gene transduction and CDDP may be an effective therapeutic modality for ovarian cancer without wild-type p53 gene.
Kigawa
J
J
Department of Obstetrics and Gynecology, Tottori University, School of Medicine.
Sato
S
S
Shimada
M
M
Takahashi
M
M
Itamochi
H
H
Kanamori
Y
Y
Terakawa
N
N
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D017239:Paclitaxel; D002945:Cisplatin