Emergence of cisplatin-resistant cells from the OVCAR-3 ovarian carcinoma cell line with p53 mutations, altered tumorigenicity, and increased apoptotic sensitivity to p53 gene replacement

Resistance to chemotherapy commonly compromises the treatment of many advan ced cancers. Evidence suggests a correlation between chemoresistance and mo re aggressive tumor growth, possibly through accumulation of additional gen etic defects in drug-treated or resistant cells. To study this process in a human ovarian cancer model, we examined OVCAR-3 cells for acute sensitivit y to cisplatin (cDDP) and subsequent emergence of drug-resistant clones fol lowing chronic cDDP exposure. Clonal cells (OVCAR-3/C-1) that displayed 20- fold reduced sensitivity to cisplatin but retained equivalent sensitivity t o paclitaxel, as compared with the parental population, were isolated. The cDDP-resistant clone had growth kinetics similar to those of parental popul ation, but when transplanted into the peritoneal cavity of nude mice, they acquired the ability to grow with the development of both ascites and solid tumor masses; such growth was not detectable after transplantation of the drug-sensitive parental cell line. C-1 cells had a p53 gene mutation (codon 266) that was not detected in the parental OVCAR-3 cell line, and infectio n of C-1 cells with p53-adenovirus (rAd-p53) caused greater apoptosis and g ene transduction than that observed in the similarly infected parental popu lation. rAd-p53 induced high levels of p21WAF1, p27Kip1, activated caspase 3 and apoptosis in C-1 cells, without causing major changes in bax or bcl-X -L levels. Together, the results suggest that alterations in tumor growth a nd gene mutations characterize cDDP-resistance in OVCAR-3 cells, and viral replacement of one of these defective genes (p53) may provide an effective treatment for elimination of drug-resistant cells.