Concomitant exposure of ovarian cancer cells to docetaxel, CPT-11 or SN-38 and adenovirus-mediated p53 gene therapy.
Owing to its central role in multiple cellular functions, p53 is an attractive candidate for gene replacement therapy. We studied the role of adenovirus-mediated p53 gene (p53Ad) therapy on sensitivity of two ovarian cancer cell lines, OVCAR-3 (p53(mut)) and SK-OV-3 (p53(wt)), to docetaxel, CPT-11 and SN-38 exposures. Expressions of Bcl-XL, Bcl-XS, p53, Gadd45, c-fos, p21(waf1/cip1), Bax, Bcl-2 and Mcl-1 were measured after concomitant p53Ad and drug exposures. In SK-OV-3 cells containing a normal p53 gene, p53Ad alone or concomitantly with docetaxel, CPT-11 or SN-38 exposures did not have an effect on cell growth, cell cycle distribution or induction of apoptosis. In OVCAR-3 cells, p53 gene therapy inhibited the cell growth and sensitized cells to CPT-11/SN-38, but not to docetaxel. Growth inhibition and sensitization were results of G2M cell cycle arrest and increased apoptosis. In SK-OV-3 cells, but not in OVCAR-3 cells, CPT-11/SN-38 exposures alone increased p21(waf1/cip1) expression. The p53Ad therapy induced strong p21(waf1/cip1) expression in both cell lines. In addition, the expression of Bax and expression ratios Bax/Bcl-2 and Bax/Bcl-XL increased in p53Ad-infected OVCAR-3 cells, but not in SK-OV-3 cells. These expression ratios were further increased in p53Ad+CPT-11/SN-38-exposed OVCAR-3 samples. These results support the combination of p53 gene therapy with topoisomerase I inhibitors SN-38/CPT-11 when tumour cells contain mutated p53. When p53 status is normal, p53 gene therapy is not effective alone or concomitantly with CPT-11/SN-38. Increased expression ratios of Bax/Bcl-2 and Bax/Bcl-XL might serve as positive markers for effective p53 gene therapy and concomitant topoisomerase I inhibitor therapy.
Miettinen
Susanna
S
Department of Cell Biology, Medical School, Tampere University Hospital, Tampere, Finland. susanna.miettinen@regea.fi
Ylikomi
Timo
T
D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D000077146:Irinotecan; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D043823:Taxoids / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D000077146:Irinotecan; D002166:Camptothecin