Influence of the proto-oncogene c-fos on cisplatin sensitivity.
Cisplatin resistance has been associated with overexpression of the c-fos gene in a human ovarian carcinoma cell line. To determine whether the correlation between c-fos overexpression and cisplatin resistance was limited to this cell line or was a more generalized phenomenon, we investigated cisplatin sensitivity in rat fibroblast cells that overexpressed the c-fos gene. The cisplatin Ic50 values for two different c-fos transfectants, CMVc-fos and L1-3c-fos, were 7.6 +/- 0.8 and 5.6 +/- 1.0 microM, respectively, whereas the cisplatin Ic50 value for the parental line, 208F, was 2.4 +/- 0.1 microM. This represented a 3.2- and 2.3-fold resistance to cisplatin for CMVc-fos and L1-3c-fos cells, respectively. The correlation between c-fos expression and cisplatin resistance also was examined in a human ovarian carcinoma cell line, 2008, and its cisplatin-resistant variant, C13*. Expression of c-fos was elevated slightly at both the mRNA and protein levels in the C13* cells compared with 2008 cells, and c-Fos protein levels were induced in C13* cells following cisplatin treatment. In addition, it was observed that C13* cells were significantly more sensitive than 2008 cells to a c-fos antisense oligonucleotide. The Ic50 values for the c-fos antisense oligonucleotide were 19.9 +/- 5.0 pmol for C13* cells and 58.1 +/- 6.0 pmol for 2008 cells (P = 0.0012). Furthermore, combinations of c-fos antisense and cisplatin reduced the amount of cisplatin required to kill 50% of the C13* cells, although the interaction was not synergistic. These results suggest that expression of the c-fos gene can influence cisplatin sensitivity, and that c-fos antisense oligonucleotide based therapy may be effective at killing parental and cisplatin-resistant ovarian carcinoma cells, either alone or in combination with cisplatin.
Moorehead
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Ontario Cancer Treatment and Research Foundation, Hamilton Regional Cancer Centre, Canada.
Singh
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D016762:Genes, fos; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010051:Ovarian Neoplasms; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology; D051381:Rats; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D002945:Cisplatin