Abstract
Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Ha-ras and β-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by allele-specific oligonucleotide hybridization; β-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was ∼30% (6/20), while no β-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while ∼80% (37/46) of tumors from this group showed β-catenin mutations. These results demonstrate that PB strongly affects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation.
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Acknowledgements
We thank Dr T Devereux for gift of β-catenin-mutated DNAs which were used as positive controls during the initial phases of the project. The excellent technical assistence of Mrs J Mahr and Mrs E Zabinsky is acknowledged. This study was supported in part by the Deutsche Forschungsgemeinschaft (SCHW 329/3-1).
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Aydinlik, H., Nguyen, T., Moennikes, O. et al. Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β-catenin-mutated mouse liver tumors. Oncogene 20, 7812–7816 (2001). https://doi.org/10.1038/sj.onc.1204982
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DOI: https://doi.org/10.1038/sj.onc.1204982
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