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Chemoprevention of Lung Cancer in Transgenic Mice: Lung tumors

The incidence of lung tumors in all four groups of treated mice was 100%. p53+/-Ink4a/Arf+/+, and p53+/-Ink4a/ Arf+/- mice carrying a mutant p53 transgene (Val135) with or without Ink4a/Arf heterozygous deletion had a higher number of lung tumors (an average of 25 tumors per mouse) after treatment with benzo(a)pyrene than wild-type and p53+/+Ink4a/Arf+/- mice (an average of 12.0 tumors per mouse). More interestingly, mice with p53-dominant negative mutation and Ink4A/Arf heterozygous deficiency (p53+/-Ink4a/Arf+/-) exhibited a striking increase in tumor volume (approximately 23-fold) compared to a ninefold increase in tumor volume in mice with only the p53-dominant negative mutation (p53+/-Ink4a/Arf+/+). There was also an approximate 50% and an approximate fourfold increase in tumor volume in Ink4a/Arf heterozygous-deficient mice (p53+/+Ink4a/Arf+/-), indicating that the effect of Ink4A/Arf heterozygous deficiency is mostly on late-stage lung tumor progression. In addition, most of the lung tumors (approximately 60%) from mice with a p53 mutation and deletion of Ink4A/Arf (p53+/-Ink4a/ Arf+/-) were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in < 10% of the lung tumors from the wild-type mice, and approximately 50% of the lung tumors from either p53 transgenic mice or Ink4a/Arf heterozygous-deficient mice. These results clearly indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression. http://life-without-allergy.com/

In the studies of mice with the dominant negative р53 mutant transgene on an A/J background, either from control mice or mice treated with lung carcinogens, we have observed a low incidence of lymphomas (< 15%) or sarcomas (< 5%). This may reflect both the A/J background as well as the fact that mice were kept for < 10 months. The p16-deficient mice have routinely had rapidly growing sarcomas, in agreement with other studies. Furthermore, mice with both p53 and p16 alterations acquired sarcomas in a relatively high percentage of mice. This may pose some limitations for routine studies with these doubly transgenic mice. This problem might be overcome with a lung-specific knockout of p16.