A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin

Recent evidence indicates that individuals with a p53 germ-line mutation (L i-Fraumeni syndrome) have a 50% risk of developing lung cancer by age 60, I n this study, p53 heterozygous knockout mice and p53 transgenic mice carryi ng a dominant negative mutant were crossed with the A/J mouse, which is hig hly susceptible to lung tumor induction, to investigate whether a p53 germ- line mutation is a predisposing gene for carcinogen-induced pulmonary adeno mas in mice. The number of lung tumors was not significantly increased in ( TSG-p53 x A/J)F-1 p53 heterozygous knockout mice as compared with that in ( TSG-p53 x A/J)F-1 wt mice 16 weeks after exposure to N-nitrosomethylurea (M NU). In contrast, an average of 22 lung tumors were observed in (UL53-3 x A /J)F-1 mice carrying a mutant p53 transgene (135Valp53) compared with an av erage of 7 lung tumors seen in (UL53-3 x A/J)F-1 wt mice after treatment wi th N-nitrosomethylurea. Similar enhancement of lung tumor multiplicity (sim ilar to 3-fold) was seen when mutant versus wt mice were treated with the t obacco-related carcinogens benzo[a]pyrene or 4-(methylnitro-samino)-1-(3-py ridyl)-1-butanone. These results suggest that the mutant p53 transgene may have a dominant negative effect on the wt p53. The potential usefulness of this new mouse model in lung cancer chemoprevention and chemotherapy was ex amined. The chemopreventive efficacy of the green tea or a combination of d ietary dexamethasone and myoinositol and the chemotherapeutic efficacy of T axol or Adriamycin was examined in wt mice or mice with a mutation in the p 53 gene. Mice treated with dexamethasone/myo-inositol and green tea display ed an average of 70 and 50% inhibition of lung tumors, respectively, regard less of p53 status, Similarly, when mice bearing established lung adenomas were treated with Taxol or Adriamycin, a decrease in tumor volume of simila r to 70% was observed independent of p53 mutation status. Thus, the (UL53-3 x A/J)F-1 p53 transgenic mouse seems to be an excellent model for human ca rriers of p53 germ-line mutations (Li-Fraumeni syndrome). Furthermore, the lung adenomas generated in this model possess mutations in both the K-ras p roto-oncogene and the p53 tumor suppressor gene. This model should prove di rectly useful for chemoprevention and chemotherapy studies.