We have developed a mouse model system in which rapid chemical induction of lung adenocarcinomas and T-cell lymphomas allows us to study lung carcino-genesis in vivo, and test potential countermeasures. Tumors are induced in NFS x AKR mice by transplacental injection of I-ethyl-l-nitrosourea on day 16 of gestation. Tumor promotion by butylated hydroxytoluene nearly halves the latency period for these tumors and results in approximately 90% of animals succumbing within 5 to 14 weeks of age. Normal-sized Raf-I protein and RNA are expressed at very high levels in all of the tumors and we are now examining raf-1 for possible small or point mutations. In addition, we have examined raf family RNAs in a variety of mouse tissues in order to define normal expression patterns. Vaccination of carcinogen-treated mice with purified raf protein (patent pending) was previously shown to effectively eliminate the promoted phase of tumor development. However, the immunological basis for this tumor modulation is unclear and we are implementing experiments using recombinant raf-expressing vaccinia virus and syngeneic cells expressing different forms of Raf-I to delineate the host response. Hopefully this will lead to the identification of an immunogenic epitope(s) and enable us to design more effective anti-tumor vaccination regimens.
