GLIAL TUMORS IN THE MNU RAT MODEL - INDUCTION OF PURE AND MIXED GLIOMAS THAT DO NOT REQUIRE TYPICAL MISSENSE MUTATIONS OF P53

Gliomas were induced in adult male Sprague-Dawley rats by continuous e xposure to 100 ppm of N-nitrosmethylurea (MNU) in drinking water. Late ncy periods for such tumors were 20 and 50 weeks following completion of exposure intervals of 20, 15, and 10 weeks, respectively. Based on histomorphology and the pattern of GFAP immunoreactivity, a large perc entage of MNU-induced tumors (>40%) were anaplastic mixed gliomas, hav ing both neoplastic astrocytic and oligodendroglial components. Typica l oligodendrogliomas and astrocytomas also occurred less frequently. U nlike the majority of tumors induced by ethylnitrosourea (ENU), MNU yi elded glial tumors that did not express synaptophysin. Anaplastic mixe d gliomas and glioblastoma multiforme (GBMs) had no missense p53 mutat ions in the commonly mutated exons 4 through 8 and did not overexpress wild-type p53, suggesting that MNU-induced oncogenesis in rat brain t umors may not require inactivation/alteration of the p53 tumor suppres sor gene. The K-ras gene was also analyzed and found to have no activa ting mutations in brain tumors. This model is suitable for studying ge netic events leading to the majority of gliomas that apparently expres s functional p53.