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Of four nitrosoureas administered to F344 rats that were offspring of mothers treated with ethylnitrosourea during pregnancy, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and its methyl derivative were particularly effective in blocking tumor development.

The immunohistochemical distribution of glial fibrillary acidic protein (GFAP) in neoplastic lesions induced in the rat by ENU is reported. GFAP was present in hypertrophic reactive astrocytes, which were numerous in early neoplastic proliferations, in microtumors of the white matter, and in those collected at the periphery of large tumors. They were absent in cortical oligodendroglial foci and microtumors. No GFAP-positive cells were observed in hyperplasias of the white matter: astrocyte-like cells of large tumors were GFAP-negative. The significance of reactive astrocytes and the problem of the astrocytic component in transplacental ENU tumors are discussed.

Experimental cerebral tumors have been induced by transplacental ENU. The morphologic study of the brains of treated rats revealed that cellular hyperplasias appear at the 30th day of extrauterine life in the paraventricular white matter, i.e., before the already known "early neoplastic proliferations". Cytofluorimetric investigations failed to demonstrate differences between treated and control rats during the 1st month. On the contrary, adenylate cyclase activity is very high in that period. The duration of the latency period is discussed.

Tumours of the nervous system have been induced by transplacental ENU. Until the fourth month of life the tumoural lesions appear as mixed glial proliferations or oligodendroglial foci. From the fourth month on they develop as glial micro- and macrotumours or as isomorphic and polymorphic oligodendrogliomas. The adenylate cyclase activity studied during these two distinct phases of tumour development was markedly reduced in brain tumours, independent of their cellular origin, compared with the level in the normal brain. On the other hand, the activity of the enzyme responsible for the synthesis of cyclic AMP is significantly increased during the first period of tumour development when early neoplastic proliferations are present.

The occurrence, distribution and concentration of GAGs in ENU and MNU experimental brain tumors induced in the rat are reported. GAGs have been histochemically studied by Alcian Blue methods; they have been quantified and qualitatively evaluated by electrophoresis of brain extracts. The pattern of GAGs in normal rats is consistent with the data of the literature. No GAG accumulation precedes the tumor development. Early neoplastic proliferations, oligodendroglial and mixed glial microtumors are strongly alcian-positive; the alcianophilia spares clusters of cells developing a cytoplasm. In large tumors, GAGs are histochemically demonstrable in the honey-comb areas of oligodendrogliomas and in peripheral infiltration areas of polymorphic gliomas. The role of the normal nervous tissue and oligodendroglial cells in the accumulation of the GAGs is discussed. The accumulated GAGs seem to rise from the nervous tissue included in the tumors, rather than from the metabolism of tumor cells.

GAGs accumulate in the oligodendrogliomas and in the oligodendroglial component of mixed gliomas induced in rats by transplacental ENU. We studied the period between birth and the appearance of the earliest tumoral lesions and did not find any accumulation preceding the early neoplastic proliferations. These findings, together with the observation that GAGs are present only in the oligodendroglial component of tumors, are in agreement with our previous interpretation that the tumoral transformation of oligodendroglia takes place after it has acquired the ability to interfere with GAG metabolism during myelinogenesis.

Experimental cerebral tumors have been induced by transplacental ENU. A systematic diachronic study of the brains has been performed starting from the 15th day of extrauterine life. The tumoral lesions firstly appear as "early stage proliferations" or oligodendroglial foci and develop as glial micro- and macrotumors or as isomorphic and polymorphic oligodendrogliomas respectively. Neurinomas appear later than glial tumors. The duration of the different lesions is sketched out. The usefulness of the model for chemotherapy studies is discussed.

The application of BCNU, CCNU and MeCCNU has been shown to greatly reduce the number of tumors induced in rats by transplacentally administered ENU and to inhibit the full development of tumor proliferation. Moreover, no neurinomas appeared after treatment with CCNU. The application of GCNU proved to be much less effective. Our statistics in the form of tables showing these findings are included and discussed.