Short and long term effects of methyl- and ethylnitrosourea (MNU & ENU) on the developing nervous system of the rat. II. Short term effects: concluding remarks on chemical neuro-oncogenesis.

The cytotoxic action of various single doses of MNU and ENU on developing neural and extraneural tissues was studied at different stages of development. Examination revealed lethal damage. (L.I.) and mitotic inhibition (M.I.), confined to proliferating cells only, and caused by the number of alkyl groups administered. In studying the duration of M.I. a difference was found in duration of the cell cycle arrest after MNU or ENU. The arrest lasted longer for MNU than for ENU, and the neural tissues turned out to be more sensitive than the extraneural ones. Moreover, among the reappearing mitotic figures abnormal ones were noticed frequently. After pulse-labeling with thymidine this arrest could be traced to take place in or before entering the S-phase. During the period of this arrest a low, but specific, activity was found that might point to the existence of repair-processes in vivo. Finally, we directly demonstrated alkylations in tissue-sections by the use of (14C-methyl)-MNU. High radioactivity was found with a random distribution over the various tissues, cell types and even cellular compartments. Therefore--in contrast with the cytotoxic effects--alkylation seems to occur in all cell types. In conclusion, it seems justified to consider the matrices of proliferating cells in the central nervous system as the target tissue-areas for the carcinogenic action of both MNU and ENU. Re-entrance of these damaged cells into their cycle prior to the elimination of altered bases from DNA might be of great importance for the problem of oncogenesis.