Carcinogenic nitrosamides and cell cultures

Abstract

THE acylnitrosamides ethylnitrosourea (ENU) and methyl-nitrosourea (MNU) are potent carcinogens in a variety of animals. Rats, especially, provide a useful experimental system since a single dose administered at the perinatal age can be tumorigenic and in certain strains the nitrosamides in these conditions are relatively site specific in that they produce a high proportion of neural tumours^1–6. Although these tumours rarely become clinically apparent before six months, the short term effects of nitrosamides have been studied both in vitro and in vivo in an attempt to elucidate the oncogenic mechanism. Thus histological examination of tissues from rats recently treated with nitrosamides has revealed a toxic effect on dividing cells⁷ while the use of cell cultures has shown an effect on DNA synthesis and the cell cycle⁸. It has been assumed that both the carcinogenicity and the short term effects occur as a result of the alkylation of macromolecules, in particular DNA⁹. Earlier reports concerned the nature of the chemically modified bases^10,11 whereas more recently the turnover of such bases has become the focus of attention^12,13. We present evidence that the short term effects can be explained by an alternative mechanism to the alkylation of cellular macro-molecules; cyanate ions are shown to be a product of TVTNU and ENU breakdown and it is the cyanate ion which is responsible for short term effects and cytotoxicity.