Development of nitrosourea-induced brain tumours—With a special note on changes occurring during latency

Abstract

Nitrosourea compounds fulfil the requirements of ideal carcinogens, in that they produce a high incidence of tumours selectively and consistently in the nervous system, they induce neoplasms that have morphological and biological similarities to naturally occurring neural tumours in man and animals and they represent an environmental hazard. N-Ethyl- N-nitrosourea (ENU) has a preferential transplacental and neonatal action, a single intravenous or intraperitoneal injection inducing an almost 100% incidence of neural neoplasms. Transplacental carcinogenesis by ENU provides an ideal experimental model in which the sequential development of brain tumours can be studied. Investigations of the early stages of brain carcinogenesis induced by transplacentally administered ENU have shown that: (1) the earliest histologically detectable changes appear in 8-wk-old animals and are composed of stem cells; (2) these early lesions are frequently multiple and become larger with increasing age; (3) they are not distributed at random, but occur in areas in which tumours develop later; (4) the carcinogens endow the cells, even only 2 days after exposure, with a malignant potential which may subsequently become manifest either in vivo or in culture; (5) half-way through latency, malignant cells are present in the brain; (6) the emergence of the malignant phenotype in cultured brain cells is a stepwise process which culminates in the concomitant appearance of tumorigenicity and invasiveness.