Chemical induction of brain tumors in rats by nitrosoureas: molecular biology and neuropathology

Abstract

Nitrosourea-induced rat brain tumors are among the best investigated experimental systems for neuropathological, biochemical, diagnostic and therapeutic research in neurooncology. This review summarizes data concerning molecular biology, neuropathology, in vitro studies, transplantation models and antigen expression of experimental gliomas in inbred rat strains. Systemic application of nitroso-compounds, i.e., ENU and MNU, leads to the alkylation of DNA bases, which, due to a specific repair deficiency, persist in the nervous system remarkably longer than in other organs. The hypothesis is that alkylated bases cause base-mispairing and point mutations followed by uncontrolled expression of oncogenes and growth factor receptors, resulting in permanent cell proliferation. Thus, nitrosoureas are considered to be biological hazards, especially as potent endogenous and exogenous neurotoxins. Neuropathology and growth characteristics of these experimental tumors are comparable to human malignant gliomas. Similar to the human WHO grade III and IV tumors, they reveal cellular pleomorphism, elevated mitotic activity, proliferation of blood vessels, blood-brain barrier disturbances, necrosis and invasiveness. Nitrosourea-induced brain tumors have been used in investigations concerning glioma growth and regression, brain edema, glioma immunology, metabolism, regional biochemistry, and experimental therapy. The studies included conventional morphology, immunohistochemistry, -cytochemistry and -electronmicroscopy, morphometry, cell culture, hybridoma technology, tumor transplantation and regional imaging by autoradiography, bioluminescence, magnetic resonance and immunoscintigraphy.