Persistence of O 6-Ethylguanine in Rat-Brain DNA: Correlation with Nervous System-Specific Carcinogenesis by Ethylnitrosourea

Abstract

The nervous system specificity of the carcinogenic effect of N-ethyl-N-nitrosourea Present evidence suggests that the probability of neoplastic transformation is not a simple function of the degree of cellular interaction with an oncogenic agent, but is also strongly dependent on the proliferative and functional state of the target cell (6, 1). In the search for cellular determinants of malignant transformation the tissue specificity of carcinogens may be a factor of considerable heuristic value, provided it is not primarily due to activation of the compounds by enzymes particularly active in the tissues in question.The carcinogenic (8) and mutagenic (9) acylalkylnitrosamide N-ethyl-N-nitrosourea (EtNU) yields an electrophilic ethyl cation via nonenzymatic, heterolytic decomposition, occurring with a half-life of about 8 min under physiological conditions (7). A single pulse of EtNU, applied to fetal or newborn rats up to an age of 10-20 days, specifically results in a high incidence of malignant neuroectodermal tumors associated with the central and peripheral nervous system (refs.

Lack of Influence of MGMT Codon Leu84Phe and Codon Ileu143Val Polymorphisms on Esophageal Cancer Risk in the Kashmir Valley

“…Mohd A Shah 1 , Sheikh M Shaffi 1 , Ghulam Nabi Lone 2 , Syed Mudassar Jan 1 * A considerable volume of data now exists which indicates that the formation of O 6 -alkylguanine and O-alkylpyrimides is biologically more important than N-7-alkylation of guanine in the initiation of the carcinogenic process by nitrosamines in a specific tissue or cell (Swann & Magee, 1968;Loveless, 1969;Goth & Rajewsky, 1974). O6-methylguanine is repaired by MGMT protein in human cells.…”

The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis

“…Rat cells had about one-fifth the basal level of O6-MT as human cells (Grafstrom et al, 1984) with between 21000 and 28000 molecules per cell in rat kidney cells in culture . In both rats and humans, the highest levels were found in liver, followed by organs of the digestive tract such as stomach, colon and intestine, while brain tissue had approximately one-tenth the level of liver (Goth and Rajewsky, 1974;Singer et al, 1981;Myrnes et al, 1983;Krokan et al, 1983;Grafstrom et al, 1984;Kyrtopoulos et al, 1984). The higher levels of O6-MT in organs which might be exposed first to dietary alkylating carcinogens, and the correlation between rat-liver cell differentiation and O6-MT levels (Hesse et al, 1984) is suggestive of genetic regulation of O6-MT levels during differentiation.…”

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

“…ENU is a potent monofunctional ethylating agent that is mutagenic in a wide variety of test systems and carcinogenic in various mammalian organs [7]. O 6 -EtGua is one of a dozen ethylation products formed in DNA upon exposure to ENU [8]. However, factors that influencing the formation and repair of O 6 -EtGua adduct have not been fully elucidated.…”