The activity of O6-methylguanine-DNA methyltransferase was determined in fibroblast cultures from 45 patients with lung cancer, 39 patients with cutaneous malignant melanoma, and 29 healthy controls. This enzyme is a critical parameter for the capacity to repair O6-methylguanine (O6-mGua) adducts in DNA, and a decreased activity might therefore be responsible for an enhanced susceptibility to c...

The methylating agent N-methylnitrosourea (MNU) is biased, surprisingly, in its carcinogenic potential toward the mouse thymus. Previous studies have shown that single doses of MNU administered to adult mice induced thymic lymphomas in over 80% of mice, while transgenic mice expressing high levels of the human O6-alkylguanine-DNA alkyltransferase gene in the thymus (MGMT-CD2 transgenics) were p...

To elucidate the mechanism of antimutagenicity of caraway, we examined the effects of caraway seed extract on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced mutagenesis in DNA methyltransferase-deficient Salmonella typhimurium strains, O6-methylguanine DNA adduct formation, and thiol content in S. typhimurium cells. MNNG was highly mutagenic for ogt- strains YG7104 (ogt- ada+) and YG7108 (...

DNA mismatch repair (MMR) sensitizes human and Escherichia coli dam cells to the cytotoxic action of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) while abrogation of such repair results in drug resistance. In DNA methylated by MNNG, MMR action is the result of MutS recognition of O6-methylguanine base pairs. MutS and Ada methyltransferase compete for the MNNG-induced O6-methylguanine residues, a...

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but t...

The effects of fat content and nitrite-curing of pork were investigated on the formation of cytotoxic and genotoxic lipid oxidation products (malondialdehyde, 4-hydroxy-2-nonenal, volatile simple aldehydes), protein oxidation products (protein carbonyl compounds) and NOC-specific DNA adducts (O6-carboxy-methylguanine) during in vitro digestion. The formation of these products during digestion i...

We have used a combination of thin-layer chromatography (TLC) and high pressure liquid chromatography (HPLC) to achieve separation of 32P-postlabelled 7-methylguanine and 7-(2-hydroxyethyl)-guanine adducts. The level of these two adducts was determined in human total white blood cells (mean values 0.7 to 1.5 adducts per 10(7) normal nucleotides) and isolated lymphocytes (mean values 1.1 to 12 a...

The biochemical and genetic characteristics of a clone of Chinese hamster ovary cells displaying resistance to Vmrih>l-.Viiiiroviurra (MNU) and 6-thioguanine (6-TG) were analyzed. The initial level of 7methylguanine, 3-methyladenine, and 06-methylguanine formation and the repair rates for these alkylated bases were the same in the resistant and in the parental cell line, indicating that the res...

Pretreatment of H4 (rat hepatoma) cells for 48 hr with low nontoxic doses of alkylating agents [methyl methanesulfonate (MMS), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and N-methyl-N-nitrosourea] renders the cells more resistant to the toxic effect of these compounds. Crossreactivity for survival is also observed with the different alkylating agents tested. Pretreatment with MNNG enables th...

Normal adult human tissues and cultured bronchial epithelial cells and fibroblasts exhibit O6-alkylguanine-DNA alkyltransferase activity in vitro by catalyzing the repair of the promutagenic alkylation lesion O6-methylguanine from DNA. The amount repaired by extracts of liver, peripheral lung, and colon extracts was proportional to the amount of extract protein. Repair of O6-methylguanine led t...