Adaptive resynthesis of O ⁶ -methylguanine-accepting protein can explain the differences between mammalian cells proficient and deficient in methyl excision repair

Cancer predisposition, carcinogen hypersensitivity, and aberrant DNA metabolism

“…Site restoration is accomplished by the direct transfer of the offending alkyl group to a cysteine residue in an acceptor protein, DNA alkyltransferase, forming an S-alkylcysteine product. Interestingly, it has been reported that pretreatment of cells with nonlethal concentrations of an alkylating agent, such as N-methyl-N'-nitro-N-nityosoguanidine (MNNG), results in an enhanced synthesis of DNA alkyltransferase protein (Waldstein et al, 1982).…”

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

“…Normal human fibroblasts contained 40000-80000 molecules per cell (Metcalf and Lawley, 1981), human lymphoid cells had 10000-25000 per cell and human tumor cells had between 30000 and 100000 per cell (Yarosh et al, 1983a;Foote et ai., 1983;Foote and Mitra, 1984;Myrnes et al, 1982;Waldstein et al, 1982a). 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 .…”

“…DNA-repair activities analogous to E. coli 0 6-MT were soon identified in mouse liver (Bogden et al, 1981), rat liver (Renard and Verly, 1980;Mehta et al, 1981), human liver , and these activities were present in human cells in culture (Waldstein et al, 1982a;Myrnes et al, 1982;Foote et al, 1983;Yarosh et al, 1983a, b). Evidence for an adaptive response in mammalian cells which paralleled the E. eoli response was more ambiguous.…”

Activity of a new nitrosourea (TCNU) in human lung cancer xenografts

“…This effect may be explained by the fact that this tumour lacks the DNA repair protein 06-methylguanine-DNA methyltransferase and presumably was unable to inhibit the formation of DNA crosslinks caused by the drug. This enzyme is found in foetal and adult human cells (Waldstein et al, 1982;D'Ambrosio et al, 1987) with a marked variation noted between individuals (Myrnes et al, 1983). Mer -ve cells are more sensitive to nitrosoureas than Mer +ve cells (Day et al, 1980;Erickson et al, 1980) and clearly the therapeutic index of these drugs may depend on the relative activity of this enzyme in malignant and nonmalignant tissues.…”