Enzymatic elimination of O6-ethylguanine from the DNA of ethylnitrosourea-exposed normal and malignant rat brain cells grown under cell culture versus in vivo conditions.
The developing rat brain exhibits a pronounced susceptibility to the tumorigenic effect of ethylnitrosourea (EtNU) and an extremely low repair activity for the DNA alkylation product O6-ethylguanine (O6-EtGuar-). We have recently found that a collection of malignant neural cell lines originating from prenatal BDIX-rat brain cells were all highly O6-EtGua repair-proficient (O6-EtGuar+). Subcloned lines showed considerable variability of the repair capacity, suggesting instability of the O6-EtGua repair phenotype. Using one of the subcloned lines (BT3Caf) as a model, we show here that BT3Caf cells grown in monolayer culture repair O6-EtGua much more rapidly than those grown in the form of s.c. tumors in BDIX-rats (whereas O4-ethylthymine is not repaired under either condition). Furthermore, normal prenatal BDIX-rat brain cells (O6-EtGuar- in vivo) gradually acquire an O6-EtGuar+ phenotype upon transfer to long-term monolayer culture. The cellular capacity for enzymatic DNA repair is of particular relevance in relation to both the malignant transformation of normal cells and the therapeutic inactivation of cancer cells by DNA-reactive drugs. Further analyses are thus required of the molecular mechanisms controlling the expression of DNA repair enzymes as a function of cell differentiation, in terms of the cellular response to altered microenvironmental conditions, and in search for possibilities to reduce the repair capacity of cancer cells.
Huh
N H
NH
Institut für Zellbiologie (Tumorforschung), Universität Essen (GH), FRG.
Rajewsky
M F
MF
D000818:Animals; D001932:Brain Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D005038:Ethylnitrosourea; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D051381:Rats; D014407:Tumor Cells, Cultured
C007673:6-ethylguanine; D006147:Guanine; D004247:DNA; D005038:Ethylnitrosourea