Cell proliferation and DNA repair in the liver during early stages of chemical carcinogenesis.
X-chromosomal phosphoglycerate kinase mocaicisms in organ samples of female heterozygous mice provided a means to prove, because of a selective expression of one of the two allozymes, the clonal origin of carcinogen-induced preneoplastic hepatocellular populations (see also ref. 61). The occurrence of these clonal preneoplastic foci was used in rats to determine cell cycle dependent differences of transformation sensitivity and DNA repair. The highest transformation rate was found after carcinogen exposure in late G1/early S phase of the cell cycle. Experimental disturbance of DNA precursor pools by continuous thymidine infusion during carcinogen exposure results in an increased formation of preneoplastic clones. This is a further argument in favor of an essential role of base-mispairing during initiation. Cell cycle dependent fluctuations of O6-methylguanine DNA transferase with an increasing enzyme activity in late G1 and a maximum in early S phase indicate that cells possess an increased potential for eliminating promutagenic O6-methylguanine during the most transformation sensitive parts of the cell cycle to prevent base-mispairing during DNA replication or transcription. However, this putatively protective effect is limited because the enzyme is rapidly expended in the reaction and drops again in later stages of the cell cycle.
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D004260:DNA Repair / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014960:X Chromosome
D002273:Carcinogens; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D015073:2-Acetylaminofluorene; D010735:Phosphoglycerate Kinase