Programmed cell death and mutation induction in AHH-1 human lymphoblastoid cells exposed to m-amsa.
One role of programmed cell death (apoptosis) is the removal of cells with DNA damage from the population. Certain cells, however, are able to suppress the signals for apoptotic cell death and maintain viability. This suggests that the susceptibility of a cell to either undergo apoptosis or escape from the apoptotic death pathways may be an important factor in chemical mutagenesis. In order to provide insight into the role of apoptosis in the recovery of chemically induced mutants, AHH-1 cells were exposed to the chromosomal mutagen, m-amsa, and the percentage of cells undergoing apoptosis or necrosis quantified by flow cytometry. Logistic regression analysis revealed that the primary manner of cell death was by apoptosis. Two specific-locus mutations assays, the tk and the hprt, were utilized as markers for cells with DNA damage and that retained clonogenicity under conditions known to induce apoptosis. Analysis of variance indicated that the concentration-dependent increase in the mutant fraction at the tk locus was significant and the result of the recovery of clones with the slow-growth phenotype. Because this phenotype is thought to reflect chromosomal mutations, these results are consistent with the survival and clonogenicity of damaged cells. This suggests that the ability to recover mutant cells may be influenced by the suppression of or an escape from the apoptotic death pathways.
Morris
S M
SM
Department of Health and Human Services, US Public Health Service, Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Domon
O E
OE
McGarrity
L J
LJ
Chen
J J
JJ
Casciano
D A
DA
D000677:Amsacrine / Q000633:toxicity*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002469:Cell Separation; D002470:Cell Survival; D004249:DNA Damage; D005434:Flow Cytometry; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D009336:Necrosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013489:Suppression, Genetic / Q000187:drug effects
D000677:Amsacrine; D007041:Hypoxanthine Phosphoribosyltransferase; D011505:Protein-Tyrosine Kinases