Gamma-ray-induced cell killing and chromosome abnormalities in the bone marrow of p53-deficient mice.
Resistance to the lethal effects of ionizing radiation has been demonstrated in a wide variety of cell types with defects in the p53 gene (thymocytes, splenic B and T cells, in vitro hemopoietic colony-forming cells and intestinal cells of the mouse, embryo cells of the rat, and human Burkitt's lymphoma cells). In contrast, Slichenmeyer et al. (Cancer Res. 53, 4164-4167, 1993) found no evidence of resistance in fibroblasts derived from p53 null mice. The aim of our study was to compare the radiation response of hemopoietic colony-forming cells (in vitro CFC) and of fibroblastoid colony-forming cells or units (CFU-F) within the same tissue (marrow) in p53 null mice (-/-), heterozygotes (+/-) and wild-type animals (+/+). We have also tested the hypothesis that, in proliferating cells, radiation-induced cell killing is mediated through chromosome damage by examining the relationship between these end points in hemopoietic cells of the three mouse types. Both in vitro CFC and CFU-F of -/- mice were resistant to cell killing compared with +/+ and +/- mice whose cellular sensitivities were indistinguishable. The resistance was characterized by a broader "shoulder" on the cell survival curve, i.e. a higher extrapolation number but similar D0 values using the multitarget model or a lower alpha coefficient using the linear-quadratic model. The frequency of chromosomally abnormal marrow cells after irradiation was similar for the three genotypes. However, marrow cells with aberrations carried more aberrations in -/- mice than in +/+ or +/- mice such that the total number of aberrations per 100 cells was higher in -/- mice. Since there were no differences in the yields of aberrations between genotypes in spleen lymphocytes or in CFU-F (both noncycling at the time of irradiation) and less mitotic inhibition in -/- marrow cells than in +/+ or +/- cells, the chromosomal radiosensitivity of -/- marrow hemopoietic cells might be related to reduced cell cycle delay allowing insufficient time for repair, but other explanations have been considered. We postulate that the radiation resistance of both hemopoietic CFC and CFU-F in -/- mice is a consequence of the failure of DNA/chromosome damage to trigger apoptosis or permanent cell cycle arrest to the same extent as in the +/+ or +/- mice: hence the lack of correlation between chromosome damage and cell death in the three mouse types.
Wang
L
L
Paterson Institute for Cancer Research, Christie CRC Research Centre, Manchester, United Kingdom.
Cui
Y
Y
Lord
B I
BI
Roberts
S A
SA
Potten
C S
CS
Hendry
J H
JH
Scott
D
D
D000704:Analysis of Variance; D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D001854:Bone Marrow Cells; D002051:Burkitt Lymphoma; D016923:Cell Death / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian; D005720:Gamma Rays; D016158:Genes, p53; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000473:pathology / Q000528:radiation effects*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008940:Mitotic Index / Q000528:radiation effects; D051381:Rats; D013234:Stem Cells; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
D016159:Tumor Suppressor Protein p53