Absence of ATM truncations in patients with severe acute radiation reactions.
OBJECTIVE
Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia-telangiectasia (A-T).


METHODS
Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM.


RESULTS
LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested.


CONCLUSIONS
All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.
Clarke
R A
RA
Division of Cancer Services, St. George Hospital, Sydney, NSW, Australia.
Goozee
G R
GR
Birrell
G
G
Fang
Z M
ZM
Hasnain
H
H
Lavin
M
M
Kearsley
J H
JH
D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line / Q000528:radiation effects; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D005260:Female; D016195:G2 Phase / Q000528:radiation effects; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000528:radiation effects; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases