p53 status, cellular recovery and cell cycle arrest as prognosticators of in vitro radiosensitivity in human pancreatic adenocarcinoma cell lines.
OBJECTIVE
To investigate the factors contributing to the in vitro radiosensitivity of four human pancreatic adenocarcinoma cell lines differing in p53 status, and the basis for the lack of post-irradiation G1 arrest in the two cell lines that have retained a wild-type p53 allele.


METHODS
Cells were X-irradiated and the parameters related to radiosensitivity, as well as the modulation of gene products linked to regulation of cell cycle transit (p53, p21/WAF1/CIP1, pRb) or DNA replication and repair (DNA topoisomerase I and II), were determined.


RESULTS
Both cell lines expressing either mutant (mt) R248W or R273H p53 proteins were more radioresistant. All the cell lines arrested in G2. None of the cell lines arrested in G1 and this was linked to the inability to upregulate p21/WAF1/CIP1. There were no correlations between p53 status and the magnitude or time of maximum G2 arrest. However, there was a negative correlation between a protracted arrest in G2 and the ability to recover from potentially lethal damage (PLD).


CONCLUSIONS
Variation in radiosensitivity is related to p53 status, but the survival advantage conferred by having mutant p53 status is not readily explained neither by recovery from PLD nor by cell cycle arrest kinetics. There is no p53-independent pathway for the recruitment of p21 in these cell lines following irradiation.
Ng
C E
CE
Ottawa Regional Cancer Centre, Ontario, Canada. Cheng_Ng@cancercare.on.ca
Banerjee
S K
SK
Pavliv
M
M
Wang
G
G
Raaphorst
G P
GP
Aubin
R A
RA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D000483:Alleles; D002453:Cell Cycle / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D016193:G1 Phase / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D016158:Genes, p53 / Q000528:radiation effects*; D006801:Humans; D009154:Mutation / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D011379:Prognosis; D011836:Radiation Tolerance / Q000528:radiation effects*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D014965:X-Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II