Radiobiological characteristics of solid tumours depending on the p53 status of the tumour cells, with emphasis on the response of intratumour quiescent cells (original) (raw)
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Relationship between p53 status and radiosensitivity in human tumour cell lines
British journal of cancer, 1996
We examined the relationship between p53 levels before and after irradiation, radiation-induced cell cycle delays, apoptotic cell death and radiosensitivity in a panel of eight human tumour cell lines. The cell lines differed widely in their clonogenic survival after radiation, (surviving fraction at 2 Gy: SF2=0.18-0.82). Constitutive p53 protein levels varied from 2.2 +/- 0.4 to 6.3 +/- 0.3 optical density units (OD) per 10(6) cells. p53 after irradiation (6 Gy) also varied between the cell lines, ranging from no induction to a 1.6-fold increase in p53 levels 4 h after treatment. p53 function was also assessed by G1 cell cycle arrest after irradiation. The cellular response to radiation, measured as G0/G1 arrest, and the induction of apoptosis were in good agreement. However, a trace amount of DNA ladder formation was found in two cell lines lacking G1 arrest. Overall cellular radiosensitivity correlated well with the level of radiation-induced G1 arrest (correlation coefficient r=...
Anticancer research
Intratumor quiescent (Q) cells and p53-mutated tumor cells are more difficult to control than intratumor proliferating (P) cells and p53 wild-type tumor cells, respectively. The usefulness of 3 hypoxic cell radio-sensitizers was compared in terms of a radio-sensitizing effect under aerobic and hypoxic conditions and a repair-inhibiting effect following irradiation on both Q and total (P + Q) cell populations in solid tumors. The dependency of these effects on the p53 status of tumor cells was also examined using tumor cell lines with identical genetic backgrounds except for their p53 status. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. The nude mice bearing the tumors and C3H/He mice bearing SCC VII tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all the P cells in the tumors. Tumor-bearing mice r...
Stem Cells, 1995
We investigated the possible relationship between immunohistochemically detected p53 expression and in vitro response to γ-irradiation in 24 primary cultures of human ovarian cancers and cutaneous melanomas. The frequency of p53-positive tumors was around 60% within each tumor histotype. The range of the surviving fraction at 2 Gy (SF2) was similar in p53-positive (0.10-0.76) and p53-negative (0.23-0.65) tumors, with median values of 0.36 and 0.33, respectively. No differences were observed in the accumulation of DNA-double strand breaks, assessed by neutral filter elution after exposure to 50 Gy, between p53-positive and p53-negative tumors. As regards DNA lesion repair, after 2 h of recovery the percentage of rejoined DNA-double strand breaks ranged from 19% to 99% in the different cultures, but again the distribution of values was similar for p53-positive and p53-negative tumors. Specifically, the median percentage of repaired DNA-double strand breaks was 70% and 74% in the two groups. On the whole, our data do not support the hypothesis that p53 overexpression is a major determinant of in vitro radiation response.
Cellular radiosensitivity is directly correlated with the mechanism of DNA repair, in which p53 protein plays a major role. In this context, this study correlated cell death with p53 expression in lymphocytes irradiated in vitro with different doses of gamma-radiation. For this, peripheral blood samples were collected from 10 healthy subjects. Each sample was divided in aliquots and, separately, irradiated with doses of 0.5; 2 and 4 Gy. After this, peripheral blood mononu-clear cells (PBMCs) were isolated and cultivated during 72 hours in 5% CO 2 at 37˚C without mi-togen stimulation. The expression of p53 protein was evaluated by flow cytometry. In parallel, cell viability was determined by trypan blue staining. Statistical analysis was performed using analysis of variance (ANOVA), differences were considered as statistically significant when p < 0.05. The results showed an increase of p53 expression with the absorbed dose, which was proportional to cell death, suggesting that p53 can be used as bioindicator of individual radio-sensitivity.