55 research outputs found
Apoptosis, ageing and cancer susceptibility
No full textWe have previously shown that peripheral blood lymphocytes (PBL) from individuals carrying a germline TP53 mutation show a dramatically reduced apoptotic response to radiation. As part of a study of this phenomenon, we also investigated apoptotic response in a series of breast cancer patients lacking TP53 mutations and in a control group of individuals without cancer. There was a significant reduction in mean apoptotic response with increasing age in all groups. These findings are consistent with a number of studies in rodents, which have demonstrated a reduction in DNA damage-induced apoptosis with increasing age. In addition, after adjusting for age, breast cancer patients showed significantly reduced apoptotic responses compared with normal controls (P=0.002). The odds ratio for breast cancer in women with an apoptotic response of <35%, compared with women with a response of >49%, was 6.42 (95% CI 1.68-24.6). The data further support the hypothesis that a reduction in apoptotic response to DNA damage with increasing age may play a significant role in the age-related increase in cancer
Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins
No full textApoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis plays a vital role in the maintenance of genomic stability by the removal of damaged cells. Previous studies of the apoptotic response ( AR) to radiation-induced DNA damage of lymphoid cells from individuals carrying germline TP53 mutations have demonstrated a defective AR compared with normal controls. We have also previously demonstrated that AR is reduced as individuals age. Results from the current study on 108 twins aged 18-80 years confirm these earlier findings that the AR of lymphoid cells to DNA damage is significantly reduced with increasing age. In addition this twin study shows, for the first time, that DNA-damage-induced AR has a strong degree of heritability of 81% ( 95% confidence interval 67-89%). The vital role of DNA-damage-induced apoptosis in maintaining genetic stability, its relationship with age and its strong heritability underline the importance of this area of biology and suggest areas for further stud
p53 functional assays: detecting p53 mutations in both the germline and in sporadic tumours
No full textThe tumour suppressor gene p53 is the gene most often reported to be mutated in clinical cancers with something like half of all tumours harbouring mutations. Further, many studies have suggested that p53 mutations have prognostic importance and sometimes are a significant factor in determining the response of tumours to therapy, The value of knowing the p53 status of individual tumours will increase if currently researched strategies aimed at developing p53-based treatment protocols come to fruition. There are quite a number of techniques used to detect p53 defects in both tumours and in the germline of cancer-prone families, although some of these methods are indirect and each has certain drawbacks. In this brief review we will discuss the value of two assays of p53 function as a means of detecting and partly characterizing p53 mutations. The two assays are the apoptotic assay, which measures the response of peripheral blood lymphocytes to radiation-induced DNA damage and the FASAY, a yeast based assay which assesses the ability of a given p53 protein to transactivate p53 target genes, Both of these assays are rapid, yielding results within 5 days. Further, they not only offer the possibility of detecting p53 mutations but also of characterizing a given mutation in terms of two of p53's most important functions, namely the induction of apoptosis and the transactivation of target genes
A POSSIBLE SCREENING-TEST FOR INHERITED P53-RELATED DEFECTS BASED ON THE APOPTOTIC RESPONSE OF PERIPHERAL-BLOOD LYMPHOCYTES TO DNA-DAMAGE
No full textThe use of vincristine to measure the cell production rate in a mouse c3h mammary carcinoma following irradiation. Abstr.
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IN VIVO CELL SYNCHRONY IN THE L1210 MOUSE LEUKAEMIA STUDIED WITH 5-FLUOROURACIL OR 5-FLUOROURACIL FOLLOWED BY COLD THYMIDINE INFUSION
No full textSummary.-[3H]-TdR and [3H]-UdR labelling indices and mitotic indices were followed in tumour-bearing mice after application of either 5-fluorouracil (FU) alone or of FU followed by cold TdR infusion. With FU alone, accumulation of cells at the beginning of S was found, but there was no indication of a synchronous passage of the accumulated cells further round the cycle. When FU injection was followed by cold TdR infusion, a synchronous passage of the accumulated cells through the cycle was observed. However, there was a large variation in the response of individual mice to this treatment. IN recent years, the concept of cell-cycle-specific therapy of tumours following synchronization of the tumour cells has found increasing attention. Three sub-stances which have been used clinically to achieve synchrony are hydroxyure
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