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Survival fraction at 2 Gy was found to be inversely proportional to the amount of unrepaired DSB, whatever the genes mutations and the assay applied. However, no single assay discriminates the full range of human radiosensitivity. Particularly, nuclear foci formed by the phosphorylation of H2AX do not predict well moderate radiosensitivities. Our findings suggest the existence of an ATM-dependent interplay between the activation of DNA-PK and MRE11. A classification of diseases according their cellular radiosensitivity, their molecular response to radiation and the functional assays permitting their evaluation is proposed.

A prospective study of the prognostic significance of the labelling index (LI) was undertaken in 1972. The LI of the primary tumor was measured consecutively on 128 patients with mammary carcinoma at the time of initial treatment, following in vitro incubation of specimens with tritiated thymidine. The follow-up for all patients has now extended over 10 years. Relapse-free survival and total survival are significantly higher in patients with a low LI. A multivariate analysis of the prognostic factors, carried out with Cox's model, showed that LI is the most predictive indicator with respect to survival. The size of the tumor is the second most predictive indicator, while histological grading and the number of involved lymph nodes are less predictive. These results strongly suggest that proliferative activity as assessed by LI is directly related to metastatic dissemination probability, independent of other prognostic factors.

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Summary Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation. 2017-2021© 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2171, available online at http://www.idealibrary.com on http://www.bjcancer.com 2 These authors contributed equally to the work.(EGFR), insulin-like growth factor receptor (IGF-1R) in a selective manner (Gazit et al, 1989).Tyrphostin AG 1024, one tyrosine kinase inhibitor specifically targeting IGF-1 receptor, is metabolized intracellularly, creating substances with increased activity towards the receptor and downregulated activity of Akt kinase. The objective of this study was to examine the potential therapeutic purpose of Tyrphostin AG 1024 in combination with irradiation to counteract tumour cell proliferation and to modulate cellular radiosensitivity and apoptosis in a human breast cancer cell line, MCF-7. MATERIALS AND METHODS MaterialsAll materials and chemicals were purchased from Sigma (St Louis, MC, USA) unless noted otherwise. The inhibitor of IGF-1R, Tyrphostin AG 1024 was purchased from Alexis Biochemicals. Akt, phospho-Akt, and NIH-3T3 PDGF-treated protein were purchased from New England Biolabs, Inc. Bax and bcl-2, and p21 antibodies were purchased from Santa Cruz Biotechnology, Inc.Horseradish peroxidase-linked anti-rabbit and anti-mouse antibody were from Jackson ImmunoResearch Laboratory Inc.; molecular markers and fetal bovine serum were from Biological Industries and ECL was purchased from Amersham Biotech Com. ApopTag™ Plus apoptosis Detection Kit-Fluorescence was purchased from Oncor Inc. Cell lineMCH-7 was maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/ml of penicillin and streptomycin, 2 mM L-glutamine at 37˚C in a humidified atmosphere of 5% CO 2 . IGF1R inhibitor treatmentThe ant...

Thymidine labelling index (LI) was prospectively assayed in vitro in a series of 128 consecutive patients with breast cancer. The follow-up was longer than 15 years for all patients. The distribution of LI was log normal and patients were subdivided into 3 groups (patients with LI = m +/- sigma, lower than m - sigma and greater than m + sigma where m is the geometrical mean). The incidence of relapse and death remained significantly lower in the group with a low LI than in the 2 other groups, whereas the difference between the 2 other groups faded away when follow-up exceeded 10 years. Multivariate analyses show that LI is one of the two most important independent prognostic indicators for relapse or death, the other being histological grading. Data concerning 2,648 patients treated at our Institute, prior to the introduction of chemotherapy into treatment protocols, have been used to investigate the influence of tumor growth rate on the probability of distant dissemination. A model of the natural history was used, in order to generate metastasis appearance curves, in 3 subgroups of patients, according to the value of the tumor doubling time (TDT). Our results show that after a follow-up exceeding 8 years, there is no longer any difference between the subgroups of patients with rapid or intermediate growth rate, whereas after 25 years large and highly significant differences in relapse and survival between the slow-growing tumors and the other two subgroups still remain. These two sets of data concur to show that tumor growth rate or proliferation rate correlates with the probability of metastatic dissemination.

The aim of this work was to measure simultaneously and in a quantitative manner double-strand breaks (DSBs), interphase chromosome breaks and cell lethality either immediately after irradiation, or at various times thereafter (up to 24 h), in cells of three nontransformed human fibroblast cell lines of widely different intrinsic radiosensitivity. We wished to assess initial damage, repair kinetics and residual damage at the DNA and the chromosome level, and to correlate these parameters with cell killing. We employed HF19 cells, a normal fibroblast cell line, AT2 cells, a radiosensitive cell line from a patient suffering from ataxia telangiectasia (AT), and 180BR cells, a radiosensitive cell line from a patient with no clinical symptoms of AT. AT2 and 180BR cells, in addition to being radiosensitive, also display a reduced ability to repair potentially lethal damage compared to HF19 cells. The yield of DSBs, as measured by pulsed-field gel electrophoresis, is similar in all three cell lines (slopes correspond to 1.6-1.7% Gy-1 of DNA-associated radioactivity released from the gel well into the lane). In contrast, residual DSBs measured 24 h after irradiation are almost zero for HF19 cells (0.1% confidence interval = 0-1.4%), but are 12.5% (+/- 2.3%) and 43.8% (+/- 1.2%) of those measured immediately after irradiation in AT2 and 180BR cells, respectively. Residual interphase chromosome breaks are 11.6% (+/- 1.6%), 29.7% (+/- 5.7%) and 41.4% (+/- 2.2%) of those measured immediately after irradiation in HF19, AT2 and 180BR cells, respectively. Neither the initial yield of DSBs nor that of excess interphase chromosome breaks can explain the differences in radiosensitivity between the three cell lines; however, there is a correlation between residual DSBs, rate of DSB rejoining at 24 h, residual interphase chromosome breaks on the one hand and cell survival on the other hand.