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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A quantitative method of replicon analysis of DNA fibre autoradiographs has been used to study the relationship between mean rate of DNA chain growth (R) and distance between adjacent replicons (ID) in fibroblasts from cancer-prone conditions. Results are expressed in terms of the mean linear regression R = delta +(K.ID)10-2. When replicon behaviour was examined in cells from patients with ataxia telangiectasia, basal cell naevus and Bloom's syndromes grown at high density after 48 h in culture, no significant differences could be found in replicon behaviour between these syndromes and normal cultures. However when Bloom's cells were grown at low density and examined 24 h earlier, the mean rate of chain growth R was reduced compared to normal cells at the same density. Both cell types at high densities at 24 h showed equal but lower R values than at 48 h after plating the cultures. The lower rate of chain growth in Bloom's was accompanied by a longer S-period and cell cycle. Studies of cell proliferation kinetics using consecutive mitoses after bromodeoxyuridine (BUdR) incorporation and harlequin banding showed that Bloom's cells at low cell density require a longer period to recover a normal cell cycle length after plating than do normal cells at the same density. Plating densities and using conditioned media shorten the recovery period in Bloom's cells, and when foetal calf serum/MEM is replaced by human AB serum/McCoy 5a medium as the growth media, cell cycle behaviour of low density Bloom's and normal cells are equal at a much earlier time. It is concluded that the slow rate of DNA chain growth in Bloom's cells is an artefact introduced by culture conditions and also may be present in normal cells at an earlier period. The behaviour of replicons during this recovery period appears to be similar in Bloom's and normal cells except for the time lag. As recovery proceeds, the DNA chain growth in the associated replicon pairs recover progressively. This alters both the mean R value from 0.4 to 0.8 micron/min, the slope of the regression K from less than 1.0 to approximately 1.0 while the distance between initiation sites (ID) remains constant throughout. Pretreatment of all cultures with fluorodeoxyuridine (FUdR) produced the same differential effect on release from DNA synthesis inhibition, that is a similar increase in the activation of normally inactive replicons and a slightly slower rate of chain growth over all replicons. No evidence of a substance released by Bloom's cells in culture capable of increasing the sister-chromatid frequency in normal cells could be found. Since SCE frequencies were found to increase with fixation time after BUdR introduction it is concluded that some of the reported changes could be due to differences in cell cycle kinetics brought about by the different media conditions.
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PMID:Quantitative replicon analysis of DNA synthesis in cancer-prone conditions and the defects in Bloom's syndrome. 53 82

Cell kinetics were measured in vivo in four experimental rat prostatic adenocarcinomas grown in normal or castrated rats. The aim was to investigate the effect of castration on growth rate and cell kinetics in hormone sensitive and hormone insensitive prostatic carcinomas. We used two anaplastic, hormone insensitive, fast growing tumors (Dunning R-3327-AT1 H and E), as well as two well differentiated, hormone sensitive, slow growing tumors (R-3327-H and R-3327-PAP). DNA ploidy, S-phase transit time (Ts), the labeling index (LI) and potential doubling time (Tpot) was determined by dual parameter flow cytometry, after in-vivo labeling, using bromodeoxyuridine (BUdR) and the tumor doubling time (DT) was determined from growth curves. After castration DT in the hormone sensitive H-subline changed from 21.7 days to 82.0 days, and in the PAP-subline from 22.2 days to 33.2 days. No significant changes in Tpot were observed. In the anaplastic tumors no differences in neither DT nor Tpot were seen. The cell loss factor (CLF) was relatively low in the two anaplastic tumors (0.55-0.59) compared to the well differentiated tumors. The CLF was unaffected by castration in the poorly differentiated tumors, whereas it increased significantly (from 0.75 to 0.92, P = 0.005) after castration in the H-tumor, and showed a non-significant increase in the PAP-tumor. This implies that the decrease in tumor growth in the hormone sensitive tumors is due to an increase in cell death, not a decrease in cell proliferation. These data indicate that CLF is the dominating factor in the reduced growth following androgen ablation in an androgen sensitive tumor. This study suggests that Tpot might be an additional predictor of a tumors proliferating rate and it may provide important information of the human prostatic cancer.
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PMID:The effect of castration on tumor growth rate and cell kinetics in hormone sensitive and hormone insensitive rat prostatic adenocarcinomas. 857 60

Pulsed high-energy ultrasound shock waves (PHEUS), similar to those used for clinical lithotripsy, can deposit energy deep in tissue and thereby destroy the microvasculature of solid tumors. We investigated the potential of PHEUS, generated by an electromagnetic shockwave source (19 kV capacitor voltage, 1 Hz pulse frequency), as a local cancer-therapy modality alone and in combination with local tumor hyperthermia (43.5 +/- 0.1 degrees C, 30 min). Copenhagen rats transplanted with the anaplastic Dunning-prostate-tumor sub-line R3327-AT1 received 1000 PHEUS pulses, which delayed tumor growth by one tumor-doubling time (5 days). Histopathology revealed hemorrhage, disruption of tumor vasculature, and necrosis in the focus of the sound field. Bromodeoxyuridine (BUdR) incorporation was significantly lower in PHEUS-treated tumors than in controls. Dynamic magnetic resonance imaging (MRI) studies using gadolinium-DTPA as contrast agent showed a strong reduction of tumor perfusion after PHEUS treatment, although this effect was partly reversible within 3 days after PHEUS. While hyperthermia alone produced no significant delay in tumor growth, the combination of PHEUS and hyperthermia produced tumor-growth delay by 2 tumor-volume-doubling times. The maximum growth delay was achieved when PHEUS and hyperthermia were separated by 24 hr at the time of maximum perfusion reduction indicated by MRI. Thus, the cytotoxic effect of PHEUS was enhanced by hyperthermia in the anaplastic prostate tumor R3327-AT1 grown on Copenhagen rats in a synergistic manner, due to blood-flow reduction. In conjunction with other agents, such as hyperthermia, PHEUS might become a local cancer-therapy modality in solid tumors accessible to ultrasound.
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PMID:Synergistic interaction of ultrasonic shock waves and hyperthermia in the Dunning prostate tumor R3327-AT1. 1036 Aug 25

Homologous recombination is an important biological process that facilitates genome rearrangement and repair of DNA double-strand breaks (DSBs). The induction of Epstein-Barr virus (EBV) lytic replication induces ataxia telangiectasia-mutated (ATM)-dependent DNA damage checkpoint signaling, leading to the clustering of phosphorylated ATM and Mre11/Rad50/Nbs1 (MRN) complexes to sites of viral genome synthesis in nuclei. Here we report that homologous recombinational repair (HRR) factors such as replication protein A (RPA), Rad51, and Rad52 as well as MRN complexes are recruited and loaded onto the newly synthesized viral genome in replication compartments. The 32-kDa subunit of RPA is extensively phosphorylated at sites in accordance with those with ATM. The hyperphosphorylation of RPA32 causes a change in RPA conformation, resulting in a switch from the catalysis of DNA replication to the participation in DNA repair. The levels of Rad51 and phosphorylated RPA were found to increase with the progression of viral productive replication, while that of Rad52 proved constant. Furthermore, biochemical fractionation revealed increases in levels of DNA-bound forms of these HRRs. Bromodeoxyuridine-labeled chromatin immunoprecipitation and PCR analyses confirmed the loading of RPA, Rad 51, Rad52, and Mre11 onto newly synthesized viral DNA, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling analysis demonstrated DSBs in the EBV replication compartments. HRR factors might be recruited to repair DSBs on the viral genome in viral replication compartments. RNA interference knockdown of RPA32 and Rad51 prevented viral DNA synthesis remarkably, suggesting that homologous recombination and/or repair of viral DNA genome might occur, coupled with DNA replication to facilitate viral genome synthesis.
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PMID:Homologous recombinational repair factors are recruited and loaded onto the viral DNA genome in Epstein-Barr virus replication compartments. 1938 20