This study was designed to provide the reciprocal relationship among labelling indices of 5-bromodeoxyuridine (BUdR LI), Ki-67 (Ki-LI), and tumour doubling time (Td) of recurrent meningiomas. In our series of 182 primary intracranial meningiomas, 46 cases recurred. The average of BUdR LI and Ki LI for nonrecurrent meningiomas were 0.77 ± 0.13 % and 4.71 ± 1.96 %, respectively. Recurrent meningiomas had significantly higher LIs at the first operation: BUdR LI was 3.77 ± 1.22 % and Ki LI was 14.78 ± 3.17 %. The recurrent ratio significantly increased with the degrees of each LI. And the linear regression analysis has demonstrated a significant correlation between BUdR and Ki LI. Td was calculated accurately by NIH, a computer software. Td showed a significant inverse correlation with each of the labelling indices. Consequently, BUdR, Ki LIs and Td of individual tumours correlate mutually well. Of the 46 recurrent cases, 4 received radiation after the operation. Td of the irradiated meningiomas tended to be longer than expected for their higher level of BUdR and Ki LIs before radiation therapy. Thus, it was shown that the radiation therapy delays the regrowth of meningiomas. (author)
The potential use of bromodeoxyuridine (BUdR) as a radiosensitizer given by an intermittent intravenous route is being studied in a Phase I/II trial at the Naitonal Cancer Institute. In order to assess the extent of radiosensitization, we have studied the radiation response of human bone marrow cells CFUc taken form 6 patients prior to and after a 14-day infusion of BUdR. Varying concentrations (1000-1500 mg) of BUdR were infused for 12 hours 12 hours every 24 hours for up to 14 consecutive days. Cells survival was determined by colony formation of CFUc in soft agar suspensions. X ray survival curves were generated over a dose range of 0-300 rad and the slopes of the survival curves (D0) before and after BUdR infusion were compared. Radiation enhancement ratios (ER)(D0 per-BUdR/D0 post-BUdR) ranged form 1.0-2.2 and appeared to be BUdR dose dependent. Above 650 mg/m2/12 hours is well tolerated and may result in radiosensitizaiton of CFUc in man
Combined modality treatment was given in nine patients of osteogenic sarcoma wherein the tumor was unresectable because of location or amputation was refused. This alternative to massive surgery comprised hypofractionated irradiation, intra-arterial infusion of the radiosensitizer 5'-bromodeoxyuridine (BUdR) and adjuvant systemic chemotherapy. Local control was achieved in seven of the nine patients. Four survived, all without evidence of disease at 6, 7.1, 8.8, and 10.5 years after completion of irradiation. Pulmonary metastases developed in six patients - of whom one survives, following high-dose pulmonary irradiation and additional chemotherapy. Significant soft-tissue injury occurred in five patients. On the basis of our experience, the authors believe that new approaches using modifications of external beam irradiation with different fractionation schedules or better radiosensitizing compounds may hold promise for patients with non-resectable osteosarcoma
Purpose: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. Methods and Materials: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. Results: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in
Chebotarev, A N; Chernyshova, N A
Cell distribution was analysed with the help of the BrDU label for the number of chromosome aberrations and breaks induced by one-center (thiophosphamide and phosphamide) and two-center (dipine and fotrine) mutagens at the stage G0 in the Ist mitosis of human lymphocytes harvested at different times of culturing (from 56 to 96 h). The comparison was made between the type of aberration distribution in cells and the dependence of their frequency on the harvesting point for various mutagens. Poisson aberration distribution in cells for two-center mutagens was found to correspond to their constant frequency observed at different times of harvesting. On the other hand, for one-center mutagens, a geometrical distribution of chromosome breaks corresponded to an exponential decrease in their frequency in time. It is suggested that two-center chemical mutagens and ionizing radiation cause largely short-live damages which are realized into chromosome aberrations rather quickly (during one cell cycle). One-center mutagens, however, cause such damages that the probability of their transformation into chromosome aberrations is decreasing rather slowly in time, under the exponential law, and their realization into chromosome aberrations can occur in subsequent cell cycle. PMID:2258036
In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas
Repairability during G1 of the inductor leisure of exchanges in the sister chromatid induced by alkylating agents in DNA substituted and no substituted with BUDR, in cells of the salivary gland of mouse In vivo; Reparabilidad durante G1 de las lesiones inductoras de intercambios en las cromatidas hermanas inducidos por agentes alquilantes en ADN sustituido y no sustituido con BrdU, en celulas de la glandula salival de raton In vivo
Gonzalez B, F
In this work you determines the repair of the lesions inductoras of Sister chromatid exchange (ICHs) generated in the cells of the salivary gland of mouse, for the treatment with the N-Methyl-N-Nitrosourea (MNU), the N-Ethyl-N-Nitrosourea (ENU), the Methyl methanesulfonate (MMS) and the Ethyl methanesulfonate (EMS) in early and slow G1 of the first one and the second cellular division, that is to say before and after the cells incorporate 5-bromine-2 -Desoxyuridine (BrdU) in the DNA. Groups witness non treaties were included with mutagen. The cells of the salivary gland repaired the generated lesions partially by the MNU, the MMS and the EMS in the 1st division, and only the lesions induced by the ENU and MMS were repaired partially in the 2nd division. The ENU generates injure that they were not repaired in the 1st division and those taken place by the EMS were little repaired in the 2nd division. The methylating agents generated but ICHs that the ethylating. One observes that the BrdU makes to the molecule of the DNA but susceptible to the damage generated by the alkylating agents that induce the formation of the ICHs. This susceptibility was incremented around 150% for the treatment with the MNU, the ENU and the MMS, on the other hand for the EMS it was 3 times minor. It is proposed that the one electronegative atom of this analog of the timine would to work as a nucleophyllic center with which the electrophyllic compounds react. (Author)
Jacob, H.E. (Akademie der Wissenschaften der DDR, Jena. Zentralinstitut fuer Mikrobiologie und Experimentelle Therapie); Golovinsky, E. (Bylgarska Akademiya na Naukite, Sofia)
The presence of 5-bromouracil (BU) as well as 5-bromo-2-deoxyuridine (BUdR) in the cultivation media of bacteria results in the distinct increase of UV sensitivity. With the nucleic acid base analogue 8-azaadenine (8-AA) a similar effect was confirmed, however, not so pronounced. The combined action of BU or BUdR and 8-AA on Escherichia coli, Proteus mirabilis, Bacillus subtilis and Bacillus cereus was investigated. The sensitization effect of BUdR does not increase if 8-AA is present additionally during cultivation. On the contrary, a decrease of sensibilization occurs. This may be caused by the protective effect of the adenine derivative against UV irradiation, if it is present in the cell, but not incorporated into the DNA.
The presence of 5-bromouracil (BU) as well as 5-bromo-2-deoxyuridine (BUdR) in the cultivation media of bacteria results in the distinct increase of UV sensitivity. With the nucleic acid base analogue 8-azaadenine (8-AA) a similar effect was confirmed, however, not so pronounced. The combined action of BU or BUdR and 8-AA on Escherichia coli, Proteus mirabilis, Bacillus subtilis and Bacillus cereus was investigated. The sensitization effect of BUdR does not increase if 8-AA is present additionally during cultivation. On the contrary, a decrease of sensibilization occurs. This may be caused by the protective effect of the adenine derivative against UV irradiation, if it is present in the cell, but not incorporated into the DNA. (author)
5-Bromo-2'-deoxyuridine (BUdR) was injected into SCC VII or EMT6/KU tumor-bearing mice intraperitoneally to label all the proliferating tumor cells. First, the mice were irradiated with X-rays at a dose of 10 Gy, followed by a dose of 0-20 Gy at 0, 12, 24 or 48 h later. During the interval, no BUdR was injected. Immediately after the second irradiation, the tumors were excised and trypsinized. The micronucleus (MN) frequency in cells without BUdR labeling was determined by means of incubation with cytochalasin-B (a cytokinesis-blocker) and immunofluorescence staining for BUdR. When the tumors were not pretreated with BUdR before the first irradiation, the MN frequency in all tumor cells was determined. To determine the labeling indices of SCC VII and EMT6/KU tumors at the time of the second irradiation, each group also included mice that were continuously administered BUdR until just before the second irradiation using mini-osmotic pumps which had been implanted subcutaneously 5 days before the first irradiation. The MN frequency of all tumor cell populations obtained immediately after the second irradiation decreased in proportion to the increase in interval time. However, in both tumor systems, the MN frequency of unlabeled cell populations, which could be regarded as quiescent cells in the tumors at the time of the first irradiation, was raised with increase in the interval time. In addition, the labeling index at the second irradiation was higher than that at the first irradiation. These findings support the occurrence of recruitment from quiescent to proliferating state during fractionated irradiation. (author)
Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of one of four patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 x 10(-7) mol/L and 1 x 10(-6) mol/L during infusion of 650 and 1000 mg/m2/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2/d) and 2.5 (with 1000 mg/m2/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%). The authors conclude that local and systemic toxicity of continuous infusion of BUdR at 1000 mg/m2/d for approximately two weeks is tolerable. The observed normal tissue toxicity is comparable with previous clinical experience with intermittent (12 hours every day for two weeks) infusions of BUdR. Theoretically, a constant infusion should allow for greater incorporation of BUdR into cycling tumor cells and thus, for further enhancement of radiosensitization
Replicon sizes were measured in Simian Virus 40 (SV40)-transformed and untransformed normal human, xeroderma pigmentosum (XP), and mouse 3T3 cells with an x-ray plus bromodeoxyuridine (BUdR) photolysis method. Replicon sizes in SV40-transformed cells were at least twice those in untransformed counterparts, but DNA fork displacement rates were only slightly increased
The following topics are discussed: steps in nucleotide excision; damage to DNA by uv-endonuclease; use of complementation to study DNA repair in Escherichia coli and mammalian cells; role of BUDR photolysis in excision repair, relation between DNA repair defect and human disease; base excision repair; and excision repair by removal of damaged region of a base in DNA without excision
Unscheduled DNA synthesis and chromosome aberrations were compared following X- or UV-irradiation or methyl methanesulfonate treatment in cultures of HeLa S3 or KB cells or human and rabbit lymphocytes. The sensitization by incorporation of the halouridines BUdR and IUdR was also investigated. Unscheduled DNA synthesis occurred in two established cell lines after irradiation with 0 to 10 kR of X-rays. The rate of unscheduled synthesis was dose dependent and differed for the two cell lines. The unscheduled synthesis was not correlated with the modal chromosome number nor with the number of aberrations produced. UV-irradiated rabbit lymphocytes exhibited unscheduled DNA synthesis which saturated after a dose of 250 ergs/mm2. In contrast the incorporation of BUdR or IUdR eliminated this saturation and caused an increasing effect with increasing dose up to 1000 ergs/mm2. The degree of sensitization varied between the two halo-uridines, BUdR being more effective at high doses while IUdR was a more potent sensitizer at low doses. Chromosome aberrations were not directly related to unscheduled DNA synthesis but were sensitized by halo-uridine incorporation. In this case IUdR was more potent than BUdR at all doses studied. Methyl methanesulfonate was an effective producer of chromosome aberration in human lymphocytes of both the chromosome and chromatid type. Prior incorporation of BUdR or IUdR did not increase the total aberration produced but did increase the number of chromosome type aberration at the expense of the chromatid type
The influence of gamma-irradiation and 5-brom-2'-deoxyuridine (BUDR) on the life span and behaviour (in photoactivity test) of D.melanogaster was studied. It was found that gamma-irradiation resulted in decrease of life span. However the form of surveys changed only under exposure to doses higher than 500 Gy. Treatment with BUDR distorted the form of survival curves and caused death of insects immediately after exclusion. It also caused abrupt decrease in photoactivity of insects, while irradiation even with very high doses did not affect this feature. It is proposed that initiating substrate in drosophila aging is DNA of nerve cells. The possible relationship between aging regularities and evolutional extinction of eukaryotic species in discussed
Five u.v. light-sensitive clones were isolated in the EUE cell line by means of a modified form of the original 5-bromodeoxyuridine (BUdR)-light method worked out by Puck and Kao for the isolation of nutritional mutants. A cell population was mutagenized with ethylmethanesulfonate. After the expression time, cells were u.v.-irradiated and incubated with BUdR to label excision patches in repair proficient cells. A subsequent irradiation with black light caused DNA strand breakage in BUdR-substituted cells. During BUdR treatment, hydroxyurea and a fluorochrome (Hoechst 33258) were added to possibly enhance the analogue incorporation into DNA and to increase the photolability of BUdR containing sequences, respectively. Out of 192 colonies selected with this method, 38 were isolated and tested for their u.v.-sensitivity. Five of them showed significant, reproducible differences with respect to the parental line. As a partial characterization, the five u.v.-sensitive clones were assayed for unscheduled [3H]thymidine incorporation after exposure to u.v. light, by means of liquid scintillation spectrometry and autoradiography. In all clones. DNA repair synthesis was significantly decreased with respect to the parental line
The following classes of radiosensitizers are discussed: electron affinic compounds, pyrimidine analogs, and antibiotics. Metronidazole and nitroimidazole are discussed as examples of electron-affinic compounds. Studies on the enhancement ratio for sensitization of x-irradiated hamster cells showed that these drugs sensitize at concentrations much lower than the toxic concentrations. Criteria for a clinically useful hypoxic cell sensitizer are listed and mechanisms of electron-affinic sensitizers are discussed. The radiosensitizing effects of the pyrimidine analogs, BUDR, BCDR, IUDR, CUDR, and FUDR, are examined and the enhancement of radiation effects by the chemotherapeutic agent, 5-fluorouracil, is discussed. Other agents discussed are methotrexate, actinomycin D, bleomycin, and adriamycin
Human kidney cells in culture and cells of mouse sarcoma-180 were allowed to incorporate bromine into their DNA. Cultured cells with and without incorporated BUdR were irradiated with electromagnetic radiations ranging in energy from 12 keV X-rays to 60Co γ-rays to find out whether or not there exists any energy dependence of the bromine dose enhancement ratio BER. Such a dependence should show in the immediate neighbourhood of the K-absorption edge of bromine (13.5 keV). Any influence of the Auger effect triggered in bromine by external irradiation should show by a significant increase of the BER for energies rising from slightly below to slight above the bromine K-edge. Values of D37, D0 and the extrapolation numbers of the cell survival curves served as biological endpoints. Measured values of BER ranged from 1.12-2.00 without any significant dependence on energy. A weakly pronounced peak was found for 50 kV X-rays of 26 keV mean energy. Sarcoma-180 were irradiated with 14 keV X-rays and 60C γ-rays. BUdR was administered i.v., i.p. and directly into the tumours in quantities of up to 1 ml of a 10-3M solution. (Auth.)
Intermediate subviral particles (ISVP) derived from reovirus represent a simple model system for the switch-on of transcriptase function. In such particles the endogenous transcriptase is present in a switched-off form, one step removed from the switched-on state. Switch-on of transcriptase function is an active process in this system and can be triggered by K+ ions. A variety of agents which affect gene expression in cells were tested for an effect on switch-on in ISVP. Marked effects on switch-on in ISVP were observed with a diverse group of test agents, including DMSO and other solvents, BUdR, TdR, caffeine, theophylline, and temperature. The correlation in response between ISVP and cells suggests that the ISVP system may be useful as a model for studying the biochemical mechanisms underlying the perturbative effects of such agents on gene expression in cells
The halogenated pyrimidine analogs, bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR) have been recognized as potential clinical radiosensitizers for over two decades. In vivo and in vitro experimental studies document that radiosensitization is directly dependent on the amount of thymidine replacement in DNA by these analogs. Based on recent in vivo and clinical pharmacology studies on continuous intravenous infusions of these drugs, clinical trials are underway evaluating the potential of radiosensitization in high grade gliomass and other poorly radioresponsive tumors using the technically safer intravenous route of administration. In this paper, the authors review the basic strategy for the use of these analogs, the ongoing clinical trials and the potential areas for future experimental and clinical studies
Nine healthy primates were used in two toxicity studies. In the first study, BUdR radiosensitization was performed with external beam x-irradiation of 6,000 cGy in five rhesus monkeys (three controls, two with pumps implanted in the common carotid artery for delivery of BUdR). MR imaging was performed 3 and 9 months after treatment. Bihemispheric lesions with long T1 and T2 values were seen in three animals. Lesion topography on MR imaging exactly matched histologic zones of microinfarcts and endothelial proliferation with surrounding parenchymal edema. MR imaging and pathologic findings in two animals were normal. In the second study, interstitial radiation therapy was delivered by stereotaxic implantation of a single I-125 seed of 3,000 cGy in two pigtail monkeys and of 6,000 cGy in another two monkeys. CT and MR imaging were performed 0, 4, 7, and 10 weeks after seed placement. MR imaging revealed progressive development of lesions with long T1 values and intermediate T2 values at the center, intermediate T1 and T2 values at the rim, and long T1, long T2 values at the periphery. These lesions were exactly centered on seed placement. The rim of intermediate values exactly matched pathologic zones of contrast enhancement on CT. The three zones seen on MR imaging corresponded to similar histologic zones of central coagulation necrosis, microinfarctions and endothelial proliferation at the rim, and peripheral edema. Lesion calcification was seen diffusely on pathologic study, poorly on MR imaging, and fairly on CT
The RCH2O radical is formed in x-irradiated 3'-cytidylic acid (3'CMP), 5-chlorodeoxyuridine (ClUdR), 5-bromodeoxyuridine (BUdR), adenosinexHCl (ARxHCl), and deoxyadenosine monohydrate (AdRxH2O) owing to the net loss of hydrogen from O5/sub prime/ of the primary hydroxylic group. ESR measurements were made between 78 and 100 K on single crystals of 3'CMP, ClUdR, BUdR, and ARxHCl and on polycrystalline AdRxH2O. The range of principal g values is g/sub max/=2.054--2.093, g/sub int/=2.005--2.009, g/sub min/ =1.995--2.000. The range of sum of the isotropic β-hydrogen hyperfine couplings is A/sup β/1/sub iso/ +A/sup β/2/sub iso/=141--156 G. The g tensors and A/sup β//sub iso/ values are used to determine which oxygen nonbonding orbital contains the bulk of the unpaired electron density. The unpaired electron 2p orbital symmetry axis is perpendicular to a plane determined by X(H) xxxO--C. Of the two relevant hydrogen bonds in the undamaged molecule, the X--HxxxO bond remains intact whereas the hydrogen in the O--HxxxY bond is displaced. The equation A/sup β//sub iso/=B0+B2 cos2theta, with B0 =0 and B2=101 +- 13 G describes the dependency of the β-hydrogen hyperfine coupling on the torsion angle theta, between the unpaired electron symmetry axis and the C--H/sub β/ bond of the RCH2O radical. Mechanisms of formation, factors in stabilization, and reactions of decay are discussed
Hayes, N. L.; Nowakowski, R. S.
The output potential of proliferating populations in either the developing or the adult nervous system is critically dependent on the length of the cell cycle (T(c)) and the size of the proliferating population. We developed a new approach for analyzing the cell cycle, the 'Saturate and Survive Method' (SSM), that also reveals the dynamic behaviors in the proliferative population and estimates of the size of the proliferating population. We used this method to analyze the proliferating population of the adult dentate gyrus in 60 day old mice of two inbred strains, C57BL/6J and BALB/cByJ. The results show that the number of cells labeled by exposure to BUdR changes dramatically with time as a function of the number of proliferating cells in the population, the length of the S-phase, cell division, the length of the cell cycle, dilution of the S-phase label, and cell death. The major difference between C57BL/6J and BALB/cByJ mice is the size of the proliferating population, which differs by a factor of two; the lengths of the cell cycle and the S-phase and the probability that a newly produced cell will die within the first 10 days do not differ in these two strains. This indicates that genetic regulation of the size of the proliferating population is independent of the genetic regulation of cell death among those newly produced cells. The dynamic changes in the number of labeled cells as revealed by the SSM protocol also indicate that neither single nor repeated daily injections of BUdR accurately measure 'proliferation.'.
The role of DNA repair mechanisms in the induction of sister chromatid exchanges (SCE) after exposure to ultraviolet radiation was investigated in xeroderma pigmentosum cells. Cells from different excision-deficient XP strains, representing the 5 complementation groups in XP, A, B, C, D and E, and from excision-proficient XP variant strains were irradiated with low doses of UVR (0-3.5 J/m2). The number of SCE was counted after two cycles in the presence of BUdR. In cells of the complementation groups A, B, C and D the number of SCE was significantly higher than in UV-exposed control cells. The frequencies of SCE in group E cells and in XP variant cells were not different from those in control cells. Treatment with caffeine (0-200 μg/ml) did not result in a different response of variant cells compared with normal cells. A simple correlation between SCE frequency and residual excision-repair activity was not observed. The response of the excision-repair deficient cells suggests that unrepaired damage, produced by UVR is involved in the production of SCE
Effects of 2'-chlorothymidine (2'-Cl-TdR) and its mother compound, thymidine (TdR), on cell killing induced by X- and UV-irradiation have been investigated. Chinse hamster V-79 (TK+) cells as well as thymidine kinase deficient (TK-) variant cells, which were isolated from parental V-79 cells following stepwise treatment with BUdR, were incubated in a medium containing 2'-Cl-TdR and TdR after X- and UV-irradiation. In the TK+ cells, both 2'-Cl-TdR and TdR enhanced the killing efficiency of X-rays and ultraviolet light. On the other hand, in the TK- cells, only 2'-Cl-TdR enhanced the killing efficiency of X- and UV-irradiation, and no effect of TdR was observed. These results suggest that phosphorylation of TdR by the enzyme is essential for its ability to modify radiation response, while the enhancement of cell killing by 2'-Cl-TdR must be explained by a mechanism at least partly independent of phosphorylation. (author)
The chromosome study for the radiation-induced enhancement in producing various types of aberrations was conducted in a cultured cell line of CHO (Chinese hamster ovary) cells that were pre-labeled with BUdR (5'-deoxybromouridine) and irradiated by monochromatic X-rays with a slightly shorter wavelength (0.9 A) than the K adsorption edge of bromine (0.92 A). The dose-response changes in terms of frequencies of single-arm breaks and isochromatid breaks have shown that a maximum effect was produced by the combination of 0.9-A wavelength of X-irradiation and Br-incorporation and was above the magnitude of the so-called brome-induced sensitization obtained with 1.0-A wavelength X-rays. Such additional effect in the bromine-sensitized cells may be interpreted as the biological effect due to Auger electrons produced by photoelectric stimulation with 0.9-A monochromatic X-rays
Michalides, R; Schlom, J; Dahlberg, J; Perk, K
The biophysical and biochemical properties of the virus particles released by guinea pig embryo cells treated with 5-bromo-2'-deoxyuridine (BUdR) have been compared to those of the B-type mouse mammary tumor virus (MMTV) and the C-type Rauscher murine leukemia virus. The high-molecular-weight (60 to 70S) RNA of the BUdR-induced guinea pig virus (GPV) has a molecular weight of 8 X 106 when measred by mixed agarose polyacylamide gel electrophoresis. The virus particles isolated from the tissue culture medium of BUdR-induced guniea pig cells have the following properties in common with MMTV: (i) a buoyant density of 1.18 g/ml in sucrose and 1.21 g/ml in CsCl, and (ii) a DNA polymerase that prefers Mg2+ over Mn2+ in an assay using the synthetic template poly(rC):oligo(dG). No nucleic acid sequence homology between GPV RNA and the viral RNAs of the MMTV, murine leukemia virus, hamster sarcoma virus, or Mason-Pfizer monkey virus could be observed in a competition hybridization assay using the radioactive-labeled GPV 60 to 70S RNA. By this same competition by hybridization assay the frequency of GPV proviral sequences was estimated to be at least 83 per haploid cellular genome of guniea pig cells. No nucleic acid sequences related to be GPV RNA were detected in the DNA of normal tissues of mice, rats, cats, dogs, baboons, or humans by direct RNA-DNA hybridization using radioactive GPV60 to 70S RNA. PMID:51933
Full Text Available Abstract Purpose To study the efficacy of whole brain radiotherapy (WBRT with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. Methods A meta-analysis of randomized controlled trials (RCT was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently. Results A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84–1.25, p = 0.77. Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 – 1.03 and brain tumor progression (OR = 1.11, 95% CI 0.9 – 1.3 when the two arms were compared. Conclusion Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide, have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast to have positive action in lung and breast carcinoma brain metastases in association with WBRT.
Hayes, N. L.; Nowakowski, R. S.
Two S-phase markers for in vivo studies of cell proliferation in the developing central nervous system, tritiated thymidine ((3)H-TdR) and bromodeoxyuridine (BUdR), were compared using double-labeling techniques in the developing mouse cortex at embryonic day 14 (E14). The labeling efficiencies and detectability of the two tracers were approximately equivalent, and there was no evidence of significant tracer interactions that depend on order of administration. For both tracers, the loading time needed to label an S-phase cell to detectability is estimated at <0.2 h shortly after the injection of the label, but, as the concentration of the label falls, it increases to approximately 0.65 h after about 30 min. Thereafter, cells that enter the S-phase continue to become detectably labeled for approximately 5-6 h. The approximate equivalence of these two tracers was exploited to observe directly the numbers and positions of nuclei entering (labeled with the second tracer only) and leaving (labeled with the first tracer only) the S-phase. As expected, the numbers of nuclei entering and leaving the S-phase both increased as the interval between the two injections lengthened. Also, nuclei leaving the S-phase rapidly move towards the ventricular surface during G2, but, unexpectedly, the distribution of the entering nuclei does not differ significantly from the distribution of the nuclei in the S-phase. This indicates that: (1) the extent and rate of abventricular nuclear movement during G1 is variable, such that not all nuclei traverse the entire width of the ventricular zone, and (2) interkinetic nuclear movements are minimal during S-phase. Copyright 2000 S. Karger AG, Basel.
One of the missions of the Laboratory of Biological Dosimetry (L.D.B.) of the Institute for Radiation and Nuclear Safety (I.R.S.N.) is to assess the radiological dose after an accidental overexposure suspicion to ionising radiation, by using radio-induced changes of some biological parameters. The 'gold standard' is the yield of dicentrics observed in patients lymphocytes, and this yield is converted in dose using dose effect relationships. This method is complementary to clinical and physical dosimetry, for medical team in charge of the patients. To obtain a formal recognition of its operational activity, the laboratory decided three years ago, to require an accreditation, by following the recommendations of both 17025 General Requirements for the Competence of Testing and Calibration Laboratories and 19238 Performance criteria for service laboratories performing biological dosimetry by cyto-genetics. Diagnostics, risks analysis were realized to control the whole analysis process leading to documents writing. Purchases, personnel department, vocational training were also included in the quality system. Audits were very helpful to improve the quality system. One specificity of this technique is that it is not normalized therefore apart from quality management aspects, several technical points needed some validations. An inventory of potentially influent factors was carried out. To estimate their real effect on the yield of dicentrics, a Placket-Burman experimental design was conducted. The effect of seven parameters was tested: the BUdr (bromodeoxyuridine), PHA (phytohemagglutinin) and colcemid concentration, the culture duration, the incubator temperature, the blood volume and the medium volume. The chosen values were calculated according to the uncertainties on the way they were measured i.e. pipettes, thermometers, test tubes. None of the factors has a significant impact on the yield of dicentrics. Therefore the uncertainty linked to their use was considered as
.v. BUdR and indicate the need to proceed with randomized Phase III studies utilizing halogenated pyrimidines and radiation. One such study has already been activated, RTOG no. 94-04
Sadava, David; Kane, Susan E.
Small-cell lung carcinoma (SCLC) has a dismal prognosis in part because of multidrug resistance (MDR). Silibinin is a flavonolignan extracted from milk thistle (Silybum marianum), extracts of which are used in traditional medicine. We tested the effects of silibinin on drug-sensitive (H69) and multi-drug resistant (VPA17) SCLC cells. VPA17 cells did not show resistance to silibinin (IC50 = 60µM for H69 and VPA17). Flow cytometry analysis after incubation in 30 µM silibinin showed no changes in cell cycle phases in VPA17 or H69 cells compared with untreated cells. Silibinin (30 µM) incubation was pro-apoptotic in VPA17 cells after >3 days, as measured by ELISA of BUdR labeled DNA fragments. Apoptosis was also indicated by an increase in caspase-3 specific activity and decrease in survivin in VPA17 MDR cells. VPA17 cells had increased Pgp -mediated efflux of calcein acetoxymethyl ester (calcein AM); however, this was inhibited in cells pre-incubated in silibinin for 5 days. Pre-incubation of VPA17 cells in 30 µM silibinin for 5 days also reversed resistance to etoposide (IC50 = 5.50 uM to 0.65 µM) and doxorubicin (IC50 = 0.620 µM to 0.035 µM). The possible synergistic relationship between silibinin and chemotherapy drugs was determined by exposure of VPA17 cells to 1:1 ratios of their respective IC50 values, with serial dilutions at 0.25–2.0 × IC50 and calculation of the combination index (CI). Silibinin and etoposide showed synergism (CI = 0.46 at ED50), as did silibinin and doxorubicin (CI = 0.24 at ED50). These data indicate that in SCLC, silibinin is pro-apoptotic, reverses MDR and acts synergistically with chemotherapy drugs. Silibinin, a non-toxic natural product may be useful in the treatment of drug-resistant SCLC. PMID:23879966