Wheat mutation rate after Chernobyl.
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Germ-Line Mutation↗
Biomedical subjects
A Arkhipov
Publications and source records attributed to A Arkhipov.
Plants experiencing chronic internal exposure to ionizing radiation exhibit higher frequency of homologous recombination than acutely irradiated plants.
Ionizing radiation (IR) is a known mutagen responsible for causing DNA strand breaks in all living organisms. Strand breaks thus created can be repaired by different mechanisms, including homologous recombination (HR), one of the key mechanisms maintaining genome stability [A. Britt, DNA damage and repair in plants, Annu. Rev. Plant. Phys. Plant Mol. Biol., 45 (1996) 75-100; H. Puchta, B. Hohn, From centiMorgans to basepairs: homologous recombination in plants, Trends Plant Sci., 1 (1996) 340-348.]. Acute or chronic exposure to IR may have different influences on the genome integrity. Although in a radioactively contaminated environment plants are mostly exposed to chronic pollution, evaluation of both kinds of influences is important. Estimation of the frequency of HR in the exposed plants may serve as an indication of genome stability. We used previously generated Arabidopsis thaliana and Nicotiana tabacum plants, transgenic for non-active versions of the beta-glucoronidase gene (uidA) [P. Swoboda, S. Gal, B. Hohn, H. Puchta, Intrachromosomal homologous recombination in whole plants, EMBO J., 13 (1994) 484-489; H. Puchta, P. Swoboda, B. Hohn, Induction of homologous DNA recombination in whole plants, Plant, 7 (1995) 203-210.] serving as a recombination substrate, to study the influence of acute and chronic exposure to IR on the level of HR as example of genome stability in plants. Exposure of seeds and seedlings to 0.1 to 10.0 Gy 60Co resulted in increased HR frequency, although the effect was more pronounced in seedlings. For the study of the influence of chronic exposure to IR, plants were grown on two chemically different types of soils, each artificially contaminated with equal amounts of 137Cs. We observed a strong and significant correlation between the frequency of HR in plants, the radioactivity of the soil samples and the doses of radiation absorbed by plants (in all cases r0.9, n=6, P<0.05). In addition, we noted that plants grown in soils with different chemical composition, but equal radioactivity, exhibited different levels of HR, dependent upon the absorbed dose of radiation. Remarkably, we observed a much higher frequency of HR in plants exposed to chronic irradiation when compared to acutely irradiated plants. Although acute application of 0.1-0.5 Gy did not lead to an increase of frequency of HR, the chronic exposure of the plants to several orders of magnitude lower dose of 200 muGy led to a 5-6-fold induction of the frequency of HR as compared to the control.
DNA Damage↗
Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.
PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.
Administration, Oral↗
Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.
PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.
Administration, Oral↗
Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study.
We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n=366) or MA 40 mg four times daily (160 mg daily; n=403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete response (CR)+partial response (PR) (15.0% vs. 12.4%) and of CR+PR+stable disease (SD)=24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR+PR+SD=24 weeks (60.1 vs. 49.1 weeks; P=0.025), time to tumor progression (20.3 vs. 16.6 weeks; P=0.037), time to treatment failure (16.3 vs. 15.7 weeks; P=0.042), and overall survival (not reached vs. 123.4 weeks; P=0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P=0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.
Administration, Oral↗
Radiation hazard caused by the Chernobyl accident in inhabited areas of Ukraine can be monitored by transgenic plants.
The genetic impact of the 1986 accident at the Ukraine Chernobyl Nuclear Power Plant (NPP) on populations of living organisms has yet to be fully assessed. Monitoring of the genotoxicity of polluted soils is a key element in the disaster management program. We used Arabidopsis thaliana and Nicotiana tabacum plants transgenic for a reporter gene revealing homologous recombination to study the genetic effects of chronic low-dose radiation stemming from the soil in inhabited areas of Ukraine where contamination by the accident ranges from 1 to 40 Ci/km2. We noted a significant dose-dependent increase of homologous recombination in plants cultivated in the affected inhabited areas, proving the persistently high genotoxicity of the radioactively contaminated soils.
Arabidopsis↗
Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group.
PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate. PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression. The efficacy and safety of exemestane were clinically and radiographically evaluated. The impact of exemestane treatment on tumor-related signs and symptoms was assessed. The effect of exemestane on serum levels of estrogens and other steroidal hormones was determined. RESULTS: Ninety-one patients were treated. There were four complete responses (CR) and eight partial responses (PR), for an objective response rate of 13% in the entire treated population. The overall success rate (CR, PR, or stable disease [SD] >/= 24 weeks) was 30%. The median duration of response and overall success was 9 months and 8 months, respectively. Most patients with CR/PR (83%; 10 of 12 patients) and SD >/= 24 weeks (80%; 12 of 15 patients) had improved or stable tumor-related signs and symptoms. Mean levels of circulating estrone (E(1)), estradiol (E(2)), and estrone sulfate decreased to 11%, 22%, and 13% of baseline levels, respectively (at week 8 or 16 of treatment). One half of the patients had undetectable E(1) and E(2) levels during treatment, including at the time of disease progression. Mild nausea (20% of patients) and hot flashes (20%) were the most common drug-related adverse events and were generally grade 1. CONCLUSION: Exemestane is an active and well-tolerated third-line hormonal therapy that represents a new treatment option for postmenopausal patients with advanced breast cancer that has become refractory to standard first- and second-line hormonal therapies.
Adult↗
The Allium cepa chromosome aberration test reliably measures genotoxicity of soils of inhabited areas in the Ukraine contaminated by the Chernobyl accident.
The accident on the Chernobyl Nuclear Power Plant reactor IV in April 1986 led to the release of an enormous amount of radioactive material into the biosphere and to the formation of a complex pattern of nuclear contamination over a large area. As a consequence more than 5 million km2 of the soil in the Ukraine became contaminated with more than 1 Ci/km2 [1,2]. An assessment of the genetic consequences of the nuclear pollution is one of the most important problems. We applied the Allium cepa test to estimate the impact on plant chromosomes of nuclear pollution in the inhabited zones of the Ukraine. We tested soil from the obligatory resettlement zone (zone 2), where the mean density of pollution is 15-40 Ci/km2; zones of enhanced radiological control-zone 3, 5-15 Ci/km2 and zone 4, 1-5 Ci/km2. We found a dose-dependent increase in the fraction of aberrant mitoses from control values of 1.6 +/- 0.9% up to 23.8 +/- 5.0%, and a corresponding monotonous decrease of the mitotic index from 49.4 +/- 4.8% to a limiting value of 22.5 +/- 4.0% at pollution levels exceeding 35 Ci/km2 (activity of the soil samples exceeding 6000 Bq/kg, respectively). We observed a strong, significant correlation of 137Cs activity of soil samples with the percentage of chromosomal abnormalities, r = 0.97 (P < 0.05), and with the mitotic index, r = -0.93 (P < 0.05), in the roots of A. cepa, respectively. The results showed high toxicity and genotoxicity of radioactively polluted soils and confirmed the efficiency of the A. cepa test as a quick and inexpensive biological test for ecological and genetic risk assessment in the 'Chernobyl' zones.
Chromosome Aberrations↗
Transgenic plants are sensitive bioindicators of nuclear pollution caused by the Chernobyl accident.
To evaluate the genetic consequences of radioactive contamination originating from the nuclear reactor accident of Chernobyl on indigenous populations of plants and animals, it is essential to determine the rates of accumulating genetic changes in chronically irradiated populations. An increase in germline mutation rates in humans living close to the Chernobyl Nuclear Power Plant site, and a two- to tenfold increase in germline mutations in barn swallows breeding in Chernobyl have been reported. Little is known, however, about the effects of chronic irradiation on plant genomes. Ionizing radiation causes double-strand breaks in DNA, which are repaired via illegitimate or homologous recombination. We make use of Arabidopsis thaliana plants carrying a beta-glucuronidase marker gene as a recombination substrate to monitor genetic alterations in plant populations, which are caused by nuclear pollution of the environment around Chernobyl. A significant (p<0.05) increase in somatic intrachromosomal recombination frequencies was observed at nuclear pollution levels from 0.1-900 Ci/km2, consistent with an increase in chromosomal aberrations. This bioindicator may serve as a convenient and ethically acceptable alternative to animal systems.
Animals↗
Ratios of transfer coefficients for radiocesium transport in ruminants.
A corollary of the multiple-compartment model for the transport of trace elements through animals was tested for cows, goats, and sheep. According to this corollary, for a given body "compartment" k of the animal (soft tissue, lung, liver, etc.), the ratio a(k) = f(k)/f(blood) of the transfer coefficients f, should exhibit similar values for physiologically similar animals. In order to verify this prediction, two experiments were performed at the Agricultural Research Station of Ioannina and at the facilities of Ria Pripyat in Pripyat, Ukraine. Eight animals in the first experiment and eighteen in the second were housed in individual pens and were artificially contaminated with a constant daily dose of radiocesium until equilibrium was reached. The animals were then sacrificed and transfer coefficients f(k) to twelve body "compartments" k were measured. These data were used to calculate the ratios a(k). The results were in accordance with predictions of the model and average values of a(k) were extracted for ruminants. It is concluded that these values may be employed for the prediction of animal contamination in any body compartment through the measurement of blood samples.
Animals↗