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1.
Cancer Biol Ther ; 20(11): 1389-1397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31423878

RESUMO

Hydroxyurea (HU) has been widely used in sickle cell disease. Its potential long-term risk for carcinogenesis or leukemogenic risk remains undefined. Here, we report a 26 y old African-American female with Sickle Cell Disease (SCD) who developed refractory/relapsed acute myeloid leukemia (AML) 6 months after 26 months of HU use. That patient's cytogenetics and molecular genetics analyses demonstrated a complex mutation profile with 5q deletion, trisomy 8, and P53 deletion (deletion of 17p13.1). P53 gene sequence studies revealed a multitude of somatic mutations that most suggest a treatment-related etiology. The above-mentioned data indicates that the patient may have developed acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) as a direct result of HU exposure.


Assuntos
Anemia Falciforme/tratamento farmacológico , Carcinogênese/efeitos dos fármacos , Hidroxiureia/efeitos adversos , Leucemia Mieloide Aguda/genética , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/patologia , Carcinogênese/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/efeitos dos fármacos , Cromossomos Humanos Par 5/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Feminino , Humanos , Hidroxiureia/uso terapêutico , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Mutação/efeitos dos fármacos , Fatores de Risco
3.
Crit Rev Toxicol ; 43(8): 661-70, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23902349

RESUMO

A recent study (Zhang et al., 2010) has provided results attributed to aneuploidy in circulating stem cells that has been characterized as providing potential support for proposed mechanisms for formaldehyde to impact bone marrow. A critical review of the study, as well as a reanalysis of the underlying data, was performed and the results of this reanalysis suggested factors other than formaldehyde exposure may have contributed to the effects reported. In addition, although the authors stated in their paper that "all scorable metaphase spreads on each slide were analyzed, and a minimum of 150 cells per subject was scored," this protocol was not followed. In fact, the protocol to evaluate the presence of monosomy 7 or trisomy 8 was followed for three or less samples in exposed workers and six or less samples in non-exposed workers. In addition, the assays used (CFU-GM) do not actually measure the proposed events in primitive cells involved in the development of acute myeloid leukemia. Evaluation of these data indicates that the aneuploidy measured could not have arisen in vivo, but rather arose during in vitro culture. The results of our critical review and reanalysis of the data, in combination with recent toxicological and mechanistic studies, do not support a mechanism for a causal association between formaldehyde exposure and myeloid or lymphoid malignancies.


Assuntos
Formaldeído/toxicidade , Leucemia Mieloide Aguda/patologia , Exposição Ocupacional/análise , Animais , Carcinógenos/toxicidade , Deleção Cromossômica , Cromossomos Humanos Par 7/efeitos dos fármacos , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/genética , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Trissomia/genética
4.
Mutat Res ; 756(1-2): 158-64, 2013 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-23792211

RESUMO

We report the case of an 84 years old prostate cancer patient with severe side effects after radiotherapy in 2006. He was cytogenetically analysed in 2009 and in 2012 in a comparative study for individual radiosensitivity of prostate cancer patients. No other patient had clonal aberrations, but this patient showed ring chromosomes in the range of 21-25% of lymphocytes. He received 5 cycles of 5-fluorouracil/folic acid for chemotherapy of sigmoid colon carcinoma in 2003, three years before radiotherapy of prostate cancer. Blood samples were irradiated ex vivo with Cs-137 γ-rays (0.7Gy/min) in the G0-phase of the cell cycle. 100 FISH painted metaphases were analysed for the control and the irradiated samples each. Multicolour in situ hybridisation techniques like mFISH and mBand as well as MYC locus, telomere and centromere painting probes were used to characterise ring metaphases. Metaphase search and autocapture was performed with a Zeiss Axioplan 2 imaging microscope followed by scoring and image analysis using Metafer 4/ISIS software (MetaSystems). In 2009 chromosome 8 rings were found in about 25% of lymphocytes. Rings were stable over time and increased to about 30% until 2012. The ring chromosome 8 always lacked telomere signals and a small amount of rings displayed up to four centromere signals. In aberrant metaphases 8pter and 8qter were either translocated or deleted. Further analyses revealed that the breakpoint at the p arm is localised at 8p21.2-22. The breakpoint at the q arm turned out to be distal from the MYC locus at 8q23-24. We hypothesise that the ring chromosome 8 has been developed during the 5 FU/folic acid treatments in 2003. The long term persistence might be due to clonal expansion of a damaged but viable hematopoietic stem cell giving rise to cycling progenitor cells that permit cell survival and proliferation.


Assuntos
Aberrações Cromossômicas/efeitos dos fármacos , Linfócitos/patologia , Neoplasias da Próstata/genética , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Células Sanguíneas/efeitos da radiação , Coloração Cromossômica , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/genética , Fluoruracila/administração & dosagem , Raios gama , Humanos , Hibridização in Situ Fluorescente , Leucovorina/administração & dosagem , Masculino , Metáfase , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Cromossomos em Anel
6.
Oncol Rep ; 24(1): 121-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20514452

RESUMO

This study was performed to investigate whether the response to neoadjuvant chemotherapy in ductal-type breast cancer could be predicted by different genomic alterations. Array-based comparative genomic hybridization (aCGH) was performed on samples from 15 patients who underwent neoadjuvant chemotherapy with epirubicin plus docetaxel (ED). Frozen tissue bank samples were retrospectively selected from 8 patients who demonstrated complete pathologic response (pCR) and from 7 patients resistant to neoadjuvant chemotherapy. We performed aCGH with 4,277 human bacterial artificial chromosome (BAC) clones, scanning the genome for DNA copy number changes. In a cluster dendrogram of aCGH data, responders showed changes clustered in S940, S984, S44, S98, S130, S115, S478, and 1150T, whereas non-responder group changes clustered in S1029, S209, S219, S660, S133, S323, and S670. Compared to responders, non-responders showed more complicated genomic alterations; the most common gains were located at chromosome 8q (717%), 13q (71%), and 20q (57%), with the smallest regions of genomic gain at 8q24.3, 8q24.22, 8q24.21, 8q22.1, 8q22.2, 8q22.3, 13q21.1, 20q13.2, and 20q13.33. The most frequently deleted regions were observed on chromosome 8p (71%) and 17p (57%), with the smallest regions of deletion at 8p23.3, 8p23.2, 8p23.1, 8p21.3, 8p21.2, and 17p13.3. The results of the current study suggest that aberrations in chromosome 8 may contribute to the resistance to taxane-based neoadjuvant chemotherapy in ductal-type breast cancer. Results of our study indicate that candidate gene identification through aCGH should be validated by specific gene analysis since the sites of chromosomal aberration are quite different among studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/tratamento farmacológico , Cromossomos Humanos Par 8/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Farmacológicos/análise , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Aberrações Cromossômicas/induzido quimicamente , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Genoma/efeitos dos fármacos , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Terapia Neoadjuvante , Prognóstico , Estudos Retrospectivos , Taxoides/administração & dosagem
7.
J Child Neurol ; 25(10): 1275-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20489041

RESUMO

Constitutional mosaic trisomy 8 syndrome occurs in approximately 1 of 35 000 live births. Clinically, it has a variable presentation. Some patients are asymptomatic, while others have multisystemic involvement. The overall incidence of neurological abnormalities has not been reported, but seizures are among the neurological symptoms associated with this condition. Previous reports describe astatic seizures, complex partial seizures, generalized tonic-clonic seizures, and absence seizures with the age of onset varying from 3 months to early childhood. However, instances of infantile spasms and the patients' response to treatment have not been reported to our knowledge. Accordingly, we report a case of a patient with constitutional mosaic trisomy 8 syndrome and infantile spasms, who became seizure free after treatment with adrencorticotropic hormone and clonazepam.


Assuntos
Espasmos Infantis/genética , Adulto , Criança , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Lactente , Masculino , Mosaicismo/efeitos dos fármacos , Espasmos Infantis/tratamento farmacológico , Trissomia/genética , Dissomia Uniparental/efeitos dos fármacos , Dissomia Uniparental/genética
8.
Cancer Epidemiol Biomarkers Prev ; 19(1): 80-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20056626

RESUMO

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures.


Assuntos
Carcinógenos , Cromossomos Humanos Par 7/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Formaldeído/efeitos adversos , Células Progenitoras Mieloides/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Adulto , Aneuploidia , Contagem de Células Sanguíneas , Células Cultivadas , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia/genética , Masculino , Células Progenitoras Mieloides/patologia
9.
Int J Lab Hematol ; 30(6): 508-12, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18983302

RESUMO

We investigated chronic myelogenous leukemia (CML) patients who developed trisomy 8 abnormalities in Philadelphia-negative (Ph-) cells during imatinib mesylate treatment to evaluate the clinical outcome and laboratory features. Of the 470 CML patients, 1.5% (n = 7) developed trisomy 8 chromosomal abnormalities in Ph- cells. The median interval of the first trisomy 8 observation was 12 months. Our follow-up cytogenetic evaluations revealed that six of the patients demonstrated a complete or partial cytogenetic response and that all of the six patients revealed no dysplastic changes following a bone marrow examination. Moreover, the percentage of trisomy 8 in metaphase karyotyping has decreased in five of the seven subjects. In conclusion, these results suggest that the emergence of trisomy 8 in Ph- cells is transient and not related to therapy-related myelodysplasia or acute leukemia.


Assuntos
Antineoplásicos/efeitos adversos , Cromossomos Humanos Par 8/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Trissomia , Adulto , Antineoplásicos/uso terapêutico , Benzamidas , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Mesilato de Imatinib , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico
10.
J Cell Sci ; 118(Pt 8): 1757-67, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15797924

RESUMO

Chromatid interchanges induced by the DNA cross-linking agent mitomycin C (MMC) are over-represented in human chromosomes containing large heterochromatic regions. We found that nearly all exchange breakpoints of chromosome 9 are located within the paracentromeric heterochromatin and over 70% of exchanges involving chromosome 9 are between its homologues. We provide evidence that the required pairing of chromosome 9 heterochromatic regions occurs in G(0)/G(1) and S-phase cells as a result of an active cellular process initiated upon MMC treatment. By contrast, no pairing was observed for a euchromatic paracentromeric region of the equal-sized chromosome 8. The MMC-induced pairing of chromosome 9 heterochromatin is observed in a subset of cells; its percentage closely mimics the frequency of homologous interchanges found at metaphase. Moreover, the absence of pairing in cells derived from XPF patients correlates with an altered spectrum of MMC-induced exchanges. Together, the data suggest that the heterochromatin-specific pairing following MMC treatment reflects the initiation of DNA cross-link repair and the formation of exchanges.


Assuntos
Pareamento Cromossômico/fisiologia , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Heterocromatina/fisiologia , Mitomicina/farmacologia , Troca de Cromátide Irmã/fisiologia , Células Cultivadas , Pareamento Cromossômico/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/fisiologia , Cromossomos Humanos Par 9/efeitos dos fármacos , Cromossomos Humanos Par 9/fisiologia , Reagentes de Ligações Cruzadas/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fase G1/fisiologia , Heterocromatina/efeitos dos fármacos , Humanos , Interfase/fisiologia , Metáfase/fisiologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/fisiologia , Fase S/efeitos dos fármacos , Fase S/fisiologia , Homologia de Sequência do Ácido Nucleico , Troca de Cromátide Irmã/efeitos dos fármacos , Xeroderma Pigmentoso/genética
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 21(4): 360-4, 2004 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-15300634

RESUMO

OBJECTIVE: To investigate the frequency of numerical aberrations for chromosomes 7 and 8 in the sperms of workers exposed to benzene series. METHODS: Numerical aberrations in the sperms of workers were detected by two-color fluorescence in situ hybridization with biotin labeled chromosome 7 probe (D7Z1) and digoxingenin labeled chromosome 8 probe (D8Z1). RESULTS: The time-weight average air concentration (TWA) of benzene in the workshop was 42.29 mg/m(3), which was significantly higher than that of the national maximum allowable concentration [6 mg/m(3)]. The concentration of urinary trans,trans-muconic acid(ttMA) in the exposed group was also higher than that of the control group. In all, 155721 sperm nuclei from 15 workers in the exposed group and 123771 sperm nuclei from 12 individuals in the control group were examined. The results showed that the frequency of diploidy sperms and the frequencies of disomic sperm for chromosomes 7 and 8 in the exposed group (0.129%, 0.170%, 0.078%) were significantly higher than those of the control group (0.055%, 0.053%, 0.033%), respectively. The frequencies of nullisomic sperm for chromosomes 7 and 8 in the exposed group (0.165%, 0.088%) were also significantly increased, compared with those of the control group (0.056%, 0.029%). A statistically significant difference in the frequency of overall numerical chromosome aberrations was seen between the exposed group (0.745%) and the control group (0.289%). CONCLUSION: The results suggested that higher concentration of benzene may induce higher frequencies of numerical aberrations in the sperms of workers exposed to benzene series.


Assuntos
Benzeno/intoxicação , Aberrações Cromossômicas/induzido quimicamente , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Hibridização in Situ Fluorescente/métodos , Exposição Ocupacional/análise , Espermatozoides/efeitos dos fármacos , Adulto , Cromossomos Humanos Par 8/efeitos dos fármacos , Feminino , Humanos , Masculino , Doenças Profissionais/diagnóstico , Doenças Profissionais/genética , Espermatozoides/metabolismo
12.
Mutagenesis ; 17(3): 233-9, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11971995

RESUMO

Fluorescence in situ hybridization (FISH) was used to evaluate spontaneous and aneuploidogen-induced micronucleus frequencies and non-disjunction of chromosomes X and 8 in cultured binucleated lymphocytes of women of two age groups. Demecolcine and vincristine were used as model aneuploidogens to induce micronuclei and chromosome malsegregation. Four of the women were aged 22-26 (mean 24.3) years and four 47-50 (mean 49.0) years. Pancentromeric FISH was applied to micronuclei to identify chromosomes and double-color centromeric FISH, performed in binucleates of two young and two older women, was used to assess the involvement of chromosomes X and 8 in micronuclei and non-disjunction. It was confirmed that age increases micronucleus frequency. Micronuclei containing whole chromosomes predominated in older females. Age also enhanced micronuclei containing acentric chromosome fragments. The inclusion of chromosomes X and 8 in micronuclei was enhanced by age and chromosome X was generally overrepresented. Non-disjunction of chromosomes X and 8 also increased with age, chromosome X being the more sensitive. Treatment of lymphocytes with vincristine and demecolcine increased micronucleus frequency and malsegregation of chromosomes X and 8 in both age groups. Comparison of the estimated frequencies of micronucleation and non-disjunction for all human chromosomes showed that non-disjunction is the main type of chromosome malsegregation.


Assuntos
Aneuploidia , Antineoplásicos Fitogênicos/farmacologia , Cromossomos/efeitos dos fármacos , Demecolcina/farmacologia , Linfócitos/efeitos dos fármacos , Vincristina/farmacologia , Adulto , Fatores Etários , Ciclo Celular , Cromossomos Humanos Par 8/efeitos dos fármacos , Feminino , Humanos , Hibridização in Situ Fluorescente , Testes para Micronúcleos , Pessoa de Meia-Idade , Não Disjunção Genética , Cromossomo X/efeitos dos fármacos
13.
Mutat Res ; 516(1-2): 49-56, 2002 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-11943610

RESUMO

The cytokinesis-block micronucleus (CBMN) assay has emerged as one of the preferred methods for assessing chromosome damage. Micronuclei (MN) are small, extranuclear bodies that are formed in mitosis from acentric chromosomal fragments or chromosomes that are not included in each daughter nucleus. Thus, MN contain either chromosomal fragments or whole chromosomes. The CBMN assay, together with a fluorescence in situ hybridization (FISH) technique using specific centromeric probes for chromosomes 7 and 8, were employed in mitogen-stimulated human lymphocytes pretreated with the benzene metabolite, 1,2,4-benzenetriol (BT). Treatment of human lymphocytes resulted in the induction of MN in a dose-dependent manner. The frequency of MN in control lymphocytes was 4.5 per 1000 binucleated (BN) cells and this increased to 9.5, 14, 28 and 40 per 1000 BN cells at 10, 25, 50 and 100 microM BT, respectively. The frequency of aneuploidy 7 and 8 in BN cells also increased at each concentration. Aneuploidy 8 was more frequent than aneuploidy 7, suggesting that chromosome 8 is more sensitive to aneuploidy induction by BT. The frequency of MN containing centromere positive signals for chromosomes 7 and 8 increased with the concentration of BT. The frequency of MN with centromere positive signals was higher for chromosome 8 than for chromosome 7, also suggesting a greater sensitivity of chromosome 8 to this agent. These results suggest that combined application of the CBMN assay with a FISH technique, using chromosome-specific centromeric probes, would allow the detection of aneuploidy in human lymphocytes and identify the mechanistic origin of MN induced by a clastogen or aneugen.


Assuntos
Hidroquinonas/toxicidade , Hibridização in Situ Fluorescente , Linfócitos/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Testes para Micronúcleos , Aneuploidia , Centrômero/genética , Cromossomos Humanos Par 7/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Sondas de DNA , Humanos , Testes de Mutagenicidade
14.
Mutagenesis ; 17(1): 83-8, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11752239

RESUMO

The incidence of spontaneous aneuploidy in human somatic and germ cells is known to be positively associated with aging. However, the influence of age on the individual susceptibility to chemically induced chromosome malsegregation has not been elucidated. In this study the spindle poison vinblastine (VBL) was used as a model compound to assess the influence of donor age on chemically induced chromosome malsegregation in cultured lymphocytes. Blood cultures from 20 female donors belonging to two different age groups (10 <30 years and 10 >50 years) were treated with VBL (7.5 ng/ml) from 43 h after mitogen stimulation until harvest at 60 h, i.e. during the time interval corresponding to G2/M. In order to block cytokinesis, cytochalasin B (6 microg/ml) was added to cultures at 44 h. For each donor the incidence of micronuclei, polyploidy and malsegregation (non-disjunction and loss) of chromosomes X and 8 was determined using fluorescence in situ hybridization with chromosome-specific centromeric probes. Both background incidence of micronuclei and spontaneous chromosome X non-disjunction were significantly elevated in older donors. Individual responses to VBL treatment showed wide interindividual variability, which was not significantly associated with the age of the donor. In both age classes chromosome X was more susceptible than chromosome 8 to both spontaneous and VBL-induced malsegregation. These results indicate that donor age has a limited influence on the aneugenic effects exerted by VBL in peripheral lymphocytes in vitro. Other factors have to be considered to account for the large interindividual variation in sensitivity to VBL challenge observed in this work.


Assuntos
Envelhecimento/genética , Segregação de Cromossomos/efeitos dos fármacos , Cromossomos Humanos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Fuso Acromático/efeitos dos fármacos , Vimblastina/farmacologia , Adulto , Envelhecimento/sangue , Envelhecimento/patologia , Aneuploidia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/ultraestrutura , Cromossomos Humanos Par 8/efeitos dos fármacos , Citocalasina B/farmacologia , Resistência a Medicamentos , Feminino , Variação Genética , Humanos , Hibridização in Situ Fluorescente , Linfócitos/ultraestrutura , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Não Disjunção Genética , Vimblastina/toxicidade , Cromossomo X/efeitos dos fármacos
15.
Int J Mol Med ; 8(1): 43-7, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11408947

RESUMO

We examined karyotypic changes of tumorigenic human bronchial epithelial cell lines transformed by asbestos fibers. Using Calyculin A mediated premature chromosome condensation (PCC) assay and Giemsa-trypsin banding, we showed that the common changes of all tumorigenic cell lines were the loss of one or two copies of chromosome 5, the monosomy of chromosome 19 and the increased trisomy of chromosome 8. The results indicate that the karyotypic change of chromosome 5, 8 and 19 could play an important role in asbestos-induced tumorigenic conversion of human bronchial epithelial cells from an immortalized to tumorigenic state.


Assuntos
Asbestos Serpentinas/administração & dosagem , Brônquios/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Cariotipagem/métodos , Animais , Brônquios/citologia , Brônquios/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Transformação Celular Neoplásica/efeitos dos fármacos , Aberrações Cromossômicas , Cromossomos Humanos Par 19/efeitos dos fármacos , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 5/efeitos dos fármacos , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Camundongos , Camundongos Nus , Índice Mitótico
16.
Mutat Res ; 473(1): 85-99, 2001 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-11166028

RESUMO

While some epidemiological risk factors for breast cancer have been identified, the environmental factors responsible for transformation of mammary epithelial cells are not clear. We have exposed the spontaneously immortalized human mammary epithelial cell line MCF-10A to benzo[a]pyrene and selected transformed clones based on a loss of contact inhibition and anchorage-dependent growth. Cytogenetic studies showed that each of the transformed sublines possess an isochromosome 8q aberration. The c-Myc proto-oncogene, which is positioned at 8q24, was analyzed for changes in expression. Both c-Myc mRNA and protein levels were increased in the transformed clones relative to the parental cells. The transformed clones were not able to grow as tumors in vivo when injected into nude or SCID mice. To determine whether the involvement of chromosome 8 in BP-induced mutagenesis was a reproducible event, transformed clones were selected from three additional independently treated sets of BP-exposed MCF-10A cultures and analyzed by spectral karyotyping (SKY). These transformed sublines also harbored the isochromosome 8q abnormality. Data from this model show that benzo[a]pyrene, a ubiquitous procarcinogen, can induce selectable morphologic changes in a human mammary epithelial cell line, and that these transformed cells possess chromosomal aberrations frequently found in human breast tumors.


Assuntos
Benzo(a)pireno/efeitos adversos , Mama/patologia , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 8/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Animais , Mama/efeitos dos fármacos , Testes de Carcinogenicidade , Linhagem Celular , Linhagem Celular Transformada/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 8/genética , Células Clonais , Análise Citogenética , Análise Mutacional de DNA , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Genes myc/genética , Humanos , Camundongos , Proto-Oncogene Mas , RNA Mensageiro/metabolismo
17.
Carcinogenesis ; 21(8): 1485-90, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10910948

RESUMO

Benzene is an established human carcinogen, producing leukemia, hematotoxicity and perhaps lymphoma. Its carcinogenicity is most likely dependent upon its conversion to phenol and hydroquinone, the latter being oxidized to the highly toxic 1,4-benzoquinone in the bone marrow. Exposure of human lymphocytes and cell lines to hydroquinone has previously been shown to cause various forms of genetic damage, including aneusomy and the loss and gain of chromosomes. However, the target cells for leukemogenesis are the pluripotent stem cells or early progenitor cells which carry the CD34 antigen (CD34(+) cells). In this study, human cord blood, which is particularly rich in CD34(+) cells, was exposed to hydroquinone for 72 h in a medium that favored CD34(+) cell survival and growth. CD34(+) and CD34(-) cells were then isolated. Fluorescence in situ hybridization was employed to determine the level of aneusomy of chromosomes 7 and 8 in both cell types. CD34(+) cells were generally more susceptible to aneusomy induction by hydroquinone than CD34(-) cells. Increased trisomy and monosomy of chromosomes 7 and 8 were observed in CD34(+) cells (P(trend) < 0.001), whereas in CD34(-) cells only an increased level of monosomy 7 was detected (P(trend) = 0.002). Particularly striking effects of hydroquinone were observed in CD34(+) cells on monosomy 7 and trisomy 8, two common clonal aberrations found in myeloid leukemias, suggesting that these aneusomies produced by hydroquinone in CD34(+) cells play a role in benzene-induced leukemogenesis.


Assuntos
Aneuploidia , Antígenos CD34/sangue , Cromossomos Humanos Par 7/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Células-Tronco Hematopoéticas/ultraestrutura , Hidroquinonas/toxicidade , Mutagênicos/toxicidade , Células Cultivadas , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Hibridização in Situ Fluorescente
18.
Cancer Res ; 58(10): 2176-81, 1998 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-9605763

RESUMO

Chromosome aberrations in peripheral blood lymphocytes have been used for many years to monitor human populations exposed to potential carcinogens. Recent reports have confirmed the validity of this approach by demonstrating that elevated levels of chromosome aberrations in lymphocytes are associated with subsequent increased cancer risk, especially for increased mortality from hematological malignancies including acute myeloid leukemia (AML). We postulated that this approach could be improved in two ways: (a) by detecting oncogenic disease-specific aberrations; and (b) by using chromosome painting so that many more metaphases could be analyzed. Numerical and structural aberrations in chromosomes 8 and 21 are commonly observed in AML. In the present study, we painted chromosomes 8 and 21 in lymphocyte metaphases from 43 healthy workers exposed to benzene, an established cause of AML, and from 44 matched controls. To examine dose-response relationships the workers were divided into two groups at the median exposure level, a lower-exposed group (< or = 31 ppm; n = 21), and a higher-exposed group (> 31 ppm; n = 22). Benzene exposure was associated with significant increases in hyperdiploidy of chromosomes 8 (1.2, 1.5, and 2.4 per 100 metaphases; P < 0.0001) and 21 (0.9, 1.1, and 1.9 per 100 metaphases; P < 0.0001). Translocations between chromosomes 8 and 21 were increased up to 15-fold in highly exposed workers (0.01, 0.04, and 0.16 per 100 metaphases; P < 0.0001). In one highly exposed individual, these translocations were reciprocal and were detectable by reverse transcriptase-PCR. These data indicate a potential role for t(8;21) in benzene-induced leukemogenesis and are consistent with the hypothesis that detection of specific chromosome aberrations may be a powerful approach to identify populations at increased risk of leukemia.


Assuntos
Benzeno/toxicidade , Carcinógenos/toxicidade , Cromossomos Humanos Par 21/efeitos dos fármacos , Cromossomos Humanos Par 8/efeitos dos fármacos , Leucemia Mieloide/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Translocação Genética , Doença Aguda , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Leucemia Mieloide/genética , Masculino
19.
Somat Cell Mol Genet ; 23(2): 111-21, 1997 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9330639

RESUMO

An ionizing radiation resistant derivative was obtained from the mouse P19H22 (aprt hemizygote) embryonal carcinoma cell line by repeated exposure to 137Cs gamma radiation. Ionizing radiation resistance in the 6Gy-R cell line was not correlated with a failure to undergo cell cycle arrest or a loss of the p53 response after exposure to 137Cs gamma radiation. Moreover, the cells did not display increased resistance to bleomycin, a double strand break inducing agent. However, the cells did display increased resistance to ultraviolet radiation, ethyl methanesulfonate, and 95% oxygen. A mutational analysis demonstrated a > 700 fold-fold increase in the frequency of aprt mutants for the 6Gy-R cells, but no change in the frequency of hprt or dhfr mutants. A molecular analysis suggested that the aprt mutations in the 6Gy-R cells arose by recombinational events. A possible association between radiation resistance, DNA repair, and a mutator phenotype for large-scale mutational events is discussed.


Assuntos
Carcinoma Embrionário/genética , Raios gama , Perda de Heterozigosidade/efeitos da radiação , Mutagênicos , Tolerância a Radiação/efeitos dos fármacos , Adenina Fosforribosiltransferase/química , Adenina Fosforribosiltransferase/genética , Adenina Fosforribosiltransferase/efeitos da radiação , Animais , Carcinoma Embrionário/enzimologia , Radioisótopos de Césio , Cromossomos Humanos Par 8/efeitos dos fármacos , Cromossomos Humanos Par 8/enzimologia , Cromossomos Humanos Par 8/efeitos da radiação , Células Clonais , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/efeitos da radiação , Perda de Heterozigosidade/efeitos dos fármacos , Camundongos , Mutagênicos/efeitos da radiação , Fenótipo , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/efeitos da radiação , Células Tumorais Cultivadas
20.
Lancet ; 337(8751): 1190, 1991 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-1673740

RESUMO

Dual exposure to Epstein-Barr virus and purified 4-deoxyphorbol ester derived from the plant Euphorbia tirucalli induced a high frequency of chromosomal rearrangements in human B lymphocytes in vitro. Rearrangements most commonly affected chromosome 8, the chromosome most often showing structural changes in Burkitt's lymphoma (BL) cells. E tirucalli is indigenous in parts of Africa where BL is endemic and may be an important risk factor for the disease.


Assuntos
Linfócitos B/fisiologia , Linfoma de Burkitt/genética , Cromossomos Humanos Par 8 , Herpesvirus Humano 4/fisiologia , Plantas Medicinais , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Linfócitos B/efeitos dos fármacos , Linfoma de Burkitt/microbiologia , Cromossomos Humanos Par 8/efeitos dos fármacos , Exposição Ambiental , Humanos , Ésteres de Forbol/farmacologia
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