Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
JSLS ; 22(3)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356343

RESUMO

BACKGROUND AND OBJECTIVE: Some patients who undergo laparoscopic hysterectomy request overnight admission for pain management, thus increasing costs for a surgery that is safe for same-day discharge. We wanted to evaluate whether a paracervical block of bupivacaine with epinephrine before laparoscopic supracervical hysterectomy would decrease overnight admission rates, postoperative pain, and pain medication requirement. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group trial (Canadian Task Force classification I) at an academic medical center. Patients undergoing laparoscopic supracervical hysterectomy were randomized to a 20-mL paracervical injection of either 0.25% bupivacaine with epinephrine or 20 mL normal saline before skin incision. All providers, except the circulating nurse, were blinded. The primary outcome was overnight hospital admission rate. Secondary outcomes included postoperative pain medication use and pain scores. Analysis included t test, χ2, Wilcoxon, and ANOVA. RESULTS: One hundred thirty-two patients were enrolled-68 in the treatment group and 64 in the placebo group. Demographics were similar between groups. The unplanned overnight admission rate was 34% for the treatment group and 27% for the placebo group (P = .25). After discharge, the treatment group used on average 8.5 tablets of narcotics, whereas the placebo group used 11.7 tablets (P = .07). The treatment group took 13.1 tablets of nonnarcotic analgesics compared to 11.2 in the placebo group (P = .57). Both groups reported similar pain scores. CONCLUSION: Paracervical block with bupivacaine and epinephrine before laparoscopic supracervical hysterectomy did not decrease overnight admission rate or affect postoperative pain. Postoperative opiate use was minimally decreased.


Assuntos
Anestesia Obstétrica , Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Histerectomia , Laparoscopia , Dor Pós-Operatória/prevenção & controle , Adulto , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Epinefrina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Simpatomiméticos/administração & dosagem
2.
Int J Gynaecol Obstet ; 140(1): 26-30, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28921506

RESUMO

OBJECTIVE: To quantify the incidence of peripheral neuropathy in gynecologic laparoscopic surgery using a combination of beanbag, eggcrate foam, and shoulder supports; and to assess patient displacement during surgery in a steep Trendelenburg position and determine variables correlated with displacement. METHODS: A retrospective study included all gynecologic laparoscopic surgeries performed by one high-volume surgeon at a US center between September 15, 2007, and September 15, 2012. Data included neurologic deficits or extremity pain, any other complications, and-for the final study year-surgical time as well as patient and beanbag displacement. RESULTS: Among 967 patients, no long-term neuropathy was reported, 6 (0.6%) patients had transient shoulder pain beyond the first 24 hours (resolved by initial postoperative visit), and 7 (0.7%) were lost to follow-up. No neurologic complications were reported. Median beanbag and total patient displacement were 0 cm (interquartile range 0-0) and 0 cm (interquartile range 0-2), respectively. Patient displacement relative to the table was correlated with the total surgical time (P=0.025) and patient weight (P=0.023). The median displacement was greater in hysterectomy than non-hysterectomy procedures (P=0.003). CONCLUSION: Use of beanbags with shoulder supports and convoluted foam armboard pads was associated with minimal patient displacement and risk of arm and leg neurologic injury.


Assuntos
Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Laparoscopia/efeitos adversos , Equipamentos Ortopédicos , Traumatismos dos Nervos Periféricos/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Feminino , Procedimentos Cirúrgicos em Ginecologia/instrumentação , Procedimentos Cirúrgicos em Ginecologia/métodos , Decúbito Inclinado com Rebaixamento da Cabeça/efeitos adversos , Humanos , Histerectomia/efeitos adversos , Histerectomia/instrumentação , Histerectomia/métodos , Laparoscopia/instrumentação , Laparoscopia/métodos , Pessoa de Meia-Idade , Duração da Cirurgia , Posicionamento do Paciente , Traumatismos dos Nervos Periféricos/etiologia , Estudos Retrospectivos , Ombro/inervação , Lesões do Ombro/etiologia , Lesões do Ombro/prevenção & controle
3.
Female Pelvic Med Reconstr Surg ; 21(6): 348-54, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26506164

RESUMO

OBJECTIVES: Approaches for performing sacrocolpopexy (laparotomy, laparoscopy, and robotically assisted) differ with regard to length of surgery, postoperative pain, and cosmetic appearance of skin incisions. The aim of our study is to better understand what factors influence patient preferences for surgical approach. METHODS: A cross-sectional study was performed using a survey. Females 18 years or older presenting to gynecologic offices were asked to complete a survey that included photographs of patient incisions 6 weeks postoperatively along with a schematic representation of each incision type (laparotomy with low transverse incision, traditional laparoscopy, and robotically assisted). Patients were first asked to rank each incision based on cosmetic appearance only. They were next given varying clinical scenarios associated with each surgical approach and asked if their preference of incision changed. A sample size of 90 subjects was needed in order to detect a 30% difference in incision preference based on appearance with an α of 0.05 and 80% power. RESULTS: One hundred fifty patients completed the survey. Based on cosmetic appearance alone, 70% chose laparoscopic surgery, 23% chose open, and 7% chose the robotic approach (P < 0.0001). The majority of the subjects would not change their incision preference of laparoscopy based on differing scenarios of postoperative pain (62.6%), length of surgery (65.3%), and length of hospital stay (73.6%). When asked to rank factors important in decision making, complication rate (53.9%) and surgeon experience with the procedure (32.8%) were ranked as most important. CONCLUSIONS: Based on cosmetic appearance, patients prefer the laparoscopic approach for abdominal sacrocolpopexy for pelvic organ prolapse surgery. However, complication rates and surgeon experience with the procedure are important factors in the patient's decision making.


Assuntos
Estética , Procedimentos Cirúrgicos em Ginecologia/métodos , Preferência do Paciente , Prolapso de Órgão Pélvico/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Estudos Transversais , Tomada de Decisões , Feminino , Humanos , Laparoscopia , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários
4.
Am J Obstet Gynecol ; 209(5): 473.e1-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23665244

RESUMO

OBJECTIVE: Colpocleisis is a definitive surgical treatment for prolapse resulting in vaginal obliteration. We sought to evaluate body image, regret, satisfaction, and pelvic floor symptoms following this procedure. STUDY DESIGN: This was a prospective multicenter study through the Fellows' Pelvic Research Network. All women electing colpocleisis for management of pelvic organ prolapse were screened for enrollment. The Pelvic Floor Impact Questionnaire, Pelvic Floor Distress Inventory, and the modified Body Image Scale (BIS) were completed preoperatively and 6 weeks following surgery. Additionally, the Decision Regret Scale and the Satisfaction with Decision Scale were administered at the 6-week postoperative visit. A sample size of 88 subjects was calculated to evaluate change in the BIS score. RESULTS: In all, 87 patients were analyzed. Mean age was 79 years (SD 5.8) with a mean body mass index of 27 (SD 5.3). The majority (89.3%) was Caucasian. Six weeks after surgery, significant improvements were noted in all parameters. Mean BIS scores decreased from 4.8 to 1.2 (P < .001), signifying improved body image. Indeed, the overall number of subjects with BIS scores in the normal range doubled after surgery. Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire scores decreased significantly (P < .001 and P < .001), suggesting a positive impact on bladder, bowel, and prolapse symptoms. Finally, low levels of regret (mean score 1.35) and concurrent high satisfaction (mean score 4.73) were documented. CONCLUSION: Colpocleisis improves body image and pelvic floor symptoms while giving patients a definitive surgical option that results in low regret and high satisfaction.


Assuntos
Imagem Corporal/psicologia , Emoções , Procedimentos Cirúrgicos em Ginecologia/psicologia , Satisfação do Paciente , Prolapso de Órgão Pélvico/cirurgia , Vagina/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Prolapso de Órgão Pélvico/psicologia , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento
5.
Int Urogynecol J ; 24(4): 655-70, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22976529

RESUMO

INTRODUCTION AND HYPOTHESIS: Globally, Spanish is the primary language for 329 million people; however, most urogynecologic questionnaires are available in English. We set out to develop valid Spanish translations of the Questionnaire for Urinary Incontinence Diagnosis (QUID), the Three Incontinence Questions (3IQ), and the short Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Floor Impact Questionnaire (PFIQ-7). METHODS: The TRAPD method (translation, review, adjudication, pretesting, and documentation) was used for translation. Eight native Spanish-speaking translators developed Spanish versions collaboratively. These were pretested with cognitive interviews and revised until optimal. For validation, bilingual patients at seven clinics completed Spanish and English questionnaire versions in randomized order. Participants completed a second set of questionnaires later. The Spanish versions' internal consistency and reliability and Spanish-English agreement were measured using Cronbach's alpha, weighted kappa, and intraclass correlation coefficients. RESULTS: A total of 78 subjects were included; 94.9 % self-identified as Hispanic and 73.1 % spoke Spanish as their primary language. The proportion of per-item missing responses was similar in both languages (median 1.3 %). Internal consistency for Spanish PFDI-20 subscales was acceptable to good and for PFIQ-7 and QUID excellent. Test-retest reliability per item was moderate to near perfect for PFDI-20, substantial to near perfect for PFIQ-7 and 3IQ, and substantial for QUID. Spanish-English agreement for individual items was substantial to near perfect for all questionnaires (kappa range 0.64-0.95) and agreement for PFDI-20, PFIQ-7, and QUID subscales scores was high [intraclass correlation coefficient (ICC) range 0.92-0.99]. CONCLUSIONS: We obtained valid Spanish translations of the PFDI-20, PFIQ-7, QUID, and 3IQ. These results support their use as clinical and research assessment tools in Spanish-speaking populations.


Assuntos
Hispânico ou Latino , Distúrbios do Assoalho Pélvico/diagnóstico , Adulto , Feminino , Humanos , América Latina , Pessoa de Meia-Idade , Inquéritos e Questionários , Traduções
6.
Neurourol Urodyn ; 32(4): 336-40, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23002074

RESUMO

AIMS: We aimed to describe the current use of patient reported outcome questionnaires (PROQ) in the urogynecologic literature. METHODS: All articles from 2009 in 11 journals were reviewed and included if PROQ were used. PROQ were assigned the grades of recommendation used by the International Consultation on Incontinence (ICI). Data were collected by two independent reviewers (differences resolved by consensus). Fisher and χ(2) tests were used for statistics. RESULTS: Of the 212 articles included, 126 used multiple PROQ. Seventy-two percent used at least one grade A PROQ and 42% exclusively used grade A PROQ. Articles about urinary incontinence (UI) were more likely to use grade A PROQ than those pertaining to interstitial cystitis or anal incontinence. Eighty-three articles used PROQ in non-English languages. These articles were as likely to use ICI grade A PROQ as those using English PROQ. When translated questionnaires are used, 41.5% of articles did not provide references for a validation of the translated version. Eighty-seven different PROQ were identified and used 422 times. Of those, 75 were developed in English. Short versions were used more frequently. PROQ available online were used 9.4 times more frequently than those requiring payment. The more utilized PROQ were more often grade A than those rarely used (P < 0.001). CONCLUSIONS: Using multiple PROQ is common in the literature reviewed. 72.2% of articles used at least one PROQ with the highest ICI recommendation but only 42% used exclusively those. Short and easily available PROQ were used more often. Most PROQ are developed in English.


Assuntos
Ginecologia/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricos , Resultado do Tratamento , Urologia/estatística & dados numéricos , Intervalos de Confiança , Feminino , Humanos , Masculino , Obstetrícia/estatística & dados numéricos , Prevalência , Reprodutibilidade dos Testes , Incontinência Urinária , Doenças Urológicas/cirurgia
7.
Female Pelvic Med Reconstr Surg ; 18(1): 37-40, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22453266

RESUMO

OBJECTIVES: The objective of this study was to compare the Pelvic Organ Prolapse Quantification (POPQ) system teaching practices among obstetrics/gynecology (ob/gyn) and urology residents in the United States. METHODS: Anonymous Web-based survey was e-mailed to the residency program directors/coordinators of all urology and ob/gyn programs in the United States with a request to forward it to all their residents. Fisher exact and z tests for proportions and multivariate regression analysis examining factors associated with POPQ system use were used in the statistical analysis. RESULTS: Sixty percent (45/75) of urology and 78.9% (105/133) of responding ob/gyn residents (P = 0.006) reported having used the POPQ system, whereas 42.7% and 59.4% of them, respectively, reported current use (P = 0.03). The latter also reported more protected educational time (P < 0.001), more urogynecologists in their programs (P = 0.032), and learning more frequently from drawings (P = 0.025). Opinions about the routine clinical and scientific usefulness of POPQ system and the perceived difficulty in learning it did not vary between groups. After performing multivariate logistic regression analysis, the presence of a fellowship, the number of subspecialists in the program, and the number of POPQ system teaching sessions were the studied variables found to contribute independently to the residents' use of that system. CONCLUSIONS: Obstetrics/gynecology residents use POPQ system more frequently than do urology residents. This could be related to differences in teaching practices between urology and ob/gyn programs.


Assuntos
Ginecologia/educação , Internato e Residência , Obstetrícia/educação , Prolapso de Órgão Pélvico/patologia , Índice de Gravidade de Doença , Urologia/educação , Adulto , Coleta de Dados , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Estados Unidos
8.
Obstet Gynecol ; 119(2 Pt 2): 431-433, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22270428

RESUMO

BACKGROUND: Erosion and fistula formation are known complications of nonabsorbable materials in gynecologic surgery. The majority are diagnosed within months after surgery. CASE: A 45-year-old woman who had recurrent vaginal discharge for 4 years presented with a suprapubic abscess with a fistulous retropubic tract into the right side of the vagina 22 years after a bladder neck suspension with Dacron buttresses. The abscess was incised and drained, and the buttresses were removed (suprapubically and vaginally). The patient recovered well with antibiotics. The vagina and suprapubic skin were closed by second intention. CONCLUSION: Erosion and fistula formation can present more than two decades after using permanent material in pelvic reconstructive surgery. These complications should be included in the differential diagnosis of unexplained pelvic symptoms.


Assuntos
Abscesso Abdominal/etiologia , Complicações Pós-Operatórias/etiologia , Telas Cirúrgicas/efeitos adversos , Fístula Vaginal/etiologia , Abscesso Abdominal/diagnóstico , Abscesso Abdominal/terapia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Polietilenotereftalatos/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/terapia , Falha de Prótese/efeitos adversos , Fatores de Tempo , Incontinência Urinária por Estresse/cirurgia , Fístula Vaginal/diagnóstico , Fístula Vaginal/terapia , Adulto Jovem
9.
Obstet Gynecol ; 118(2 Pt 2): 449-451, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21768850

RESUMO

BACKGROUND: Postpartum uterine scar dehiscence is a rare but potentially lethal complication of cesarean deliveries. CASE: Concurrent abdominal and uterine dehiscences after cesarean delivery for arrest of descent with chorioamnionitis occurred in a 16-year-old patient after her first delivery. The uterine and fascia incisions were reclosed during exploratory laparotomy. Streptococcus anginosus was isolated from the peritoneal fluid. The patient remained afebrile and was discharged 6 days after relaparotomy and took levofloxacin and metronidazole orally for 5 more days. CONCLUSION: Uterine scar separation needs to be considered in patients with a fascial dehiscence after cesarean delivery for arrest of labor. Selected cases can be managed conservatively (uterine reclosure), but patients should be counseled about the possible need for hysterectomy at the time of relaparotomy.


Assuntos
Parede Abdominal/microbiologia , Complicações Pós-Operatórias/diagnóstico , Infecções Estreptocócicas/diagnóstico , Streptococcus anginosus/isolamento & purificação , Deiscência da Ferida Operatória/microbiologia , Útero/microbiologia , Parede Abdominal/cirurgia , Doença Aguda , Adolescente , Antibacterianos/uso terapêutico , Líquido Ascítico/efeitos dos fármacos , Líquido Ascítico/microbiologia , Cefazolina/uso terapêutico , Cesárea/efeitos adversos , Corioamnionite/diagnóstico , Corioamnionite/tratamento farmacológico , Corioamnionite/microbiologia , Feminino , Humanos , Levofloxacino , Metronidazol/uso terapêutico , Ofloxacino/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/microbiologia , Período Pós-Parto , Gravidez , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus anginosus/efeitos dos fármacos , Deiscência da Ferida Operatória/tratamento farmacológico , Útero/efeitos dos fármacos , Útero/cirurgia , Vasculite/diagnóstico , Vasculite/tratamento farmacológico , Vasculite/microbiologia
10.
J Low Genit Tract Dis ; 14(2): 130-3, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20354422

RESUMO

BACKGROUND: Extrapelvic infections complicating cervical conization are exceedingly rare. CASE: Seven days after conization, a 44-year-old patient presented with fever and right upper quadrant pain. Pleural effusion and pulmonary and hepatic abscesses were detected. The pathology report of the conization showed microabscesses. Blood cultures grew Fusobacterium necrophorum. Intravenous antibiotics were administered. The pulmonary findings improved but did not completely resolve after drainage of pleural effusions. The patient refused further procedures and was discharged in good clinical condition and with oral antibiotics after 37 days. CONCLUSIONS: Extrapelvic abscesses are rare complications of cervical conization. This is the first report in identifying F. necrophorum as a cause of this complication. Appropriate cultures, drainage of abscesses, and antibiotics are the mainstay of diagnosis and treatment.


Assuntos
Colo do Útero/cirurgia , Conização/efeitos adversos , Infecções por Fusobacterium/diagnóstico , Abscesso Hepático/diagnóstico , Abscesso Pulmonar/diagnóstico , Sepse/diagnóstico , Adulto , Antibacterianos/uso terapêutico , Drenagem , Feminino , Infecções por Fusobacterium/microbiologia , Fusobacterium necrophorum/isolamento & purificação , Humanos , Injeções Intravenosas , Abscesso Hepático/microbiologia , Abscesso Pulmonar/microbiologia , Derrame Pleural/cirurgia , Sepse/microbiologia
11.
Int Urogynecol J ; 21(3): 359-63, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20052574

RESUMO

INTRODUCTION AND HYPOTHESIS: A standardized system for reporting pelvic organ prolapse is important for clinical communication, patient follow-up, and meaningful comparisons between studies. In 1996, the description of the Pelvic Organ Prolapse Quantification system (POPQ) was published. We hypothesized that its use in published articles of specialized journals would increase over time. METHODS: Articles from eight journals in 2004 and 2007 were included if any attempt to grade prolapse was mentioned. Reviews, editorials, and abstracts were excluded. RESULTS: Use of POPQ increased from 64.9% to 82.1% (p = 0.01) while other systems decreased. POPQ was used more frequently in the US than other countries. Urologists used POPQ less and Baden-Walker more frequently than other specialists. CONCLUSIONS: Use of POPQ has increased in the period studied. This trend was observed in all the subgroups analyzed, showing that POPQ is being adopted as the universal language of prolapse in the published literature.


Assuntos
Ginecologia/tendências , Prolapso de Órgão Pélvico/classificação , Feminino , Humanos
12.
Contraception ; 81(1): 86-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20004279

RESUMO

Cervical stenosis can act as a barrier to the uterine cavity for surgical abortion. We present a case in which a loop electrosurgical excision procedure (LEEP) was performed during a surgical abortion to overcome a stenotic cervix. We also discuss risk factors for cervical stenosis, and other methods of treating stenosis which have been reported in the literature.


Assuntos
Aborto Induzido/métodos , Colo do Útero/cirurgia , Constrição Patológica/cirurgia , Eletrocirurgia , Feminino , Humanos , Gravidez , Adulto Jovem
13.
Mol Cancer Res ; 7(8): 1304-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19671671

RESUMO

The DNA damage response pathway controlled by the breast cancer and Fanconi anemia (FA) genes can be disrupted by genetic or epigenetic mechanisms in breast cancer. Defects in this pathway may render the affected tumors hypersensitive to DNA-damaging agents. The identification of these defects poses a challenge because of the large number of genes involved in the FA/BRCA pathway. Many pathway components form subnuclear repair protein foci upon exposure to ionizing radiation in vitro, but it was unknown whether foci can be detected in live cancer tissues. Thus, the goal of this pilot study was to identify pathway defects by using a novel ex vivo foci biomarker assay on tumor biopsies. Fresh pretreatment biopsy specimens from patients with locally advanced sporadic breast cancer were irradiated or mock-treated in the laboratory (ex vivo). Foci formation of DNA repair proteins BRCA1, FANCD2, and RAD51 was detected by immunofluorescence microscopy. Three out of seven tumors showed intact radiation-induced foci formation, whereas the other four tumors exhibited a defective foci response. Notably, three of the foci-defective tumors were estrogen receptor/progesterone receptor/HER2-negative (triple-negative), a phenotype that has been associated with BRCA1 deficiency. In conclusion, in this pilot study, we report the successful detection of BRCA1, FANCD2, and RAD51 foci in breast cancer biopsies irradiated ex vivo. Our approach represents a potentially powerful biomarker assay for the detection of pre-existing and functionally important defects within the complex FA/BRCA pathway, which may ultimately allow us to tailor cancer treatment to the DNA repair profile of individual tumors.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/patologia , Mama/patologia , Reparo do DNA , Transdução de Sinais , Proteína BRCA1/deficiência , Biópsia , Reparo do DNA/efeitos da radiação , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Feminino , Secções Congeladas , Humanos , Rad51 Recombinase/metabolismo , Radiação Ionizante , Transdução de Sinais/efeitos da radiação
14.
Cancer Res ; 68(1): 257-65, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18172318

RESUMO

Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a promising hypoxia-selective cytotoxin that has shown significant activity in advanced clinical trials in combination with radiotherapy and cisplatin. The current study aimed to advance our understanding of tirapazamine-induced lesions and the pathways involved in their repair. We show that homologous recombination plays a critical role in repair of tirapazamine-induced damage because cells defective in homologous recombination proteins XRCC2, XRCC3, Rad51D, BRCA1, or BRCA2 are particularly sensitive to tirapazamine. Consistent with the involvement of homologous recombination repair, we observed extensive sister chromatid exchanges after treatment with tirapazamine. We also show that the nonhomologous end-joining pathway, which predominantly deals with frank double-strand breaks (DSB), is not involved in the repair of tirapazamine-induced DSBs. In addition, we show that tirapazamine preferentially kills mutants both with defects in XPF/ERCC1 (but not in other nucleotide excision repair factors) and with defects in base excision repair. Tirapazamine also induces DNA-protein cross-links, which include stable DNA-topoisomerase I cleavable complexes. We further show that gamma H2AX, an indicator of DNA DSBs, is induced preferentially in cells in the S phase of the cell cycle. These observations lead us to an overall model of tirapazamine damage in which DNA single-strand breaks, base damage, and DNA-protein cross-links (including topoisomerase I and II cleavable complexes) produce stalling and collapse of replication forks, the resolution of which results in DSB intermediates, requiring homologous recombination and XPF/ERCC1 for their repair.


Assuntos
Antineoplásicos/farmacologia , Reparo do DNA/genética , DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Recombinação Genética/genética , Triazinas/farmacologia , Animais , Linhagem Celular Tumoral , Cricetinae , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Endonucleases/genética , Endonucleases/fisiologia , Histonas/metabolismo , Humanos , Mutação , Fosforilação , Tirapazamina
15.
Cancer Res ; 67(15): 7078-81, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17671173

RESUMO

The function of BRCA1 and BRCA2 in DNA repair could affect the sensitivity of cells to cytotoxic agents, and would therefore be an important component of planning therapy for breast and ovarian cancers. Previously, both BRCA1- and BRCA2-deficient tumors were shown to be sensitive to mitomycin C, and the mechanism was presumed to be a defect in the repair of interstrand crosslinks by homologous recombination. Here, we show that both BRCA1 and BRCA2 determine the sensitivity to the cytotoxic drug, etoposide, using genetic complementation of BRCA-deficient cells. Etoposide is known to bind to topoisomerase II and prevent the resolution of the "cleavable complex," in which one DNA duplex is passed through a second duplex. The specificity of this BRCA-dependent sensitivity was confirmed by the use of aclarubicin, which is a catalytic inhibitor of topoisomerase II and prevents the formation of the cleavable complex. In the presence of aclarubicin, the differential sensitivity of BRCA-proficient and BRCA-deficient cells was lost. Thus, etoposide requires the presence of topoisomerase II to show specific sensitization in the absence of the function of BRCA1 or BRCA2. We conclude that homologous recombination is used in the repair of DNA damage caused by topoisomerase II poisons. Overall, these results suggest that etoposide is a potentially useful drug in the treatment of BRCA-deficient human cancers.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Etoposídeo/farmacologia , Aclarubicina/farmacologia , Antibióticos Antineoplásicos/farmacologia , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos
16.
Nat Struct Mol Biol ; 12(10): 902-9, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16186822

RESUMO

Mediator of DNA damage checkpoint protein-1 (MDC1) is a recently identified nuclear protein that participates in DNA-damage sensing and signaling. Here we report that knockdown of MDC1 by RNA interference results in cellular hypersensitivity to the DNA cross-linking agent mitomycin C and ionizing radiation and in impaired homology-mediated repair of double-strand breaks in DNA. MDC1 forms a complex with Rad51 through a direct interaction with the forkhead-associated domain of MDC1, not the BRCA1 C-terminal domain. Depletion of MDC1 results in impaired formation of Rad51 ionizing radiation-induced foci, reduced amounts of nuclear and chromatin-bound Rad51, and a corresponding increase in Rad51 protein degradation. Together, our findings suggest that MDC1 functions in Rad51-mediated homologous recombination by retaining Rad51 in chromatin.


Assuntos
Cromatina/metabolismo , Reparo do DNA , Proteínas Nucleares/metabolismo , Rad51 Recombinase/metabolismo , Tolerância a Radiação , Recombinação Genética , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteína BRCA1/metabolismo , Ciclo Celular/genética , Proteínas de Ciclo Celular , Núcleo Celular/química , Cromatina/química , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Estabilidade Enzimática , Inativação Gênica , Humanos , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Radiação Ionizante , Transativadores/análise , Transativadores/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...