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1.
Cancer Epidemiol Biomarkers Prev ; 17(8): 2087-96, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18708401

RESUMO

BACKGROUND: Human papillomavirus (HPV) is a risk factor for head and neck cancers (HNC), yet HPV-associated tumors have better prognosis than HPV-negative tumors. METHODS: We evaluated whether pretreatment presence of antibodies to HPV capsids [virus-like particles (VLP)] or to HPV-16 oncoproteins E6 and E7 was a predictor of HPV-positive HNC and clinical outcomes. Sera from 156 HNC patients were tested for antibodies to HPV-16-derived antigens using ELISA. HPV-16 in tumors was evaluated by PCR and DNA sequencing. RESULTS: HPV-16 antibodies were found in 33% with HPV-16 VLP, 21% with HPV-16 E6, and 21% with E7. HPV-16 was detected in 26% of tumors. There was a strong correlation between detection of HPV-16 tumor DNA and antibodies to HPV-16 E6 or E7 (kappa = 0.7) but not to HPV-16 VLP (kappa = 0.4). Multivariate analyses showed significantly better disease-specific survival in seropositive HPV-16 VLP [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.1-0.9], HPV-16 E6 (HR, 0.1; 95% CI, 0.02-0.5), and HPV-16 E7 (HR, 0.3; 95% CI, 0.1-0.9) cases. Less disease recurrence occurred among those with antibodies to both E6 and E7 compared with those negative to both (P = 0.003). There was better disease-specific survival in patients who were E6 positive at baseline and remained positive at follow-up compared with individuals who were E6 negative at both time points (P = 0.03; kappa = 0.9). CONCLUSIONS: The presence of antibodies to HPV-16 E6 and E7 is associated with HPV in tumor cells and with better clinical outcomes. These findings suggest that the presence of E6/E7 antibodies before treatment is predictive of better clinical outcomes and that they may serve as biomarkers for selecting targeted therapeutic modalities developed for HPV-associated tumors.


Assuntos
Anticorpos Antivirais/sangue , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais , Proteínas E7 de Papillomavirus , Infecções por Papillomavirus/sangue , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Repressoras , Fatores de Risco , Estatísticas não Paramétricas , Análise de Sobrevida
2.
Pediatr Infect Dis J ; 26(9): 836-40, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17721381

RESUMO

OBJECTIVE: Human papillomavirus (HPV) in the oral cavity or oropharynx is associated with an increased risk of laryngeal papillomatosis, head and neck cancer, and cervical and other genital cancers. We evaluated the prevalence of HPV DNA in the oral cavity/oropharynx in a cross section of children aged 2 weeks to 20 years. METHODS: A risk factor questionnaire and oral exfoliated cells were collected from children (N = 1235). HPV DNA was detected using PCR, dot blot hybridization, and DNA sequencing. RESULTS: The HPV prevalence was 1.9% in the oral cavity/oropharynx of children. A bimodal age distribution was observed with the highest HPV prevalence in the youngest and oldest groups: 2.5% aged <1 year, 0.8% aged 1 to 4 years, 1.2% aged 5 to 11 years, 1.5% in aged 12 to 15 years, and 3.3% in aged 16 to 20 years. The prevalence of the HPV quadrivalent vaccine types (HPV-6, 11, 16, 18) reached 0.9% in the 16- to 20-year age group. In this age group, female gender [odds ratio (OR): 6.9, P = 0.04], genital warts (OR: 19.3, P < 0.01), and current smoker (OR: 6.5, P = 0.01) were associated with a higher risk of being detected with an oral HPV infection. No risk factors in parents were identified with transmission of HPV to infants. CONCLUSIONS: The age-specific prevalence rates of HPV in this large cross section of children and adolescents demonstrate that HPV infection is acquired gradually in childhood. These data support a target age for HPV vaccination before puberty to prevent serious HPV-related genital and oral diseases.


Assuntos
Alphapapillomavirus/isolamento & purificação , Boca/virologia , Infecções por Papillomavirus/epidemiologia , Faringe/virologia , Adolescente , Adulto , Alphapapillomavirus/classificação , Criança , Pré-Escolar , Feminino , Hospitais Universitários , Humanos , Lactente , Recém-Nascido , Iowa/epidemiologia , Masculino , Prevalência , Fatores de Risco , Análise de Sequência de DNA , Distribuição por Sexo , Inquéritos e Questionários
3.
Int J Cancer ; 120(4): 825-32, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17131312

RESUMO

We examined antibody response to VLP HPV-16, HPV-16 E6 and E7 antibodies as potential seromarkers of HPV-related head and neck cancer (HNC). The study included 204 HNC cases and 326 controls evaluated for HPV presence in sera using ELISAs for anti-HPV VLP antibodies and HPV-16 E6 and/or E7 antibodies, and in tumor tissue using PCR and DNA sequencing. Anti-HPV-16 VLP was detected in 33.8% of cases and 22.4% of controls, anti-E6 in 20.6% of cases and 0.9% of controls and anti-E7 in 18.6% of cases and 0.6% of controls. HPV-16 DNA was detected in 26.1% of tumors. The adjusted risk of HNC was elevated among those seropositive for HPV-16 VLP (odds ratio (OR) = 1.7, 1.1-2.5), E6 (OR = 32.8, 9.7-110.8) or E7 (OR = 37.5, 8.7-161.2). Compared to HPV DNA-negative/seronegative cases, tumor HPV-16 cases had increased risk of detection with anti-VLP antibodies (OR = 6.8, 3.1-14.9). The odds were more pronounced among cases seropositive for E6 (OR = 69.0, 19.3-247) or E7 (OR = 50.1, 14.7-171). Antibodies against E6 or E7 were associated with risk of cancer in the oral cavity (OR = 5.1, 1.2-22.4) and oropharynx (OR = 72.8, 16.0-330), and with disease characteristics: stage, grade and nodal status. Anti-E6 and/or E7 antibodies were found in 74% of tumor HPV-16 positive cases but in only 5% of tumor HPV-negative cases (K =0.7, 0.6-0.8) suggesting good correlation between the serologic marker and HPV tumor status. Antibodies to HPV-16 E6 and/or E7 represent a more specific biomarker than anti-HPV-16 VLP of an HPV-related HNC. Because of the survival advantage of HPV-related HNC, HPV-16 E6/E7 detection may be useful in therapy targeted for HPV-related tumors.


Assuntos
Anticorpos Antivirais/sangue , Proteínas de Ligação a DNA/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Proteínas Oncogênicas Virais/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/virologia , Adenocarcinoma/etiologia , Consumo de Bebidas Alcoólicas , Carcinoma Mucoepidermoide/etiologia , Estudos de Casos e Controles , DNA Viral/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/sangue , Fatores de Risco
4.
Free Radic Biol Med ; 41(2): 226-37, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16814103

RESUMO

We have studied the effects of overexpression of superoxide dismutase (SOD), a tumor suppressor protein that dismutes superoxide radical to H2O2, on breast cancer cell growth in vitro and xenograft growth in vivo. No previous work has directly compared the growth-suppressive effects of manganese SOD (MnSOD) and copper-zinc SOD (CuZnSOD). We hypothesized that either adenoviral MnSOD (AdMnSOD) or adenoviral CuZnSOD (AdCuZnSOD) gene therapy would suppress the growth of human breast cancer cells. After determining the antioxidant profiles of three human breast cell lines, MCF 10A, MDA-MB231, and MCF-7, we measured the effects of MnSOD or CuZnSOD overexpression on cell growth and survival in vitro and in vivo. Results demonstrated that infection with AdMnSOD or AdCuZnSOD increased the activity of the respective enzyme in all three cell lines. In vitro, overexpression of MnSOD or CuZnSOD decreased not only cell growth but also clonogenic survival in a dose- and transgene-dependent manner. In vivo, treatment of tumors with AdMnSOD or AdCuZnSOD decreased xenograft growth compared to controls. The first direct comparison of MnSOD to CuZnSOD overexpression indicated that CuZnSOD and MnSOD were similarly effective at suppressing cancer cell growth.


Assuntos
Neoplasias da Mama/enzimologia , Superóxido Dismutase/metabolismo , Animais , Western Blotting , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Transplante de Neoplasias , Superóxido Dismutase/genética , Transdução Genética
5.
Leuk Lymphoma ; 47(4): 657-63, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16690524

RESUMO

When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to <80% of original doxorubicin dose following grade III/IV neutropenia occurred in 29 of 187 treatments, with no episodes of febrile neutropenia. With grade III/IV neutropenia on the day of therapy, 158 treatments were administered without dose reduction or dose delay with one subsequent episode of febrile neutropenia. Neutropenia during ABVD is common, and dose modification for uncomplicated neutropenia on the day of treatment may not reduce the risk of febrile neutropenia. It may be possible to maintain dose intensity in the face of uncomplicated neutropenia during ABVD therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Febre/etiologia , Doença de Hodgkin/tratamento farmacológico , Neutropenia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Estudos de Coortes , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico
6.
Immunogenetics ; 58(1): 1-8, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16465510

RESUMO

Complement is one of primary defense mechanisms against intravascular microorganisms and could play a role in the immune response to malignancy and hence its clinical behavior. We evaluated if the sole coding polymorphism of C1qA associates with outcome in patients with breast carcinoma. Genotyping for C1qA[276A/G] was performed in 63 breast cancer subjects with localized tumor and compared with that in 38 breast cancer subjects with metastasis. Established risk factors for clinical outcome were considered and evaluated in multivariable analysis. Breast cancer subjects with heterozygous or homozygous C1qA[276G] genotype had a higher rate of metastasis than subjects with the homozygous C1qA[276A] genotype [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.1-4.1]. This association was stronger when only metastatic sites associated with hematogenous spread, i.e., to the bone, liver, and brain, were considered (HR 3.5, 95% CI 1.4-5.6) and remained statistically significant after adjustment for the number of positive lymph nodes, estrogen receptor status, and progesterone receptor status. There was no statistical difference in the C1qA[276A/G] allelic distribution between all subjects with breast cancer and controls. These results suggest there could be an association of a single nucleotide polymorphism at position 276 of the C1qA component of complement with breast cancer metastasis to sites linked to hematogenous spread of disease. The C1qA polymorphism associated with decreased distant metastasis has also been correlated with an increased incidence of subcutaneous systemic lupus and C1q deficiencies, suggesting that an altered immune response may play a role in the observed association.


Assuntos
Neoplasias da Mama/patologia , Carcinoma/patologia , Complemento C1q/genética , Metástase Neoplásica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias da Mama/sangue , Receptor alfa de Estrogênio/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/secundário , Metástase Linfática/genética , Pessoa de Meia-Idade , Receptores de Progesterona/metabolismo , Fatores de Tempo
7.
Oral Oncol ; 42(3): 288-96, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16324878

RESUMO

We investigated whether herpes simplex viruses, HSV-1 and HSV-2, are cofactors of head and neck cancer (HNC) in association with tobacco, alcohol, or HPV-16 infection. The study included 164 HNC cases and 295 controls. Serologic tests were used to distinguish HSV-1 and HSV-2. Antibodies to anti-VLP HPV-16 and HPV-16 E6 and E7 were evaluated by ELISA. After adjusting for age, tobacco, alcohol use, and number of sexual partners, risk of cancer was not significantly increased in those with HSV-1 [adjusted odds ratio (OR)=0.7] or HSV-2 (OR=0.8) compared to HSV-negative patients. Although heavy use of tobacco, alcohol and HPV-16 infection was associated with an increased risk of HNC, the adjusted risk among those infected with HSV-1 or HSV-2 lowered the odds compared to those who were not infected. Heavy smokers (OR=1.7) and heavy drinkers infected with HSV-1 (OR=4.2) or HSV-2 (smokers: OR=1.6; drinkers: OR=3.2) had lower odds compared to seronegative HSV-1 heavy users (smokers: OR=2.5; drinkers: OR=5.5) or HSV-2 (smokers: OR=1.9; drinkers: OR=6.2). Those seropositive to HPV-16 E6 and/or E7 but not HSV-1 (OR=27.4) or HSV-2 (OR=18.0) had higher risk of HNC compared to those infected with HSV-1 (OR=16.7) or HSV-2 (not estimable). These findings suggest that seropositivity to HSV-1 and HSV-2, although not independent risk factors for HNC, may modify the risk of HNC associated with exposure to tobacco, alcohol, or HPV-HR.


Assuntos
Neoplasias de Cabeça e Pescoço/virologia , Herpes Simples/complicações , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos
8.
Perspect Sex Reprod Health ; 37(3): 135-40, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16150661

RESUMO

CONTEXT: Black women are disproportionately infected with gonorrhea and chlamydia. Because of the potential impact of these infections on women's reproductive health, it is important to determine whether different factors are predictive of infection in women of different races. METHODS: Data from 31,762 women aged 15-24 who were tested for gonorrhea and chlamydia at Missouri family planning clinics in 2001 were used to calculate the prevalence of each infection by selected variables. Logistic regression analysis was used to assess factors associated with the risk of infection. RESULTS: Overall, 0.7% of women had gonorrhea, and 4% had chlamydia. The gonorrhea rate was 4% for blacks and 0.4% for whites; the chlamydia rate, 9% and 4%, respectively. Independent predictors of gonorrhea in both races were symptoms, recent sexual contact with a partner who had STD symptoms, and chlamydia infection. Predictors specific to whites were visiting the clinic for STD care and having a new partner or multiple partners in the past year. Being aged 15-21 was associated with an elevated risk of gonorrhea for blacks only. In both racial groups, chlamydia infection was associated with younger age, contact with a symptomatic partner, cervicitis, cervical friability and gonorrhea positivity. Additional predictors among whites were having a new partner, having multiple partners and having pelvic inflammatory disease; no other factors were significant for blacks. CONCLUSIONS: The prevalence and predictors of gonorrhea and chlamydia infection differ significantly between blacks and whites. Until these disparities are better understood, it will be difficult to establish screening criteria for gonorrhea.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Infecções por Chlamydia/epidemiologia , Serviços de Planejamento Familiar/estatística & dados numéricos , Gonorreia/epidemiologia , População Branca/estatística & dados numéricos , Saúde da Mulher , Adolescente , Adulto , Fatores Etários , Distribuição de Qui-Quadrado , Infecções por Chlamydia/etnologia , Infecções por Chlamydia/prevenção & controle , Feminino , Gonorreia/etnologia , Gonorreia/prevenção & controle , Educação em Saúde/normas , Humanos , Modelos Logísticos , Programas de Rastreamento/estatística & dados numéricos , Missouri/epidemiologia , Prevalência , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Inquéritos e Questionários
9.
Clin Cancer Res ; 11(10): 3733-42, 2005 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15897570

RESUMO

PURPOSE: Multiple angiogenic factors may influence tumor progression and metastasis. Several are modified by the p53 gene. We sought to identify molecular markers for high-risk stage I epithelial ovarian cancers. EXPERIMENTAL DESIGN: Seventy-seven consecutive stage I epithelial ovarian cancers were evaluated for p53, CD31 microvessel density, thrombospondin-1, vascular endothelial growth factor (VEGF), p21 immunohistochemical staining, and p53 gene mutations. Molecular marker impact upon disease-specific survival, disease recurrence, and distant recurrence was evaluated with Cox regression. RESULTS: There were 12 deaths from disease. Twelve of the 77 tumors contained p53 mutations-10 missense and 3 null (one tumor had two mutations). Fesddration Internationale des Gynaecologistes et Obstetristes substage (IA/IB versus IC; P < 0.001) and VEGF staining (P = 0.02) were significant in bivariate models with relationship to disease-specific survival. Stage (P = 0.0004), grade (P = 0.008), histology (P = 0.0025), p53 dysfunction (positive stain and/or mutation; P = 0.048), and microvessel density (P = 0.04) were significant in bivariate models with relationship to time to recurrence. In multivariate analyses among stage IC patients, failure to receive chemotherapy and microvessel density were associated with disease-specific survival, time to recurrence, and time to distant recurrence with hazard ratios of 4.8 to 44.1. CONCLUSIONS: The p53-dependent molecular markers of angiogenesis are of limited utility in developing a clinical strategy for postoperative management of stage I ovarian carcinoma. Microvessel density impacts survival and metastasis for high-risk stage IC disease. Adjuvant chemotherapy is necessary, but not sufficient, for cure of high-risk stage I epithelial ovarian cancers.


Assuntos
Genes p53 , Recidiva Local de Neoplasia/genética , Neovascularização Patológica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Quimioterapia Adjuvante , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/tratamento farmacológico , Prognóstico , Análise de Regressão , Fatores de Risco
10.
J Clin Oncol ; 23(21): 4652-61, 2005 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15837965

RESUMO

PURPOSE: To determine whether a response classification based on integration of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. RESULTS: By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. CONCLUSION: Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.


Assuntos
Fluordesoxiglucose F18 , Linfoma não Hodgkin/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto , Idoso , Intervalo Livre de Doença , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do Tratamento
11.
Cancer Epidemiol Biomarkers Prev ; 14(3): 626-32, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15767341

RESUMO

In order to examine the association between alcohol dehydrogenase 3 (ADH3) genotypes and risk of head and neck squamous cell carcinomas (HNSCC), we conducted a hospital based case-control study including 348 cases and 330 controls. DNA isolated from exfoliated cells from the oral cavity were genotyped for ADH3 polymorphisms using PCR followed by SspI digestion. Odds ratios (OR) and hazards ratios (HR) were done by unconditional logistic regression and Cox regression. Relative to ADH3(2-2) carriers, ADH3(1-1) [OR, 0.7; 95% confidence interval (CI), 0.4-1.1] and ADH3(1-2) (OR, 0.8; 95% CI, 0.5-1.2) had a nonsignificant reduced risk of HNSCC. ADH(1-2) smokers of >30 pack-years were at decreased risk of oral cavity squamous cell carcinomas compared with ADH3(2-2) (OR, 0.3, 0.1-0.9), whereas ADH3(1-1) smokers were not. After adjustment, those with ADH3(1-2) had significantly worse overall survival compared with ADH3(1-1) (HR, 0.3, 0.2-0.6) or ADH3(2-2) (HR, 0.4, 0.2-0.9) and increased recurrence (ADH3(1-1), 0.2, 0.1-0.6; ADH3(2-2), 0.6, 0.2-1.3). Our data did not show that ADH3 genotypes had a significantly independent effect on the risk of HNSCC, nor did they modify the risks increased by alcohol or tobacco consumption and high-risk human papillomavirus infection. However, participants with ADH3(1-2) genotype were associated with poorer survival compared with those who had the other two ADH3 genotypes and a higher rate of recurrence than participants with ADH3(1-1) genotype.


Assuntos
Álcool Desidrogenase/genética , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/genética , Adolescente , Adulto , Idoso , Álcool Desidrogenase/farmacologia , Carcinoma de Células Escamosas/enzimologia , Estudos de Casos e Controles , Feminino , Genótipo , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Análise de Sobrevida
12.
Environ Res ; 98(1): 104-13, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15721890

RESUMO

Although the commercial synthesis of polychlorinated biphenyls (PCBs) has been banned in the United States for several decades, they are persistent in the environment with exposure mainly being through diet. The biologic and toxic effects of PCBs and their metabolites are due in part to their ability to interact with several cellular and nuclear receptors, thereby altering signaling pathways and gene transcription. These effects include endocrine modulation and disruption. Therefore, the natural history of cancer in tissues expressing these receptors may be modulated by PCB congeners, which are known to have estrogenic, antiestrogenic, and other hormonal effects. Several frameworks for grouping PCB congeners based on these interactions have been proposed. We conducted a hospital-based, case-control pilot study of 58 prostate cancer cases and 99 controls to evaluate the association between the proposed PCB groupings and the risk of prostate cancer. Serum samples were analyzed for a total of 30 PCBs. In multivariate analyses, the odds of prostate cancer among men with the highest concentrations of moderately chlorinated PCBs or PCBs with phenobarbital-like activities (constitutively active receptor (CAR) agonists) was over two times that among men with the lowest concentrations. Increasing trends in risk across the concentration levels were also observed. These results suggest that a higher burden of PCBs that are CAR agonists may be positively associated with an increased risk of prostate cancer and they encourage further research in this area.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/intoxicação , Bifenilos Policlorados/intoxicação , Neoplasias da Próstata/induzido quimicamente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Poluentes Ambientais/sangue , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Projetos Piloto , Bifenilos Policlorados/sangue , Neoplasias da Próstata/sangue , Fatores de Risco
13.
Cancer Biol Ther ; 4(1): 95-102, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15662131

RESUMO

NAD(P)H:quinone oxidoreductase (NQO1) is elevated in human pancreatic cancers. We hypothesized that beta-lapachone, a novel 1,2-naphthoquinone with potential antitumor activity in cancer cells expressing elevated levels of NQO1, would induce cytotoxicity in pancreatic cancer cells, wherein this two-electron reductase was recently found elevated. beta-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage- independent growth in soft agar. The cytotoxic in vitro effects of beta-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In preestablished human pancreatic tumor xenografts in nude mice, beta-lapachone demonstrated greater tumor growth inhibition when given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability. Due to the poor prognosis of patients with pancreatic cancer and the limited effectiveness of surgery, chemotherapy, and radiation therapy, treatment regimens based on sound, tumor-specific rationales are desperately need for this disease.


Assuntos
Naftoquinonas/farmacologia , Neoplasias Pancreáticas/patologia , Inibidores da Transcriptase Reversa/farmacologia , Idoso , Animais , Disponibilidade Biológica , Ciclodextrinas , Humanos , Masculino , Camundongos , Camundongos Nus , Naftoquinonas/farmacocinética , Prognóstico , Inibidores da Transcriptase Reversa/farmacocinética , Transplante Heterólogo , Células Tumorais Cultivadas
14.
Clin Exp Metastasis ; 22(7): 523-32, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16475022

RESUMO

Pancreatic cancer has a dismal prognosis due to the fact that patients present late when metastatic disease is already present. Previous studies have demonstrated that pancreatic cancer cells have decreased levels of MnSOD, which correlates well with increased rates of tumor cell proliferation. Recently, we have found that nude mice injected with MIA PaCa-2 human pancreatic cancer cells in the flank occasionally develop ascites and intra-abdominal metastatic deposits. Mice that developed ascites were sacrificed and the ascites cultured. Necropsy demonstrated metastatic tumors in the retroperitoneum, which were excised, digested, and cultured. Western blots, enzyme activity and enzyme activity gels were performed for manganese superoxide dismutase (MnSOD), copper/zinc (CuZnSOD), catalase, and glutathione peroxidase (GPx) in the ascites cell line, metastatic tumor cell line, MIA PaCa-2 primary pancreatic cancer cell line, and the Capan-1, a metastatic pancreatic cancer cell line. Cell growth, plating efficiency, growth in soft agar and growth in nude mice were determined in the ascites, metastatic tumor, and MIA PaCa-2 cell lines. MnSOD, CuZnSOD, and GPx protein and activity were increased in the ascites, metastatic tumor, and Capan-1 cell lines compared to MIA PaCa-2. The ascites and metastatic tumor cell lines had decreased cell growth, plating efficiency, and growth in soft agar, but the ascites cell line had increased cell growth in 4 and 1% O(2) concentrations in vitro and more rapid growth in vivo. Metastatic disease is associated with changes in the content and activity of antioxidant enzymes with an associated change in growth characteristics depending on the O(2) concentrations.


Assuntos
Neoplasias Pancreáticas/patologia , Animais , Catalase/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Glutationa Peroxidase/metabolismo , Humanos , Cinética , Camundongos , Camundongos Nus , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/enzimologia , Superóxido Dismutase/metabolismo , Transplante Heterólogo
15.
Oncogene ; 24(1): 77-89, 2005 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-15543233

RESUMO

This study investigates the role of the antioxidant enzyme manganese superoxide dismutase (MnSOD) in androgen-independent human prostate cancer (PC-3) cells' growth rate in vitro and in vivo. MnSOD levels were found to be lower in parental PC-3 cells compared to nonmalignant, immortalized human prostate epithelial cells (P69SV40T). To unravel the role of MnSOD in the prostate cancer phenotype, PC-3 cells were stably transfected with MnSOD cDNA plasmid. The MnSOD protein and activity levels in clones overexpressing MnSOD were increased seven- to eightfold. These cell lines showed elongated cell doubling time, reduced anchorage-independent growth in soft agar compared to parental PC-3 (Wt) cells, and reduced growth rate of PC-3 tumor xenografts in athymic nude mice. Flow cytometric studies showed an increase in membrane potential in the MnSOD-overexpressing clone (Mn32) compared to Wt and Neo cells. Also, production of extracellular H(2)O(2) was increased in the MnSOD-overexpressing clones. As determined by DNA cell cycle analysis, the proportion of cells in G(1) phase was enhanced by MnSOD overexpression. Therefore, MnSOD not only regulates cell survival but also affects PC-3 cell proliferation by retarding G(1) to S transition. Our results are consistent with MnSOD being a tumor suppressor gene in human prostate cancer.


Assuntos
Neoplasias da Próstata/metabolismo , Superóxido Dismutase/genética , Androgênios/metabolismo , Animais , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo , Neoplasias da Próstata/enzimologia , Superóxido Dismutase/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas
16.
Free Radic Res ; 38(11): 1223-33, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15621700

RESUMO

Manganese superoxide dismutase (MnSOD) levels have been found to be low in human pancreatic cancer [Pancreas 26, (2003), 23] and human pancreatic cancer cell lines [Cancer Res. 63, (2003), 1297] when compared to normal human pancreas. We hypothesized that stable overexpression of pancreatic cancer cells with MnSOD cDNA would alter the malignant phenotype. MIA PaCa-2 cells were stably transfected with a pcDNA3 plasmid containing sense human MnSOD cDNA or containing no MnSOD insert by using the lipofectAMINE method. G418-resistant colonies were isolated, grown and maintained. Overexpression of MnSOD was confirmed in two selected clones with a 2-4-fold increase in MnSOD immunoreactive protein. Compared with the parental and neo control cells, the MnSOD-overexpressing clones had decreased growth rates, growth in soft agar and plating efficiency in vitro, while in vivo, the MnSOD-overexpressing clones had slower growth in nude mice. These results suggest that MnSOD may be a tumor suppressor gene in human pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Ágar , Idoso , Animais , Antioxidantes/metabolismo , Proliferação de Células , Células Cultivadas , DNA Complementar/genética , Dicumarol/farmacologia , Expressão Gênica/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Pancreáticas/genética , Superóxidos/metabolismo , Transfecção
17.
Free Radic Res ; 38(10): 1119-32, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15512801

RESUMO

It has been hypothesized that exposure of cells to hyperthermia results in an increased flux of reactive oxygen species (ROS), primarily superoxide anion radicals, and that increasing antioxidant enzyme levels will result in protection of cells from the toxicity of these ROS. In this study, the prostate cancer cell line, PC-3, and its manganese superoxide dismutase (MnSOD)-overexpressing clones were subjected to hyperthermia (43 degrees C, 1 h). Increased expression of MnSOD increased the mitochondrial membrane potential (MMP). Hyperthermic exposure of PC-3 cells resulted in increased ROS production, as determined by aconitase inactivation, lipid peroxidation, and H2O2 formation with a reduction in cell survival. In contrast, PC-3 cells overexpressing MnSOD had less ROS production, less lipid peroxidation, and greater cell survival compared to PC-3 Wt cells. Since MnSOD removes superoxide, these results suggest that superoxide free radical or its reaction products are responsible for part of the cytotoxicity associated with hyperthermia and that MnSOD can reduce cellular injury and thereby enhance heat tolerance.


Assuntos
Sobrevivência Celular , Febre , Neoplasias da Próstata/enzimologia , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Aconitato Hidratase/antagonistas & inibidores , Aconitato Hidratase/metabolismo , Ácidos Graxos Insaturados/metabolismo , Radicais Livres/metabolismo , Temperatura Alta , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos , Masculino , Potenciais da Membrana , Mitocôndrias/metabolismo , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
18.
Clin Cancer Res ; 10(13): 4550-8, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15240547

RESUMO

NAD(P)H: quinone oxidoreductase (NQO(1)) catalyzes the two-electron reduction of quinones to hydroquinones. This reaction is believed to prevent the one-electron reduction of quinones that would result in redox cycling with generation of superoxide (O(2)(.-)). We have recently demonstrated that inhibition of NQO(1) with dicumarol increases intracellular O(2)(.-) production and inhibits the in vitro malignant phenotype of pancreatic cancer cells (J. Cullen et al., Cancer Res., 63: 5513-5520, 2003). We hypothesized that inhibition of NQO(1) would increase cell killing, induce oxidative stress, and inhibit in vivo tumor growth. EXPERIMENTAL DESIGN AND RESULTS: In the human pancreatic cancer cell line MIA PaCa-2, dicumarol decreased cell viability, as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and decreased clonogenic survival. Dicumarol increased the percentage of apoptotic cells in a time-dependent and dose-dependent manner as measured by 3,3'-diaminobenzidine staining and flow cytometry, which was associated with cytochrome c release and poly(ADP-ribose) polymerase cleavage. Dicumarol also induced oxidative stress as evidenced by increased total glutathione and oxidized glutathione, as well as sensitizing to cell killing mediated by menadione. In established orthotopic pancreatic tumors in nude mice, intratumoral injections of dicumarol slowed tumor growth and extended survival. CONCLUSIONS: Inhibition of NQO(1) with dicumarol induces cell killing and oxidative stress in pancreatic cancer cells and speculate that dicumarol may prove to be useful in pancreatic cancer therapeutics.


Assuntos
Dicumarol/farmacologia , Inibidores Enzimáticos/farmacologia , Estresse Oxidativo , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Elétrons , Citometria de Fluxo , Glutationa/metabolismo , Humanos , Hidroquinonas/metabolismo , Camundongos , Camundongos Nus , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Oxigênio/metabolismo , Fenótipo , Poli(ADP-Ribose) Polimerases/metabolismo , Quinona Redutases/metabolismo , Fatores de Tempo , Desacopladores/farmacologia , Vitamina K 3/metabolismo
19.
J Natl Cancer Inst ; 96(6): 449-55, 2004 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-15026470

RESUMO

BACKGROUND: Human papillomavirus (HPV) has been associated with the development of head and neck cancers. In this study, we investigated whether the risk factors for head and neck cancer in relation to HPV infection are different from those in the absence of HPV infection and whether HPV detected in oral exfoliated cells is an independent predictor of head and neck cancer risk. METHODS: We conducted a case-control study in 201 head and neck cancer case patients and 333 control subjects, frequency matched for age and sex. Oral exfoliated cells and tumor tissue were evaluated for HPV using polymerase chain reaction and DNA sequencing to type HPV. Logistic regression was used to calculate odds ratios (ORs) for head and neck cancer with HPV infection and 95% confidence intervals (CIs), adjusted for age, tobacco use, and alcohol consumption. RESULTS: Oncogenic, or high-risk (HR), HPV types were detected in oral cells from 22.9% of case patients and 10.8% of control subjects. HPV16 was the most frequently detected type (19% versus 10% of case patients and control subjects, respectively). After adjusting for age, tobacco use, and alcohol consumption, the risk of head and neck cancer was statistically significantly greater in individuals with HPV-HR types (adjusted OR = 2.6, 95% CI = 1.5 to 4.2) but not in individuals with nononcogenic HPV types (adjusted OR = 0.8, 95% CI = 0.4 to 1.7) compared with HPV-negative individuals. Compared with individuals who were HPV-negative and did not use alcohol or tobacco, there was a statistically significant synergistic effect between detection of HPV-HR and heavy alcohol consumption (OR = 18.8, 95% CI = 5.1 to 69.5) but an additive effect between detection of HPV-HR and tobacco use (OR = 5.5, 95% CI = 2.1 to 14.1). HPV-HR types detected in oral exfoliated cells were predictive of HPV-HR types in tumor tissue. CONCLUSION: Infection of oral exfoliated cells with HPV-HR types is a risk factor for head and neck cancer, independent of alcohol and tobacco use, and acts synergistically with alcohol consumption. HPV testing of an oral rinse may be predictive of an HPV-related head and neck cancer.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/virologia , Boca/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Tabagismo/complicações , Infecções Tumorais por Vírus/complicações , Adulto , Idoso , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , DNA Viral/isolamento & purificação , Feminino , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Prevalência , Medição de Risco , Fatores de Risco , Infecções Tumorais por Vírus/virologia
20.
Hum Gene Ther ; 15(3): 239-50, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15018733

RESUMO

Pancreatic cancer has low levels of antioxidant enzymes including manganese superoxide dismutase (MnSOD), which converts superoxide radical (O(2)(*-)) into hydrogen peroxide (H(2)O(2)), and glutathione peroxidase (GPx), which converts H(2)O(2) into water. Recent studies have demonstrated that overexpression of MnSOD has a tumor-suppressive effect in pancreatic cancer. However, GPx overexpression has been shown to reverse the tumor cell growth inhibition caused by MnSOD overexpression in other types of cancer. Our aims were to determine if overexpression of GPx alters in vitro pancreatic cancer cell behavior and if delivering the GPx gene directly to tumor xenografts alters growth and survival. In vitro, AdGPx slowed tumor growth by 39% and AdMnSOD slowed tumor growth by 35%. AdGPx also decreased plating efficiency and growth in soft agar. The combination of AdGPx and AdMnSOD had the greatest effect on tumor cell growth suppression with a 71% reduction in cell growth compared to controls. In vivo, either AdGPx or AdMnSOD alone slowed tumor growth by 51% and 54%, respectively, while the combination of AdGPx and AdMnSOD potentiated tumor growth suppression by 81% of controls and increased animal survival. GPx may be a tumor suppressor gene in pancreatic cancer. Delivery of the GPx gene alone or in combination with the MnSOD gene may prove beneficial for treatment of pancreatic cancer.


Assuntos
Glutationa Peroxidase/genética , Neoplasias Pancreáticas/terapia , Adenoviridae/genética , Animais , Divisão Celular , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Vetores Genéticos/uso terapêutico , Glutationa Peroxidase/metabolismo , Humanos , Camundongos , Oxirredução , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
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