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1.
Curr Osteoporos Rep ; 16(5): 584-595, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30155844

RESUMO

PURPOSE OF REVIEW: Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ. RECENT FINDINGS: The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.


Assuntos
Remodelação Óssea/imunologia , Infecções/imunologia , Inflamação/imunologia , Doenças Maxilomandibulares/imunologia , Osteonecrose/imunologia , Inibidores da Angiogênese/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/imunologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/metabolismo , Conservadores da Densidade Óssea/efeitos adversos , Remodelação Óssea/fisiologia , Colágeno/metabolismo , Difosfonatos/efeitos adversos , Humanos , Infecções/metabolismo , Inflamação/metabolismo , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/metabolismo , Células Matadoras Naturais/imunologia , Mucosa Bucal/imunologia , Mucosa Bucal/lesões , Mucosa Bucal/metabolismo , Neutrófilos/imunologia , Osteonecrose/induzido quimicamente , Osteonecrose/metabolismo , Linfócitos T/imunologia , Cicatrização
2.
Eur J Gynaecol Oncol ; 37(3): 430-3, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27352581

RESUMO

Retroperitoneal squamous cell carcinoma (SCC) of unknown primary is very rare with variable survival rates. Standard optimal therapeutic management is not yet established.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Pélvicas/patologia , Feminino , Humanos , Pessoa de Meia-Idade
3.
Ann Oncol ; 27(7): 1257-66, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052653

RESUMO

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.


Assuntos
Carcinoma/patologia , Carcinossarcoma/patologia , Sarcoma/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Carcinoma/tratamento farmacológico , Carcinoma/epidemiologia , Carcinoma/radioterapia , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/epidemiologia , Carcinossarcoma/radioterapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Ifosfamida , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sarcoma/epidemiologia , Sarcoma/radioterapia , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/epidemiologia , Neoplasias Uterinas/radioterapia
4.
Saudi Med J ; 35(9): 1120-2, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25228186

RESUMO

We present a case of a 3½-year-old girl diagnosed as Proteus syndrome with severe cosmetic disfigurement-macrodactyly, hemi-hypertrophy of the face and limbs, megalencephaly, lymph edema of both hands and feet along with severe global developmental delay. She was found to have severe recalcitrant epilepsy and also primary hypothyroidism; the association of which is not mentioned in the previous literature.


Assuntos
Hipotireoidismo/complicações , Síndrome de Proteu/complicações , Feminino , Humanos , Hipotireoidismo/fisiopatologia , Recém-Nascido , Síndrome de Proteu/fisiopatologia
5.
Br J Cancer ; 106(12): 1967-75, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22596241

RESUMO

BACKGROUND: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. METHODS: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. RESULTS: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. CONCLUSION: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral/imunologia , Cisplatino/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Feminino , Humanos , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Transdução de Sinais , Resultado do Tratamento
6.
In Vivo ; 21(1): 35-43, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17354612

RESUMO

In recent years, the design of new antineoplastic agents that can halt the progression of human malignancies with minimal systemic damage has been at the forefront of cancer research, with cyclooxygenase-2 (COX-2) as a major target molecule. With an aim to demonstrate the expression and role of COX-2, the principal putative target of COX-2 inhibitor therapy, in endometrial adenocarcinoma (EACA) and precursor lesions, atypical complex hyperplasia (ACH) and endometrial hyperplasia (EH), an immunohistochemical (IHC) analysis of 22 primary human EACAs and 14 precursor lesions was carried out. Relevant clinicopathological data were tabulated from a random computer-generated sample of 22 primary EACA patients, treated by hysterectomy at our institution. Representative tumor sections including adjacent precursor lesions and normal endometrium (NE) were immunostained with human monoclonal anti-COX-2. Qualitative and semi-quantitative COX-2 IHC staining scores were determined based on the proportion of immunoreactive cells and the intensity of cytoplasmic COX-2 expression. Fisher's exact test and the Wilcoxon Rank Sum test were used for statistical analysis. Mean patient age was 68 years (range 51-93). All 22 EACAs were of endometrioid type, of which ten (45%) were grade I, eight (36%) grade II and four (18%) were grade III. Overall, four out of nine (44%) EHs, four out of five (80%) ACHs, and 18 out of 22 (88%) EACAs were COX-2 positive. The mean COX-2 IHC scores for EH and EACAs were 33 (SD 24.11) and 76 (SD 54.57), respectively (p = 0.022). Strong or moderate COX-2 expression was observed in 17 out of 22 (77%) adenocarcinomas as compared to two out of 14 (14%) of the precursor lesions (EH and ACH). The areas of adenomyosis were COX-2 positive, while myometrial smooth muscle and normal fallopian tube tissues stained negative for COX-2. The demonstration of frequent and strong expression of COX-2 in human EACAs supports a possible role for COX-2 inhibitors. Furthermore, an increasing expression of COX-2 from EH to invasive EACAs suggests potential usefulness of COX-2 inhibition to halt the progression of precursor lesions to invasive endometrial cancers.


Assuntos
Adenocarcinoma/enzimologia , Ciclo-Oxigenase 2/metabolismo , Hiperplasia Endometrial/enzimologia , Neoplasias do Endométrio/enzimologia , Lesões Pré-Cancerosas/enzimologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hiperplasia Endometrial/tratamento farmacológico , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia
7.
Anticancer Res ; 24(2C): 1281-6, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15154661

RESUMO

UNLABELLED: Clinical usefulness of sentinel lymph node (SLN) biopsy has been demonstrated in the management of early vulvar cancer. However, what constitutes a negative SLN has not been well defined. Furthermore, to what extent the SLNs should be sectioned for the greatest likelihood of detection of micrometastases and whether multilevel sectioning will further increase this detection rate in this setting have not been well studied. We analyzed 280 groin lymph nodes (SLNs=45, non-sentinel [NSLNs]=235) in 14 patients with invasive squamous cell carcinoma (ISCC) of the vulva treated with vulvectomy and inguinal SLN and NSLN dissection at the H. Lee Moffitt Cancer Center (HLMCC) between 1996 and 2001. Each SNL was evaluated for micrometastases by H&E and pancytokeratin AE1/3 (CKAE1/3) immunohistochemical staining. All negative SNLs (N=40) were sectioned times 3 (x3) at 50-micron intervals and independently reviewed by two pathologists in order to assess the utility of this inexpensive and logical approach to identifying additional micrometastases. Also, the Wilcoxon Rank Sum Test was used to determine if there was an association between tumor size, depth of invasion and SNL status. The patient age ranged from 35 to 81 years (mean 59 yrs); size of invasive tumor from 1.0 to 7.0 cm (mean 3.4 cm); depth of invasion from 3 to 25 mm (mean 10.8 mm). Of 45 SLNs examined from 14 patients, 11% (5/45) SNLs were positive for micrometastases on initial H&E and/or CKAE1/3 stains. Eighty-nine per cent (40/45) SNLs were negative in the remaining 9 patients. None of the latter 40 SNLs showed micrometastases on additional multilevel sectioning. Instead 3 of 135 NSLNs examined in these 9 patients revealed micrometastases on H&E (skip-micrometastases). Mean tumor size (cm) and depth of invasion (cm) were 4.06 (s.d. 1.89) and 1.20 (s.d. 0.35) for SLN (+) and 3.02 (s.d. 2.12) and 1.01 (s.d. 0.86) for SLN (-) tumor subsets (p values 0.385 and 0.348, respectively). CONCLUSION: Following routine H&E and CK AE1/3 stains, multilevel sectioning does not appear to detect additional micrometastases in sentinel lymph nodes in squamous cell carcinoma of the vulva. Even though mean tumor size and depth of invasion were greater in SNL (+) as compared to SLN (-) tumor subsets in our series, this difference did not reach statistical significance.


Assuntos
Carcinoma de Células Escamosas/patologia , Linfonodos/patologia , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Vulvares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Vulvares/cirurgia
8.
Saudi Med J ; 24(10): 1130-2, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14578985

RESUMO

Abdominal cystic lymphangioma is a very rare congenital tumor of lymphatic origin. It usually appears in the pediatric age and frequently presents with non-specific symptoms and deceptive signs causing, at times, diagnostic dilemmas. Ultrasonography and computer tomography imaging are considered the diagnostic modalities of choice. Two cases of mesenteric cystic lymphangioma, one presenting as perforated appendicitis and the other as recurrent gastritis, are reported. Infection in the first and volvulus in the second case is behind the mode of presentation. The diagnostic approach and treatment are described, with emphasis on the operative tactic applied for upper jejunal resection. A high index of suspicion, accuracy and repeated physical examination and, most important, the liberal use of ultrasonography in all cases of unclear abdominal illness may contribute considerably to a correct diagnosis and decreased morbidity.


Assuntos
Linfangioma Cístico/diagnóstico , Mesentério , Neoplasias Peritoneais/diagnóstico , Apendicite/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Gastrite/diagnóstico , Humanos , Linfangioma Cístico/cirurgia , Masculino , Neoplasias Peritoneais/cirurgia , Recidiva
9.
FEBS Lett ; 506(3): 239-42, 2001 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-11602253

RESUMO

The molecular interactions of poly(ADP-ribose) polymerase I (PARP I) and topoisomerase I (Topo I) have been determined by the analysis of physical binding of the two proteins and some of their polypeptide components and by the effect of PARP I on the enzymatic catalysis of Topo I. Direct association of Topo I and PARP I as well as the binding of two Topo I polypeptides to PARP I are demonstrated. The effect of PARP I on the 'global' Topo I reaction (scission and religation), and the activation of Topo I by the 36 kDa polypeptide of PARP I and catalytic modifications by poly(ADP-ribosyl)ation are also shown. The covalent binding of Topo I to circular DNA is activated by PARP I similar to the degree of activation of the 'global' Topo I reaction, whereas the religation of DNA is unaffected by PARP I. The geometry of PARP I-Topo I interaction compared to automodified PARP I was reconstructed from direct binding assays between glutathione S-transferase fusion polypeptides of Topo I and PARP I demonstrating highly selective binding, which was correlated with amino acid sequences and with the 'C clamp' model derived from X-ray crystallography.


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Sítios de Ligação , DNA Circular/metabolismo , Glutationa Transferase/metabolismo , Ligação Proteica
10.
Gynecol Oncol ; 82(2): 247-51, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11531274

RESUMO

OBJECTIVE: Our objective was to review our experience with carcinoma of Bartholin's gland relative to treatment and oncologic outcome. METHODS: Patient names were collected from our vulvar cancer database for the period September 1985 to September 2000. The medical records were retrospectively reviewed, and data were abstracted relative to demographics, presenting symptoms, treatment, and oncologic outcome. RESULTS: We treated 12 women with Bartholin's gland carcinoma, and 11 patients are reported. Seven women presented with a painless vulvar mass, and 8 of 11 had initially been treated for an infectious process before referral to our institution. Squamous histology was most common, and the right gland was more frequently involved. Ten patients were treated with primary surgery, followed by adjuvant radiation in 7 for inadequate resection margins or lymphatic metastases. One patient was treated with primary chemoradiation. Stage I, II, III, IVA, and IVB disease was present in 3, 1, 4, 2, and 1 patient, respectively. Recurrence was suffered by 54.5% during a mean follow-up time of 73.5 months (median, 60; range, 8-180 months). Overall survival is 58.3% to date. CONCLUSIONS: Conventional therapy for Bartholin's gland carcinoma yielded a 67% 5-year survival. Seventy-one percent of women receiving adjuvant radiotherapy recurred despite this precaution. Work is needed to identify an effective systemic therapy and to better determine which patients may benefit from pelvic radiotherapy.


Assuntos
Glândulas Vestibulares Maiores/patologia , Neoplasias Vulvares/patologia , Neoplasias Vulvares/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do Tratamento
11.
Hum Pathol ; 30(10): 1128-33, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10534157

RESUMO

The activation of the insulinlike growth factor 1/IGF-1 receptor system (IGF1/IGF1-R) has recently emerged as critical event in transformation and tumorigenicity of several murine and human tumors. Expression of IGF1 and of IGF1-R has been demonstrated in normal and neoplastic intestinal cell lines of rats and humans. However, the modulation of IGF1-R expression during the progression from normal colonic mucosa to adenoma, to carcinoma, and to metastasis, has not been evaluated. In this retrospective study, we investigated the expression of IGF1-R in 12 colonic adenomas (AD), 36 primary colorectal adenocarcinomas (CA), and in 27 corresponding metastases (MT). Normal colonic mucosa (N) was adjacent to the CA in 34 cases. Formalin-fixed, paraffin-embedded tissues of each case were immunostained using the avidin-biotin-peroxidase method. We used an anti-IGF1-R rabbit polyclonal antibody (Santa Cruz Biotechnology, CA; dilution 1:100). Positive staining was quantitated by CAS-200. Moderate to strong cytoplasmic immunostaining was observed in 34 of 36 CA (96%), and in 25 of 27 MT (93%). In all of the positive MTs, the intensity of the staining was always strong. In 10 of 12 ADs (83%), only a faint cytoplasmic stain was identified. Normal mucosa when present was negative. Strong IGF1-R positivity correlated with higher grade and higher-stage tumors (P < .01). These data suggest a role of IGF1-R expression during the progression of colorectal adenoma to carcinoma. An increased number of IGF1-R receptors may favor the metastasis of colorectal cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Receptor IGF Tipo 1/biossíntese , Adenoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Colo/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Linfonodos/metabolismo , Metástase Linfática , Masculino
12.
Cancer Control ; 6(6): 571-579, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10756388

RESUMO

BACKGROUND: Tumors arising from the renal tubular epithelium have variable characteristics and have been subject to a variety of histologic classifications. METHODS: The authors describe the distinct clinical, pathologic, phenotypic, and genotypic features of different types of renal tumors. RESULTS: The Mainz classification is now widely accepted because characteristic genetic alterations have been demonstrated in each tumor type. CONCLUSIONS: The increasing emphasis on utilizing genetic characteristics of specific tumors is reflected by the more widespread use of the Mainz classification for renal cell tumors.

13.
J Egypt Public Health Assoc ; 73(1-2): 1-10, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-17249207

RESUMO

Twenty four Campylobacter jejuni and coli isolates obtained from Egyptian children were characterized using restriction fragment length polymorphism (RFLP) of flagellin genes and polyacrylamide gel electrophoresis of whole cell and glycine-extracted proteins. The isolates were found to fall into nine polymorphism groups, eight of which were reported previously in Egypt but one group displayed by 3 isolates represented a new group that was not reported before. Furthermore, the relative prevalence of polymorphic groups in the population studied is different from that reported previously. Analysis of whole-cell and acid glycine-extracted proteins showed that the profiles of these isolates are typical profiles of Campylobacters isolated from other humans.


Assuntos
Campylobacter coli/genética , Campylobacter jejuni/genética , Genes Bacterianos , Campylobacter coli/isolamento & purificação , Campylobacter jejuni/isolamento & purificação , Criança , Egito , Eletroforese em Gel de Poliacrilamida , Flagelina/genética , Humanos , Polimorfismo de Fragmento de Restrição
14.
Int J Oncol ; 10(4): 689-95, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21533432

RESUMO

Seventeen homologs and analogs of methyl-3,5-diiodo-4(4'-methoxyphenoxy) benzoate (DIME), a hormonally inactive analog of thyroid hormones, have been synthesized and their antitumor activity scored by assaying their antitumorigenic effect in vivo following pretreatment of E-ras 20 cells with the drug. In vivo feeding of DIME in large doses had a similar antitumor effect on human tumor xenogafts in vivo without noticeable toxicity of DIME. Inhibition of clonogenicity with MDA-MB-231 cells by DIME yielded I-50 values similar to those found in tests measuring cell growth inhibition (median I-50 less than 1.0 mu M) The apparent ultimate signal for cytocidal action of DIME is the development of dose-dependent double strand cuts of DNA. All human tumor cells so far tested, with the exception of A-549 cells (lung cancer), show high sensitivity to DIME (I-50 1.0 mu M or below). The partially refractory behavior of A-549 cells to DIME is due to the presence of an esterase that cleaves the methyl ester group of DIME. Other tumor cells have negligible esterase activity, while such activity in homogenates of normal mouse tissues is high. Cells in culture take up DIME and the magnitude of uptake parallels drug sensitivity to DIME. Extrapolation from the correlations between drug efficacy, drug uptake, esterase activity and the absence of significant in vivo toxicity of DIME point to uptake of DIME by cells in culture but not by normal cells operating in intact organs in vivo. In contrast, tumor cells in vivo take up DIME and succumb to its cytocidal action just like cells in culture.

15.
Cancer Res ; 56(7): 1690-4, 1996 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-8603421

RESUMO

The early diagnosis of bladder cancer is central to the effective treatment of the disease. Presently, there are no methods available to easily and specifically identify the presence of bladder cancer cells. The prevailing method for the detection of bladder cancer is the identification of bladder cancer cells by morphological examination of exfoliated cells or biopsy material by a pathologist. A hallmark of the malignant or transformed phenotype is an abnormal nuclear shape, the presence of multiple nucleoli, and altered patterns of chromatin organization. Nuclear structural alterations are so prevalent in cancer cells that they are commonly used as markers of transformation for many types of cancer. Nuclear shape is determined by the nuclear matrix, the dynamic skeleton of the nucleus. The nuclear matrix is the structural component of the nucleus that determines nuclear morphology, organizes the DNA in a three-dimensional fashion that is tissue specific, and has a central role in the regulation of a number of nuclear processes, including the regulation of DNA replication and gene expression. Previous investigations into prostate and breast cancer have revealed that nuclear matrix protein (NMP) composition undergoes alterations with transformation and that the nuclear matrix can serve as a marker for the malignant phenotype. In this study, we have identified NMPs with which it is possible to differentiate human bladder tumors from normal bladder epithelial cells. We examined the NMP composition of 17 matched tumor and normal samples from patients undergoing surgery for bladder cancer. We have identified six proteins present in all tumor samples that are not present in the corresponding normal samples and three proteins that are unique to the normal bladder tissues in comparison with the tumor samples. Five of the six bladder cancer-associated proteins were also identified in three human bladder cancer cells lines examined (253j, UMUC-2, and T24). Therefore, we have demonstrated that nuclear matrix composition is able to differentiate bladder cancer from normal bladder tissue and may provide useful tools for early detection and recurrence of the disease. Importantly, these markers may provide valuable tools for cytopathological screening for bladder carcinoma.


Assuntos
Biomarcadores Tumorais/análise , Proteínas Nucleares/análise , Neoplasias da Bexiga Urinária/química , Antígenos Nucleares , Humanos , Peso Molecular , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/diagnóstico
16.
Int J Oncol ; 8(2): 239-52, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21544352

RESUMO

Bovine aortic endothelial cells were converted to a highly tumorigenic cell line by transfection with Ha-ras and stimulation with thrombin. Sustained pretreatment with a non-cytotoxic concentration (600 mu M) of 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a lipophilic ligand of poly(ADP-ribose) polymerase, abrogated in vivo tumorigenicity, of 10(5) cells per inoculum an effect which developed progressively during 2 to 6 weeks of drug treatment. The initial action of the drug was cytostasis, consisting of an arrest in prophase, extreme cell enlargement consistent with cytoplasmic hypertrophy, as seen by EM, and dramatic morphologic changes. Although neither DNA, RNA or protein syntheses are directly affected by INH2BP, apparently newly synthesized cellular DNA is degraded by endonucleases, which are upregulated by the inhibition of their poly-ADP-ribosylation. The drug treated cells exhibited greatly increased respiration and aerobic glycolysis, due to an augmentation of,glycolytic and respiratory enzymes in enlarged cells. These responses to the drug were reversible in cell cultures following drug removal, within 5-10 days drug exposure but the progressive loss of tumorigenicity in nude mice that developed after 3-6 weeks of drug exposure of cells, prior to inoculation to nude mice, was not reversible in vivo. Drug treatment produced a sustained 70-80% inhibition of pADPRT in intact cells at 600 mu M extracellular concentration of INH2BP. The prerequisite for the abrogation of tumorigenicity was the maintenance of pADPRT inhibition. The arrest of cell multiplication and a large decrease of Topo I, especially of Topo II and MAP kinase activities occurred without loss of enzyme protein as assayed in cell extracts of drug-treated cells. However INH2BP had no direct effect on these enzymes. Drug treatment down-regulated DNA-methyltransferase, PKC, ODC proteins, diminished cyclin A protein, but the hypophosphorylated form of Rb protein was significantly augmented. None of the enzymatic components of signal pathways so far studied, were directly affected by INH2BP. The inhibition of pADPRT by INH2BP coincided with an induction or activation of alkaline phosphatase and leucyl and glutamyl peptidase. The pADPRT content or the expression of pADPRT gene were not influenced by drug treatment, but the expression of ras gene was completely absent in nontumorigenic drug-treated cells, without a loss of ras gene from genomic DNA. Telomerase activity was not directly influenced by INH2BP treatment when assayed in diluted cell extracts, but the addition of homogeneous pADPRT to cell extracts, to approach physiological concentration of this protein in the cell, inhibited telomerase activity by binding of the polymer-free pADPRT to telomer templates. We conclude that inhibition of pADPRT indirectly down-regulates growth stimulatory signal pathways and sustains growth-arrested cells in culture at a pre-apoptotic threshold which explains the absence of tumorigenicity in vivo.

17.
Biochem Pharmacol ; 50(5): 705-14, 1995 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-7669074

RESUMO

A C-nitroso prodrug, 4-iodo-3-nitrobenzamide, was synthesized, and its action on a variety of tumor cells of human and animal origin tested. This prodrug was reduced transiently by tumor cells to 4-iodo-3-nitrosobenzamide at a very low rate, which was, however, sufficient to kill tumor cells. The final reduction product was 4-iodo-3-aminobenzamide, and no intermediates accumulated. No toxicity could be observed in hamsters even at 200 mg/kg, given i.p. daily for 7 days. The chemical reactivity of both 4-iodo-3-nitrosobenzamide and its noniodinated homolog with reduced ascorbate yielded the hydroxylamines. With glutathione, 4-iodo-3-aminobenzamide was formed, suggesting glutathione sulfinic acid formation. Confirming earlier studies, 4-iodo-3-nitrosobenzamide inactivated poly(ADP-ribose) polymerase by zinc ejection from the first zinc finger of this nuclear protein. The iodinated nitroso compound was more effective than its iodine-free analog. Selective tumoricidal action appeared to correlate with the reduction of the nitro group to nitroso in tumor cells, and with the previously described subsequent induction of tumor apoptosis by the C-nitroso intermediate. These processes were accelerated by buthionine sulfoximine, which diminishes cellular GSH.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ácido Ascórbico/química , Benzamidas/química , Cricetinae , Glutationa/química , Humanos , Mesocricetus , Oxirredução , Inibidores de Poli(ADP-Ribose) Polimerases , Células Tumorais Cultivadas , Zinco/química
18.
J Biol Chem ; 270(7): 3370-7, 1995 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-7852424

RESUMO

Cellular proteins extracted from normal and cancer cells bind polymerizing ADP-ribose transferase (pADPRT) on nitrocellulose membrane transblots. Histones at 1 mg/ml concentration completely prevent the binding of pADPRT to cellular proteins, indicating that the binding of histones to pADPRT sites competitively blocks the association of pADPRT to proteins other than histones. The direct binding of pADPRT to histones is shown by cross-linking with glutaraldehyde. The COOH-terminal basic histone H1 tail binds to the basic polypeptide domain of pADPRT. The basic domain present in the NH2-terminal part of core histones is the probable common structural feature of all core histones that accounts for their binding to pADPRT. Two polypeptide domains of pADPRT were identified, by way of CNBr fragments, to bind histones. These two domains are located within the 64-kDa fragment of pADPRT and are contiguous with the polypeptide domains that were shown to participate in self-association of pADPRT, ending at the 606th amino acid residue. The polypeptide domains of pADPRT which participate in DNA binding are thus shown to associate also with other proteins. Intact pADPRT binds to both the zinc-free or zinc-reconstituted basic polypeptide fragments of pADPRT. Histones activate auto-poly(ADP)-ribosylation of pADPRT by increasing the number of short oligomers on pADPRT. This reaction is also dependent in a biphasic manner on the concentration of pADPRT. Histones in solution are only marginally poly(ADP)-ribosylated but are good polymer acceptors when incorporated into artificial nucleosome structures.


Assuntos
Histonas/metabolismo , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Células 3T3 , Neoplasias das Glândulas Suprarrenais , Animais , Sítios de Ligação , Células CHO , Bovinos , Cricetinae , Reagentes para Ligações Cruzadas , Brometo de Cianogênio , Endopeptidases , Glutaral , Histonas/isolamento & purificação , Substâncias Macromoleculares , Camundongos , Nucleossomos/metabolismo , Células PC12 , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Fragmentos de Peptídeos/metabolismo , Feocromocitoma , Poli Adenosina Difosfato Ribose/biossíntese , Poli(ADP-Ribose) Polimerases/isolamento & purificação , Ratos , Timo/enzimologia , Zinco/metabolismo
19.
Biochimie ; 77(5): 374-7, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8527492

RESUMO

A non-covalently binding inhibitory ligand of poly(ADP-ribose) polymerase, 5-iodo-6-amino-1,2-benzopyrone, when incubated at 5-600 microM external concentration with an E-ras-transformed tumorigenic cell line or with human prostatic carcinoma cells for 40 to 60 days converts both cancer cells to a non-tumorigenic phenotype that is characterized by drastic changes in cell morphology, absence of tumorigenicity in nude mice, and a high rate of aerobic glycolysis.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Cumarínicos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Genes ras , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/patologia , Animais , Bovinos , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Glicólise , Humanos , Ligantes , Masculino , Camundongos , Camundongos Nus , Fenótipo , Neoplasias da Próstata/metabolismo , Transplante Heterólogo , Células Tumorais Cultivadas
20.
Proc Natl Acad Sci U S A ; 89(16): 7703-7, 1992 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-1502187

RESUMO

6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] at one zinc-finger site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease. This endonuclease is maintained in a latent form by poly(ADP-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.


Assuntos
Benzamidas/farmacologia , Morte Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Células-Tronco Hematopoéticas/citologia , Neutrófilos/citologia , Compostos Nitrosos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Células-Tronco/citologia , Animais , Neoplasias Encefálicas , Morte Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Replicação do DNA , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Cinética , Leucemia , Ligantes , Macaca mulatta , Neutrófilos/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células Tumorais Cultivadas
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