RESUMO
BACKGROUND/AIMS: Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-κB (NF-κB) activation is a critical event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-κB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC. METHODS: Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of IκBα, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well. RESULTS: GS inhibited DCA-induced IκBα phosphorylation. GS and the NF-κB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction. CONCLUSION: GS suppressed DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/prevenção & controle , Anticarcinógenos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/prevenção & controle , Proteínas de Homeodomínio/metabolismo , NF-kappa B/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Pregnenodionas/farmacologia , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Fator de Transcrição CDX2 , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colagogos e Coleréticos/farmacologia , Ácido Desoxicólico/farmacologia , Dinoprostona/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Esofágicas/patologia , Humanos , Proteínas I-kappa B/metabolismo , Fosforilação/efeitos dos fármacosRESUMO
BACKGROUND: Guggulsterone, a plant polyphenol guggulipid, has several antitumour effects and acts as an antagonist for the farnesoid X receptor. Although bile acids induce caudal-related homeobox 2 (CdX2), a transcription factor essential for intestinal development and gut tumourigenesis, the effects of guggulsterone on regulation of CdX2 in the gut are unknown. MATERIALS AND METHODS: Regulation of CdX2 expression by treatment with bile acids and/or guggulsterone was analysed by immunoblot analysis in human gut-derived adenocarcinoma, Bic-1 cells. Nuclear factor-kappaB (NF-kappaB) activity and the cell cycle distribution were also examined. RESULTS: Chenodeoxycholic acid and deoxycholic acid increased CdX2 expression in Bic-1 cells. Guggulsterone reduced bile acid-induced and constitutive CdX2 expression at 5 microM. Guggulsterone (up to 5 microM) did not affect cell viability or the cell cycle and did not attenuate bile acid-induced or constitutive NF-kappaB activation. CONCLUSION: Guggulsterone may be used as a novel drug to target CdX2 expression in certain gut adenocarcinomas.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Ácidos e Sais Biliares/antagonistas & inibidores , Proteínas de Homeodomínio/antagonistas & inibidores , Neoplasias Intestinais/tratamento farmacológico , Pregnenodionas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Fator de Transcrição CDX2 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Intestinais/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismoRESUMO
We previously reported that fecal cyclooxygenase 2 (COX-2) mRNA assay, detecting COX-2 mRNA in feces, is useful for identifying subjects with colorectal cancer (CRC). To further improve the sensitivity, we evaluated the usefulness of the combination of COX-2 mRNA and matrix metalloproteinase 7 (MMP-7) mRNA assays as a marker of CRC. The study cohort included 62 patients with CRC and 29 control patients without colorectal neoplasia. RNA was isolated from routinely collected fecal samples. The expression levels of COX-2 and MMP-7 mRNAs were determined by nested reverse transcription-PCR. PCR conditions were optimized where the specificity of fecal COX-2 and MMP-7 mRNA assay result in 100%. The sensitivity of each fecal assay was 87% [95% confidence interval (95% CI), 76-94%] and 65% (95% CI, 51-76%) for CRC, respectively. The sensitivity of fecal RNA test (either marker being positive) was high for CRC (90%; 95% CI, 80-96%). The sensitivity of the fecal RNA test was also high (93%; 95% CI, 80-98%) in patients with stage I or II who are often cured by surgical resection. The fecal RNA test using COX-2 and MMP-7 mRNAs improved the sensitivity to detect CRC without decreasing the specificity. These results suggest that the fecal RNA test would be a promising approach for CRC screening, although larger clinical investigations are indicated.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/diagnóstico , Ciclo-Oxigenase 2/análise , Fezes/enzimologia , Programas de Rastreamento/métodos , Metaloproteinase 7 da Matriz/análise , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/análise , Antígeno Carcinoembrionário/genética , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Ciclo-Oxigenase 2/genética , Detecção Precoce de Câncer , Fezes/química , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 7 da Matriz/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sangue Oculto , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e EspecificidadeRESUMO
BACKGROUND/AIMS: Helicobacter pylori (H. pylori) eradication increases the serum pepsinogen I/ pepsinogen II ratio and the percentage change in pepsinogen I/pepsinogen II ratios is a useful marker of H. pylori eradication. We studied whether the pepsinogen method could be an early diagnostic marker of H. pylori eradication even in patients persistently treated with a proton pump inhibitor. METHODOLOGY: Sixty-two H. pylori-positive patients underwent H. pylori-eradication therapy, followed by treatment with a proton pump inhibitor to cure ulcers. Serum levels of pepsinogen I and pepsinogen II were measured before, at the end of, and at 4 weeks after the eradication therapy. The cut-off values of percentage changes in pepsinogen I/pepsinogen II ratios for the diagnosis of eradication of H. pylori were set in proportion to pepsinogen I/pepsinogen II ratios before eradication in accordance with a previous report. RESULTS: Using the results of 13C-urea breath test as the standard, the sensitivity, specificity and validity of the pepsinogen method were 100.0%, 89.8% and 90.3%, respectively, at 4 weeks after eradication therapy. CONCLUSION: The percentage change in serum pepsinogen I/pepsinogen II ratios is useful as an early diagnostic marker for judgment of H. pylori eradication irrespective of proton pump inhibitor treatment.
Assuntos
Infecções por Helicobacter/sangue , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Pepsinogênios/sangue , Diagnóstico Precoce , Feminino , Infecções por Helicobacter/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
BACKGROUND: Anti-inflammatory cytokines play an important role in downregulation of inflammation and the prevention of neoplastic disorders. Genetic variations of anti-inflammatory cytokines are assumed to influence such responses. The aim of the present study was to clarify the association between the IL-10 polymorphism, one of the representative anti-inflammatory cytokines, and susceptibility to gastric cancer and peptic ulcer in Japan. METHODS: The IL-10-1082 (A/G)/-819 (T/C)/-592 (A/C) polymorphisms were assessed in Helicobacter pylori-positive patients with gastritis only (n = 162), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and H. pylori-negative controls (n = 168) by allele specific primer-polymerase chain reaction methods. RESULTS: The carriage of IL-10-592 C (age and sex-adjusted odds ratio [OR]: 1.851, 95% confidence interval [CI]: 1.018-3.380) and IL-10-819 C (adjusted OR: 1.868, 95%CI: 1.023-3.411) allele were associated with an increased risk for gastric cancer development, not gastric ulcer and duodenal ulcer. The IL-10-1082 polymorphism had no association with development of gastric cancer and peptic ulcers. The presence of the ATA/GCC haplotype of IL-10-1082/-819/-592 polymorphism significantly increased the risk of gastric cancer development (adjusted OR: 2.805, 95%CI: 1.258-6.254) compared with presence of the ATA/ATA haplotype. CONCLUSIONS: The IL-10-1082/-819/-592 genotype status and haplotype were associated with an increased risk for gastric cancer development, not peptic ulcer, in Japan. The genotyping test of this anti-inflammatory cytokine would be useful for the detection of individuals with higher risk of gastric cancer development.
Assuntos
Interleucina-10/genética , Úlcera Péptica/epidemiologia , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/epidemiologia , Citocinas/genética , Primers do DNA , Feminino , Gastrite/genética , Genótipo , Infecções por Helicobacter/genética , Helicobacter pylori , Humanos , Japão , Masculino , Razão de Chances , Úlcera Péptica/genética , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND AND AIMS: Susceptibility to clarithromycin of Helicobacter pylori (H. pylori) is caused by single nucleotide polymorphisms (SNPs) of the 23SrRNA gene. Allele specific primer-polymerase chain reaction (ASP-PCR) is one of the methods for determining SNPs, which can measure SNPs easily within a short period by PCR amplification alone without digestion with restriction enzymes. The aim of the present study was to develop the ASP-PCR assay for determining SNPs at positions 2,142 and 2,143 of the 23S rRNA gene of H. pylori. METHODS: In total, 112 patients with H. pylori infection based on positive results of a rapid urease test (RUT) were enrolled in the study. Thirty-five had failed to eradicate H. pylori by a clarithromycin-based regimen. DNA was extracted from the RUT-positive gastric tissue samples. SNPs from adenine to guanine at positions 2,142 and 2,143 of the 23S rRNA of H. pylori (A2,142G and A2,143G) were determined by the ASP-PCR method. Minimum inhibitory concentrations (MICs) of clarithromycin for H. pylori were also measured. RESULTS: Forty-nine of 112 patients were infected with wild-type strains of H. pylori. Thirty-nine patients were infected with strains with A2,143G mutations. Twenty-three patients were infected with both wild-type strains and those with A2,143G mutations. Only one patient was infected with the strain with A2,142G mutation. H. pylori strains with A2,143G or A2,142G mutation had significantly higher MICs for clarithromycin. CONCLUSION: The ASP-PCR assay for 23S rRNA mutation of H. pylori is a useful method to detect clarithromycin-resistant strains of H. pylori easily.
Assuntos
Helicobacter pylori/genética , Mutação , Reação em Cadeia da Polimerase , RNA Ribossômico 23S/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Úlcera Duodenal/microbiologia , Feminino , Gastrite/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Gástrica/microbiologiaAssuntos
Adenocarcinoma/complicações , Linfonodos/patologia , Neoplasias Gástricas/complicações , Síndrome da Veia Cava Superior/etiologia , Adenocarcinoma/secundário , Idoso , Biópsia , Diagnóstico Diferencial , Endoscopia Gastrointestinal , Evolução Fatal , Feminino , Seguimentos , Humanos , Metástase Linfática , Pescoço , Neoplasias Gástricas/patologia , Síndrome da Veia Cava Superior/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUNDS AND AIMS: Development of safe and effective rescue regimens for eradication failure of Helicobacter pylori infection by standard regimens is an urgent task. We designed the prospective study to compare the efficacy of two rescue regimens after eradication failure by the standard triple therapy. METHODS: One hundred and thirty-two patients in whom eradication of H. pylori infection failed initial triple therapy with lansoprazole 30 mg b.i.d, amoxicillin 750 mg b.i.d. and clarithromycin 400 mg b.i.d. for 1 week were randomized to either the 1-week triple therapy with rabeprazole 10 mg b.i.d., amoxicillin 750 mg b.i.d., and metronidazole 250 mg b.i.d. (RAM) or the 2-week dual therapy with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. (RA). Eradication of H. pylori was judged by (13)C-urea breath test 1 month later. RESULTS: The intention-to-treat and per-protocol-based eradication rates were 92.4% (95% CI: 83.2-97.5) and 95.3% (95% CI: 86.9-99.0) for the RAM therapy and 90.9% (95% CI: 81.2-96.6) and 93.8% (95% CI: 84.8-98.3), respectively, for the RA therapy (P > 0.2 for both). No clinically recognizable adverse events were observed with either regimen. CONCLUSION: RA as well as RAM therapy are safe and effective rescue regimens for H. pylori infection after eradication failure by the standard triple therapy.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Antiulcerosos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Metronidazol/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Antiulcerosos/administração & dosagem , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Helicobacter pylori , Humanos , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , RabeprazolRESUMO
BACKGROUND AND AIM: In Western countries, polymorphism of pro-inflammatory cytokine genes is associated with the development of gastric cancer and duodenal ulcer. The aim of this study was to clarify the association of polymorphisms of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha with susceptibility to peptic ulcer diseases and gastric cancer in Japan. METHODS: The IL-1beta-511/-31 and TNF-alpha-308/-857/-863/-1031 genotypes were determined in Helicobacter pylori-positive patients with gastritis only (n = 164), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and in H. pylori-negative controls (n = 172). RESULTS: Carriage of the alleles TNF-alpha-857 T (odd ratio [OR], 1.826; 95% confidence interval [CI], 1.097-3.039), TNF-alpha-863 A (OR, 1.788; 95% CI, 1.079-2.905) and TNF-alpha-1031 C (OR, 1.912; 95% CI, 1.152-3.171) was associated with increased risk for gastric ulcer development. Carriage of the alleles TNF-alpha-857 T (OR, 1.686; 95% CI, 1.003-2.832), TNF-alpha-863 A (OR, 1.863; 95% CI, 1.118-3.107) and TNF-alpha-1031 C (OR 2.074; 95% CI, 1.244-3.457) was also associated with increased risk of gastric cancer development. There was no relationship between the development of H. pylori-related diseases and polymorphisms of IL-1beta-511/-31 and TNF-alpha-308. The simultaneous carriage of three different high-producer alleles of TNF-alpha-857/-863/-1031 significantly increased the risk of gastric ulcer (OR, 6.57; 95% CI, 2.34-18.40) and gastric cancer (OR, 5.20; 95% CI, 1.83-14.78). CONCLUSIONS: Polymorphisms in TNF-alpha rather than IL-1beta are associated with increased risk for gastric ulcers and gastric cancer in Japan. The simultaneous carriage of more than one high-producer allele of TNF-alpha further increased the risks for gastric ulcer and cancer.
Assuntos
Interleucina-1beta/genética , Úlcera Péptica/genética , Polimorfismo Genético , Neoplasias Gástricas/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Feminino , Predisposição Genética para Doença , Helicobacter pylori/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Gastrointestinal motility is impaired in patients with diabetes mellitus (DM). Interstitial cells of Cajal (ICC) in the gastrointestinal tract play a central role in gastrointestinal motility. The present study examined whether ICC density, or expression of neuronal nitric oxide synthase (nNOS)- and substance P (SP)-containing nerves in the gastric antrum, were altered in patients with type 2 DM. METHODS: Paraffin-embedded gastric specimens from 51 controls and 36 male DM patients with gastric cancer were used for immunohistochemistry. Serial sections were stained with Kit and mast cell tryptase-specific antibodies. Fresh-frozen gastric specimens from patients with gastric cancer were used for immunofluorescence. The specimens were stained with antibodies to Kit, nNOS, and SP, and levels of expression of these three markers were compared between controls and DM patients. RESULTS: ICC density in the inner circular muscle layer, but not in the myenteric plexus, was lower in patients with severe DM than in controls in paraffin-embedded specimens. In addition, decreased expression of nNOS and SP accompanied by reduced ICC density was observed in frozen specimens from patients with DM. CONCLUSIONS: These results suggest that lower gastric ICC, nNOS, and SP densities in patients with DM may be associated with the pathogenesis of diabetic gastroparesis.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Mucosa Gástrica/inervação , Plexo Mientérico/patologia , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/biossíntese , Substância P/biossíntese , Biomarcadores , Contagem de Células , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Esvaziamento Gástrico/fisiologia , Mucosa Gástrica/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Plexo Mientérico/metabolismo , Neurônios/patologia , Estudos RetrospectivosRESUMO
BACKGROUNDS AND AIMS: Most low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas respond to eradication of H. pylori, however, some are refractory. The effectiveness of radiotherapy for MALT lymphoma refractory to H. pylori eradication has been demonstrated. However, the long-term outcome and associated late radiation morbidity of radiotherapy for gastric MALT lymphoma are unclear. We evaluated the efficacy of radiotherapy and the radiation-associated adverse effects for gastric MALT lymphoma refractory to H. pylori eradication therapy. METHODS: Eighteen patients with H. pylori-positive gastric MALT lymphoma received H. pylori eradication therapy, of which three patients refractory to eradication of H. pylori were subsequently treated with irradiation (median 39 Gy, range 36-40 Gy). Efficacy of radiotherapy and associated radiation morbidity were evaluated. Adverse events were evaluated according to RTOG and NCI-CTC criteria. RESULTS: Radiation was well tolerated. All three patients treated with radiotherapy achieved complete remission, which was sustained for a median follow-up period of 42.0 months (range, 24-72 months). As acute radiation side effects, all patients experienced mild nausea (Grade 1 by RTOG and 1 point [1 category] in NCI-CTC). One patient had Grade 1 appetite loss. There were no severe late adverse events. One patient had left kidney atrophy of approximately 10%, but none had renal dysfunction. CONCLUSIONS: Radiotherapy for patients with gastric MALT lymphoma refractory to H pylori eradication was effective without any critical acute or late adverse events.
Assuntos
Linfoma de Zona Marginal Tipo Células B/radioterapia , Neoplasias Gástricas/radioterapia , Idoso , Mucosa Gástrica/efeitos da radiação , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/microbiologia , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/microbiologia , Resultado do TratamentoRESUMO
Tight junctions are commonly disrupted in cancer cells, including gastric cancer. Various growth factors have been reported to affect the localization of tight junction-associated proteins such as ZO-1 and occludin. We investigated the effect of epidermal growth factor (EGF), a growth factor that is often overexpressed in gastric cancer, and fetal bovine serum (FBS) on the localization of ZO-1 and occludin in a gastric cancer cell line. In the poorly differentiated gastric cancer cell line TMK-1, immunohistochemistry demonstrated that ZO-1 and occludin were predominantly localized to the cytoplasm, although there was some weak expression at the cell-cell contact. When the medium was replaced with fresh medium containing 10% FBS, ZO-1 and occludin were rapidly translocated from the cytosol to the cell-cell contact. A similar effect was seen in EGF exposure. These effects induced by FBS or EGF were attenuated in the presence of protein kinase C (PKC) inhibitors calphostin C and bisindolylmaleimide I, but not another PKC inhibitor Gö6976, PD98059 (MAPK inhibitor), LY294002 (PI3 kinase inhibitor) or KT5720 (protein kinase A inhibitor). These results suggest that serum-derived factors, including EGF, can rapidly alter the localization of ZO-1 and occludin via a protein kinase C signaling pathway in TMK-1 gastric cancer cells.
Assuntos
Fator de Crescimento Epidérmico/fisiologia , Proteínas de Membrana/metabolismo , Proteína Quinase C/metabolismo , Neoplasias Gástricas/enzimologia , Junções Íntimas/metabolismo , Animais , Bovinos , Comunicação Celular/fisiologia , Linhagem Celular Tumoral , Meios de Cultura , Citoplasma/enzimologia , Citoplasma/metabolismo , Humanos , Imuno-Histoquímica , Ocludina , Fosfoproteínas/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína da Zônula de Oclusão-1RESUMO
Long-term administration of a histamine H2 receptor (H2R) antagonist (inverse agonist) induces upregulation of H2R in parietal cells, which may be relevant to the rebound hypersecretion of gastric acid that occurs after withdrawal of treatment. The mechanisms underlying this effect are unknown. We hypothesized that the H2R upregulation could be related to receptor trafficking and used H2R-green fluorescent protein (H2R-GFP) to test the hypothesis. Human H2R-GFP was generated and functionally expressed in HEK-293 cells. Binding of the H2R antagonist [3H]tiotidine was performed to quantify H2R expression, and H2R-GFP was imaged in living cells by confocal and evanescent wave microscopy. The binding affinity of [3H]tiotidine was not significantly different between H2R-GFP- and wild-type H2R-expressing HEK-293 cells, both of which had constitutive activity of adenylate cyclase. Visualization of H2R-GFP revealed that the agonist-induced H2R internalization and the antagonist-induced recycling of the internalized H2R from the recycling endosome within 2 h. Long exposure to the antagonist increased GFP fluorescence in the plasma membrane and also induced upregulation of H2R-GFP estimated by the binding assay, whereas long exposure to the agonist enhanced degradative trafficking of H2R-GFP. We examined whether the upregulation reflected an increase in receptor synthesis. Treatment with antagonist did not augment H2R mRNA, and subsequent inhibition of protein synthesis by cycloheximide had no effect on H2R upregulation. These findings suggested that upon exposure to an antagonist (inverse agonist), the equilibrium between receptor endocytosis and recycling is altered before H2R upregulation, probably via suppressing H2R degradation.
Assuntos
Antagonistas dos Receptores H2 da Histamina/farmacologia , Receptores Histamínicos H2/metabolismo , Regulação para Cima/efeitos dos fármacos , Linhagem Celular , Cimetidina/farmacologia , Famotidina/farmacologia , Humanos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ranitidina/farmacologia , Receptores Histamínicos H2/biossíntese , Receptores Histamínicos H2/genéticaRESUMO
BACKGROUND AND OBJECTIVE: A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition. METHODS: Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8. RESULTS: For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206). CONCLUSIONS: The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.
Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Famotidina/farmacologia , Ácido Gástrico/metabolismo , Antagonistas dos Receptores H2 da Histamina/farmacologia , Omeprazol/análogos & derivados , Omeprazol/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis , Adenosina Trifosfatases/antagonistas & inibidores , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Benzimidazóis/administração & dosagem , Ritmo Circadiano , Citocromo P-450 CYP2C19 , Sinergismo Farmacológico , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Famotidina/administração & dosagem , Feminino , Genótipo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Oxigenases de Função Mista/genética , Omeprazol/administração & dosagem , Polimorfismo Genético , ATPases Translocadoras de Prótons/antagonistas & inibidores , RabeprazolRESUMO
Photodynamic therapy (PDT) is a useful strategy for treating various cancers. Details of the mechanisms of PDT have not been made clear yet. We intended to study the efficacy of PDT in relation to the cell cycle. HeLa S3 cells were synchronized by the thymidine block method. Cells in different cell cycle phases after release were treated with the water-soluble photosensitizer, ATX-S10(Na). The cellular viability after PDT was determined by the MTT assay. Intracellular levels of ATX-S10(Na) in different cell cycle phases were also determined. We found that cells in the S and G(2)/M phases were hypersensitive to PDT with ATX-S10(Na) in comparison with those in the G(1) phase, and that cellular levels of ATX-S10(Na) were increased in cells in the S and G(2)/M phases compared to those in the G(1) phase. We conclude that cellular ATX-S10(Na) levels differ among the different cell cycle phases, which is associated with the cell-cycle-dependent efficacy of PDT with ATX-S10(Na).
Assuntos
Ciclo Celular/efeitos dos fármacos , Células HeLa/efeitos dos fármacos , Fotoquimioterapia/métodos , Porfirinas/farmacologia , Análise de Variância , Feminino , Células HeLa/citologia , Humanos , Técnicas In Vitro , Probabilidade , Sensibilidade e Especificidade , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
OBJECTIVE: For the treatment of gastroesophageal reflux disease, intragastric pH should be lower than 4.0 for no more than 4 hours a day (<16.7%). We aimed to develop optimal dosage regimens for rabeprazole to control nocturnal acidity in relation to cytochrome P450 (CYP) 2C19 genotypes. METHODS: Fifteen Helicobacter pylori -negative volunteers, comprising 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took placebo and rabeprazole, at a dose of 20 or 40 mg once daily (at 10 pm ) for 8 days. Plasma rabeprazole concentrations and 24-hour intragastric pH were determined on days 7 and 8, respectively. Because the nocturnal intragastric pH was lower than 4.0 for more than 16.7% of the time with once-daily regimens in homozygous EMs and heterozygous EMs, they were administered 20 mg rabeprazole twice daily (8 am and 10 pm ) or 10 mg rabeprazole 4 times daily (8 am , 12:30 pm , 6 pm , and 10 pm ). RESULTS: With 40 mg rabeprazole once daily, the median percent time with nocturnal pH lower than 4.0 was less than 16.7% in PMs (9.5% [range, 3.0%-31.1%]) but not in homozygous EMs (45.3% [range, 29.0%-52.2%]) ( P = .043) and heterozygous EMs (41.3% [range, 33.0%-59.0%]) ( P = .043). The mean plasma rabeprazole concentrations differed among the different CYP2C19 genotype groups. With 20 mg rabeprazole twice daily and 10 mg rabeprazole 4 times daily, the median percent times with nocturnal pH lower than 4.0 were 5.0% (range, 0.0%-42.0%) and 1.0% (range, 5.0%-7.1%) in heterozygous EMs and 62.0% (range, 10.8%-68.3%) and 14.7% (range, 0.0%-41.7%) in homozygous EMs, respectively, and plasma concentrations were sustained longer than with the once-daily regimens. CONCLUSIONS: We propose that rabeprazole dosage regimens for sufficient acid inhibition are 20 mg once daily for PMs, 20 mg twice daily for heterozygous EMs, and 10 mg 4 times daily for homozygous EMs or heterozygous EMs.
Assuntos
Antiulcerosos/farmacologia , Hidrocarboneto de Aril Hidroxilases/genética , Benzimidazóis/farmacologia , Ácido Gástrico/metabolismo , Oxigenases de Função Mista/genética , Polimorfismo Genético/fisiologia , Estômago/efeitos dos fármacos , 2-Piridinilmetilsulfinilbenzimidazóis , Administração Oral , Antiulcerosos/administração & dosagem , Antiulcerosos/farmacocinética , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Citocromo P-450 CYP2C19 , Esquema de Medicação , Feminino , Mucosa Gástrica/metabolismo , Genótipo , Humanos , Masculino , Omeprazol/análogos & derivados , ATPases Translocadoras de Prótons/antagonistas & inibidores , RabeprazolRESUMO
BACKGROUND & AIMS: Cyclooxygenase 2 (COX-2) is overexpressed frequently in aerodigestive tumors, especially in colorectal tumors. Therefore, it may be a suitable biomarker for colorectal cancer (CRC) screening. We performed a pilot study of whether detecting COX-2 expression in fecal RNA enables us to discriminate between patients with and without CRC. METHODS: The study cohort included 29 patients with CRC, and 22 control patients without neoplastic disease of the colon or rectum. RNA was isolated from routinely collected stool samples using a modified method. The expression levels of carcinoembryonic antigen (CEA) and COX-2 were determined by nested reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: The sensitivity and the specificity of fecal COX-2 assay for CRC were 90% (95% confidence interval [CI], 73%-98%) and 100% (95% CI, 85%-100%), respectively, whereas those of the fecal CEA assay for CRC were 100% (95% CI, 88%-100%) and 5% (95% CI, 2%-23%), respectively. COX-2 messenger RNA (mRNA) was detected in 3 of 4 patients with Dukes' stage A, 13 of 14 patients with Dukes' stage B, and 10 of 11 patients with Dukes' stage C or D. COX-2 mRNA was detected in 5 of 7 patients with proximal cancer and in 21 of 22 patients with distal cancer. The COX-2 assay was superior to the CEA assay for detecting CRC in terms of specificity, although both assays had high sensitivity. CONCLUSIONS: This fecal COX-2 assay had high sensitivity and high specificity for detecting CRC. These results suggest that it would be a promising approach for detecting CRC, although a larger study is necessary to assess the sensitivity and the specificity.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Fezes , Isoenzimas/genética , Programas de Rastreamento/métodos , Prostaglandina-Endoperóxido Sintases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclo-Oxigenase 2 , Feminino , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e EspecificidadeRESUMO
Congenital absence of the portal vein (CAPV) is a rare malformation that is often accompanied by other anomalies such as cardiac and skeletal malformations and/or hepatic tumors. We describe here a case of CAPV complicating hepatic tumors in a 16-year-old Japanese girl. Abdominal ultrasonography revealed a hyperechoic tumor in the liver and dilatation of the portal vein that appeared to be connected directly with the inferior vena cava. Subsequent abdominal computed tomography (CT) revealed tumors and magnetic resonance angiography confirmed that the portal vein entered directly into the inferior vena cava just above the liver. In addition, there was absence of the right portal vein and the left intrahepatic branch except for the presence of left portal vein only within the porta hepatis. These findings led to a diagnosis of CAPV complicated hepatic tumors. Careful monitoring of these hepatic tumors is ongoing due to the possibility of malignant transformation.
Assuntos
Neoplasias Hepáticas/complicações , Veia Porta/anormalidades , Adolescente , Feminino , Humanos , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Angiografia por Ressonância Magnética , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler em CoresRESUMO
Evidence suggests that the erythropoietin-producing hepatocellular (EPH) receptor tyrosine kinases (RTKs) and their ephrin (EFN) ligands are involved in human carcinogenesis. Expression of two of them, EFNA1 ligand and its receptor, EPHA2, has been proposed to contribute to tumor-induced neovascularization. Colorectal cancers were examined for expressions of EPHA2 and its ligand EFNA1 by semi-quantitative RT-PCR, and double-immunostained for EPHA2 and CD34. Microvessels in the tumors were counted. Double-staining was also performed in 25 cases of adenoma with focal cancer for comparison. Trends of overexpression of both EPHA2 and EFNA1 was found in tumor tissue compared to the corresponding normal tissue in the same specimen [22/37 (59.5%) and 25/37 (67.5%), respectively; P = 0.100 for EPHA2 and P = 0.009 for EFNA1]. Overexpression of EPHA2 and EFNA1 was noted more frequently in the early stage than in the late stage [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P = 0.007; EFNA1, 15/21 (71.4%) vs. 10/16 (62.5%), P = 0.007]. Both EPHA2 and EFNA1 were more frequently overexpressed in smaller tumors (less than 5 cm) than in larger tumors [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P = 0.017; EFNA1, 16/21 (76.2%) vs. 8/16 (50%), P = 0.001]. Tumors less than 5 cm in diameter and in stages I and II were significantly more likely to overexpress EPHA2 and EFNA1 (P = 0.001 for EPHA2, P = 0.001 for EFNA1). Microvessel counts (MVCs) after immunostaining for CD34 were significantly correlated (r = 0.343, P = 0.037) with overexpression of EPHA2. EPHA2-expressing focal cancer also surrounded microvessels in adenomas with focal cancers. These findings suggest an involvement of EPHA2 in colon carcinogenesis, mainly in stages I and II, and probably through their effect on microvessel induction.