RESUMEN
This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is â¼ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan.
Asunto(s)
Alelos , Genes APC , Predisposición Genética a la Enfermedad , Neoplasias/epidemiología , Neoplasias/genética , Adulto , Anciano , Femenino , Genotipo , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Oportunidad Relativa , Polimorfismo Genético , Prevalencia , Pronóstico , RiesgoRESUMEN
PURPOSE: Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. METHODS: Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. RESULTS: Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10). CONCLUSION: We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].
Asunto(s)
Detección Precoz del Cáncer , Neoplasias de los Genitales Femeninos , Masculino , Humanos , Femenino , Estados Unidos , Adulto , Persona de Mediana Edad , Adulto Joven , Anciano , Anciano de 80 o más Años , Mama , Pulmón , Sistema de Registros , Tamizaje MasivoRESUMEN
BACKGROUND: Cancer is a leading cause of mortality worldwide. The most effective way to combat cancer is by prevention and early detection. OBJECTIVES: To evaluate the outcome of screening an asymptomatic population for the presence of benign and neoplastic lesions. METHODS: Routine screening tests for prevention and/or early detection of 11 common cancers were conducted in 300 consecutive asymptomatic apparently healthy adults aged 25-77 years. Other tests were performed as indicated. RESULTS: Malignant and benign lesions were found in 3.3% and 5% of the screenees, respectively, compared to 1.7% in the general population. The most common lesions were in the gastrointestinal tract followed by skin, urogenital tract and breast. Advanced age and a family history of a malignancy were associated with increased risk for cancer with an odds ratio of 9 and 3.5, respectively (95% confidence interval 1.1-71 and 0.9-13, respectively). Moreover, high serum C-reactive protein levels and polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a malignant lesion was extremely high (23.1%; OR 14, 95% CI 2.5-78). CONCLUSIONS: Screening asymptomatic subjects identifies a significant number of neoplastic lesions at an early stage. Incorporating data on genetic polymorphisms in the APC and CD24 genes can further identify individuals who are at increased risk for cancer. Cancer can be prevented and/or diagnosed at an early stage using the screening facilities of a multidisciplinary outpatient clinic.
Asunto(s)
Prestación Integrada de Atención de Salud/organización & administración , Detección Precoz del Cáncer , Tamizaje Masivo/organización & administración , Neoplasias/diagnóstico , Neoplasias/epidemiología , Adulto , Factores de Edad , Anciano , Femenino , Pruebas Genéticas , Humanos , Israel , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Proyectos Piloto , Estudios Prospectivos , Factores de RiesgoRESUMEN
PURPOSE: Cyclooxygenase-2 inhibitor (celecoxib, Pfizer) is a promising chemopreventive agent, yet its long-term use may be limited due to increased cardiovascular toxicity. This study was aimed to identify genes and pathways involved in colorectal tumorigenesis and affected by celecoxib. EXPERIMENTAL DESIGN: Normal rat enterocytes (IEC18 cells) and their Ras-transformed derivatives (R1) were exposed for 72 h or over 6 months to celecoxib and analyzed for gene expression pattern using Genechip (RG-U34). Cluster and pathway analyses were done using GeneSpring software and Gene Ontology database. Cyclin D1 was overexpressed in IEC18 cells using stable transfection; cell cycle and prostaglandin synthesis were assessed. RESULTS: Five hundred thirty-eight genes were differentially expressed after transformation, and 70 and 126 genes, respectively, were affected by short and long treatments with celecoxib. Clusters of expression showed different expression in the transformed cells that revert to normal after treatment; they included Ras/Erk/Ral-B, Jagged2/Notch, calcineurin, lysyl-oxidase, etc. Cyclin D1 is up-regulated under the Ras pathway and is down-regulated by celecoxib. Thus, we showed that cyclin D1-transformed cells are resistant to inhibition by celecoxib. Celecoxib was also shown to work via cyclooxygenase-2 inhibition in transformed cells. CONCLUSIONS: Celecoxib selectively affects transformed and not normal enterocytes by targeting genes and pathways that are involved in the transformation. Thus, an alternative mechanism is proposed for the cancer-preventive role of celecoxib other than the classic mechanism of inhibiting prostaglandin synthesis, stressing mainly the role of cyclin D1. These data may help in the development of safer and more effective preventive drugs.
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Anticarcinógenos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Enterocitos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Celecoxib , Línea Celular Transformada , Quimioprevención , Perfilación de la Expresión Génica , Genes ras , Humanos , RatasRESUMEN
Bak is a pro-apoptotic gene, which plays an important role in the multi-step process of gastrointestinal tumorigenesis. We hypothesized that downregulation of Bak expression in normal enterocytes will result in a transformed phenotype. The nontumorigenic intestinal epithelial cell line (IEC18) was transfected with the vector pMV12-AS-bak (encoding anti-sense bak). Three clones, with Bak protein levels similar to those seen in colon cancer cell lines and significantly lower than those found in the parental cells, were further evaluated. The three clones proliferated faster, demonstrated anchorage-independent growth in soft agar and a higher saturation density and plating efficiency. Furthermore, when injected into nude mice, these cells generated tumors after approximately 2-3 weeks. The cells were more resistant to the induction of apoptosis by sulindac sulfide and sulindac sulfone but more sensitive to COX 2 inhibitors (celecoxib and nimesulide). The levels of p16, cyclin D1 and COX 2 were higher in the three transformed clones. In summary,downregulation of Bak expression in normal enterocytes contributes to abnormal growth and tumorigenesis. COX 2 inhibitors may serve as important agents in the prevention and treatment of CRC as they only inhibit the growth of malignant cells.
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Apoptosis/fisiología , Transformación Celular Neoplásica/metabolismo , Enterocitos/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Adenocarcinoma/etiología , Adenocarcinoma/secundario , Animales , Ciclo Celular/fisiología , Línea Celular , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Dinoprostona/metabolismo , Regulación hacia Abajo , Enterocitos/patología , Enterocitos/fisiología , Expresión Génica , Humanos , Neoplasias Hepáticas/secundario , Ratones , Ratones Desnudos , Ratas , Transfección , Proteína Destructora del Antagonista Homólogo bcl-2/genéticaRESUMEN
Mutation of the adenomatous polyposis coli (APC) gene is an important initiating factor in the early stages of the multi-step colorectal cancer (CRC) carcinogenesis. APC E1317Q and I1307K variants have been linked to CRC. The aim of this study was to examine the association of these variants with non-colorectal cancers. Mutation screening was performed using real-time PCR. The APC E1317Q variant was detected in 1.25% individuals undergoing testing. Among 2076 patients that were analyzed for this mutation, 404 had cancer outside of the colon. None of the non-colorectal cancer patients was a carrier of the E1317Q polymorphism. The I1307K variant was found in 32 subjects with non-CRC (7.9%). We conclude herein that the E1317Q gene variant in the APC gene is not found in cancers outside of the colon. The prevalence of the more common I1307K variant is similar to that of CRC.
Asunto(s)
Genes APC/fisiología , Neoplasias/genética , ADN de Neoplasias/genética , Frecuencia de los Genes , Genotipo , Heterocigoto , Humanos , Mutación/genética , Polimorfismo Genético , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Functional activation of beta-catenin/T-cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. In past recent years accumulated evidence has demonstrated a significant role for the Wnt pathway in the development and progression of human prostate cancer. The objective of the current study was to use a gene-targeting approach to selectively kill human prostate cancer cells with activated beta-catenin/Tcf signaling. METHODS: A recombinant adenovirus that carries a lethal gene (PUMA) under the control of a beta-catenin/T-cell factor (Tcf)-responsive promoter (Ad-TOP-PUMA), was used to selectively target human prostate cancer cells (PC-3) in which the beta-catenin/Tcf pathway is activated, and compared its killing efficiency in cancer cells in which this pathway is inactive (DU145 cells). Ad-FOP-PUMA, carrying a mutant Tcf binding site, was used as a control virus. Cell viability was measured by methylene blue assay, and the level of beta-catenin/Tcf activity was measured by luciferase assay. RESULTS: The Ad-TOP-PUMA adenovirus inhibited PC-3 cell growth in a dose and time-dependent fashion, but did not had any effect on DU145 cell growth. CONCLUSIONS: Selective targeting of prostate cancer cells with the activated beta-catenin pathway may be a novel and effective therapy in prostate cancer.
Asunto(s)
Terapia Genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Transducción de Señal/fisiología , Proteínas Wnt/genética , Proteínas Wnt/fisiología , Adenoviridae/genética , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular , Marcación de Gen , Genes Letales/genética , Vectores Genéticos , Humanos , Luciferasas/química , Masculino , Azul de Metileno , Plásmidos/genética , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción TCF/genética , Regulación hacia Arriba/genética , beta Catenina/genéticaRESUMEN
BACKGROUND: Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model. METHODS: Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts. RESULTS: The average number of ACF per rat colon was 64.2 +/- 3 in the control group, 39 +/- 5 and 47 +/- 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 +/- 6 in the group that had received both agents. CONCLUSIONS: In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Curcumina/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Análisis de Varianza , Animales , Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Biopsia con Aguja , Celecoxib , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Inmunohistoquímica , Masculino , Probabilidad , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , Sensibilidad y EspecificidadRESUMEN
PURPOSE: Nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer. The cyclooxygenase (COX) pathway of arachidonic acid metabolism is an important target for nonsteroidal anti-inflammatory drugs. Increased expression of COX-2 was recently shown to be an important step in the multistep process of colorectal cancer carcinogenesis. The new COX-2-specific inhibitors offer the benefit of cancer protection without the gastrointestinal toxicity reported for the old drugs. The purpose of this study was to compare the growth effects of two specific COX-2 inhibitors, celecoxib (Pfizer, Inc., New York, NY), and rofecoxib (Merck, White House Station, NJ) in normal and transformed enterocytes. EXPERIMENTAL DESIGN: Cultures of normal rat intestinal epithelial cell line, IEC-18, vector control cells, c-K-ras, c-K-ras-bak, and antisense-bak derivatives were treated with different dosages of celecoxib (0-60 micro M) and rofecoxib (0-20 micro M). Cell cycle analysis and apoptosis were assessed by fluorescence-activated cell sorting analysis. Protein expression was assessed by Western blot analysis and caspases 3 and 8 activities by ELISA. RESULTS: Celecoxib inhibited cell growth and induced apoptosis in a time- and dose-dependent manner. IEC18 parental cells were two to four times more resistant to celecoxib than ras, ras-bak, and antisense bak transformed cells that overexpress the COX-2 protein. The induction of apoptosis by celecoxib involved the caspase pathways. Rofecoxib, up to its maximal concentration of 20 micro M, did not inhibit cell growth or induce apoptosis. CONCLUSIONS: Celecoxib may prove to be a very efficient component in the prevention and treatment of gastrointestinal tumors because it inhibits the growth of cancerous cells without affecting the growth of normal cells.
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Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Transformada/efectos de los fármacos , Enterocitos/efectos de los fármacos , Lactonas/farmacología , Sulfonamidas/farmacología , Animales , Caspasa 3 , Caspasa 8 , Caspasas/metabolismo , Celecoxib , Línea Celular Transformada/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Enterocitos/citología , Enterocitos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Genes ras/fisiología , Técnicas In Vitro , Pirazoles , Ratas , SulfonasRESUMEN
BACKGROUND: The p.I1307K adenomatous polyposis coli (APC) gene variant, prevalent among Ashkenazi Jews, may increase the risk for colorectal neoplasia. We studied the clinical importance of screening for this polymorphism in 3305 Israelis undergoing colonoscopy. PATIENTS AND METHODS: Clinical data regarding potential risk factors for colorectal cancer (CRC) were collected from individuals undergoing colonoscopic examination at the Tel-Aviv medical center. The APC p.I1307K was detected using real-time PCR (polymerase chain reaction) from DNA extracted from peripheral mononuclear cells. RESULTS: The overall prevalence of the p.I1307K polymorphism was 8.0% (10.1% among Ashkenazi and 2.7% among Sephardic Jews, p<0.001). The overall adjusted odds ratio (OR) for colorectal neoplasia among carriers was 1.51 (95% confidence intervals (CI), 1.16-1.98). Among average risk Ashkenazi Jews, the adjusted OR was 1.75 (95% CI 1.26-2.45). A multiplicative interaction was identified between Ashkenazi ethnicity and APC p.I1307K carrier status (P(INTERACTION) = 0.055). The histopathological features of adenomas and carcinomas did not differ between carriers and non-carriers. CONCLUSIONS: The APC p.I1307K gene variant is an important risk factor for colorectal neoplasia in average risk Ashkenazi Jews. Carriers in this group should be considered for screening colonoscopy at the age of 40, to be repeated every 5 years, similar to recommendations in individuals with family history of colorectal cancer.
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Neoplasias Colorrectales/genética , Genes APC , Judíos/genética , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etnología , Femenino , Predisposición Genética a la Enfermedad/etnología , Heterocigoto , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Cancer is a leading cause of mortality worldwide. Screening is a key strategy for reducing cancer morbidity and mortality. METHODS: We aimed to describe the experience of an integrated cancer prevention center in screening an asymptomatic population for the presence of neoplasia. One-thousand consecutive asymptomatic, apparently healthy adults, aged 20-80 years, were screened for early detection of 11 common cancers that account for 70-80% of cancer mortality. RESULTS: Malignant and benign lesions were found in 2.4% and 7.1% of the screenees, respectively. The most common malignant lesions were in the gastrointestinal tract and breast followed by gynecological and skin. The compliance rate for the different screening procedures was considerably higher than the actual screening rate in the general Israeli population - 78% compared to 60% for mammography (p<0.001) and 39% compared to 16% for colonoscopy (p<0.001). Advanced age, family history of cancer and certain lifestyle parameters were associated with increased risk. Moreover, polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a neoplastic lesion was extremely high (OR 2.3 [95% CI 0.94-5.9]). CONCLUSIONS: One stop shop screening for 11 common cancers in the setting of a multidisciplinary outpatient clinic is feasible and can detect cancer at an early stage.
Asunto(s)
Enfermedades Asintomáticas/epidemiología , Detección Precoz del Cáncer/métodos , Tamizaje Masivo , Neoplasias , Centros Médicos Académicos/métodos , Adulto , Factores de Edad , Anciano , Antígeno CD24/genética , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Genes APC , Humanos , Israel/epidemiología , Estilo de Vida , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Neoplasias/clasificación , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/genética , Polimorfismo Genético , Servicios Preventivos de Salud/métodos , Factores de RiesgoRESUMEN
This study was performed to evaluate whether down-regulation of prostaglandin E(2) (PGE(2)) synthesis by celecoxib treatment is associated with inhibition of cell growth in human colon carcinoma cell lines. Physiologic concentrations of celecoxib (5-10 microM) inhibited 80% to 90% of PGE(2) production in HT-29 cells that express high levels of COX-2 protein. In these concentrations, celecoxib had a minor inhibitory effect (20-30%) on cell growth. There was a significant change in induction of apoptosis only at higher concentrations of celecoxib (>20 microM). Treatment by low concentrations of celecoxib did not alter the levels of COX-1, beta-catenin, P(27), Bcl-2, and Bcl-x proteins. The effect of celecoxib on cell growth inhibition was higher on the COX-2-positive HT-29 cell line (IC(50)=20 microM) than on the COX-2 deficient SW-480 cell line (IC(50)=35 microM). In conclusion, inhibition of PGE(2) synthesis is an early, but not sufficient, step in the mechanism of celecoxib-mediated cell growth inhibition. These results support the need for additional evaluation of independent COX-2 pathways of celecoxib in chemoprevention of CRC.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma/patología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/biosíntesis , Regulación hacia Abajo , Pirazoles/farmacología , Sulfonamidas/farmacología , Carcinoma/metabolismo , Celecoxib , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Células HT29 , HumanosRESUMEN
BACKGROUND: Functional activation of beta-catenin/T-cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. Recently, it was demonstrated that adenomatous polyposis coli or beta-catenin genes are mutated frequently in gastric cancer cells. The objective of the current study was to use a gene-targeting approach to kill human gastric cancer cells selectively with activated beta-catenin/Tcf signaling. METHODS: A recombinant adenovirus that carries a lethal gene (p53 up-regulated modulator of apoptosis [PUMA]) under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) was used selectively to target gastric cancer cells (AGS) that posses an active beta-catenin/Tcf pathway. The combined effect of AdTOP-PUMA and several chemotherapeutic agents (5-florouracil, doxorubicin, paclitaxel) also was evaluated. Cell viability was measured by methylene blue assay, protein expression was measured by Western blot analysis, and cell cycle and apoptosis were evaluated by fluorescent-activated cell sorter analysis. RESULTS.: The TOP-PUMA adenovirus inhibited AGS cell growth in a dose- and time-dependent fashion. Growth inhibition was associated with the up-regulation of PUMA expression and the induction of apoptosis. Chemotherapy synergistically enhanced the killing effect of AdTOP-PUMA. CONCLUSIONS: Selective targeting of gastric cancer cells with the activated beta-catenin pathway may be a novel and effective therapy in gastric cancer. Combination of this gene-therapy approach with standard therapy may improve efficacy and reduce toxicity.
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Proliferación Celular , Transducción de Señal/genética , Factores de Transcripción TCF/genética , beta Catenina/genética , Adenoviridae/genética , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Doxorrubicina/farmacología , Citometría de Flujo , Fluorouracilo/farmacología , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HCT116 , Humanos , Microscopía Fluorescente , Paclitaxel/farmacología , Plásmidos/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/fisiopatologíaRESUMEN
New selective cyclooxygenase-2 inhibitors offer the benefit of cancer protection with less gastrointestinal toxicity associated with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). We hypothesize that MF tricyclic and sulindac can retard all stages of tumor formation in nude mice. In a blinded placebo controlled study, 3 types of experiments were performed: 1) 2.5 x 10(6) cells were injected into 2 flanks of nude mice subcutaneously, as a model for in situ cancer (n = 192); 2) 1 x 10(6) cells were injected into the cecum of mice as a model for in situ colorectal cancer (n = 78) and 3) 0.5 x 10(6) cells were implanted into the splenic subcapsule to establish a colorectal cancer liver metastasis model (n = 78). The animals were fed with standard chow containing either placebo, MF tricyclic (67 mg/kg of chow) or sulindac (150 mg/kg of chow). Mice that were given MF tricyclic or sulindac, at clinical anti-inflammatory plasma concentrations, were significantly more tumor free and had significantly smaller primary tumors and fewer metastases, as compared to mice that consumed placebo. The mortality and the latency period were significantly better in the treatment groups. These findings suggest that selective COX-2 inhibitors may serve as an adjunct to standard therapy in colorectal cancer.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/prevención & control , Inhibidores de la Ciclooxigenasa 2/farmacología , Furanos/farmacología , Sulindac/farmacología , Administración Oral , Animales , Quimioprevención , Modelos Animales de Enfermedad , Inyecciones Subcutáneas , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Ratones , Ratones Desnudos , Placebos , Distribución Aleatoria , Método Simple CiegoRESUMEN
Cyclin D1 plays an important role in the multi-step process of gastrointestinal tumorigenesis. We hypothesize that normal enterocytes over-expressing cyclin D1 will demonstrate a transformed phenotype. The nontumorigenic intestinal epithelial cell line, IEC-18, was transfected with the vector pMV7-CCND1, encoding cyclin D1. Three clones, with cyclin D1 levels similar to those seen in colon cancer cell lines, were further evaluated in comparison to the vector control cells. They proliferated faster and demonstrated anchorage-independent growth in soft agar, higher saturation density, and higher plating efficiency. When injected into nude mice, tumors were generated after 6-8 weeks. On the other hand these cells were more sensitive to induction of apoptosis. There was no change in the level of beta-catenin protein. In conclusion, cyclin D1 can act as an oncogene in vitro and in vivo, when produced in immortalized normal intestinal epithelial cells. This model may be useful for understanding the role and interrelationships of cyclin D1 in colorectal tumorigenesis.