RESUMEN
Dendritic cell (DC) based anti-cancer immunotherapy is well tolerated in patients with advanced cancers. However, the clinical responses seen after adoptive DC therapy have been suboptimal. Several factors including scarce DC numbers in tumors and immunosuppressive tumor microenvironments contribute to the inefficacy of DCs as cellular vaccines. Hence DC based vaccines can benefit from novel methods of cell delivery that would prevent the direct exposure of immune cells to suppressive tumor microenvironments. Here we evaluated the ability of DCs harbored in biocompatible scaffolds (referred to as biomatrix entrapped DCs; beDCs) in activating specific anti-tumor immune responses against primary and post-surgery secondary tumors. Using a preclinical cervical cancer and a melanoma model in mice, we show that single treatment of primary and post-surgery secondary tumors using beDCs resulted in significant tumor growth retardation while multiple inoculations were required to achieve a significant anti-tumor effect when DCs were given in free form. Additionally, we found that, compared to the tumor specific E6/E7 peptide vaccine, total tumor lysate induced higher expression of CD80 and CD40 on DCs that induced increased levels of IFNγ production upon interaction with host lymphocytes. Remarkably, a strong immunocyte infiltration into the host-implanted DC-scaffold was observed. Importantly, the host-implanted beDCs induced the anti-tumor immune responses in the absence of any stromal cell support, and the biomatrix structure was eventually absorbed into the surrounding host tissue. Collectively, these data indicate that the scaffold-based DC delivery may provide an efficient and safe way of delivering cell-based vaccines for treatment of primary and post-surgery secondary tumors.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Células Dendríticas/citología , Neoplasias/terapia , Linfocitos T Citotóxicos/citología , Animales , Antígenos de Neoplasias/metabolismo , Técnicas de Cocultivo , Humanos , Inmunosupresores/uso terapéutico , Inmunoterapia , Interferón gamma/metabolismo , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunología , Fenotipo , Bazo/citología , Microambiente TumoralRESUMEN
Cervical cancer is a high-incidence female cancer most commonly caused by human papilloma virus (HPV) infection of the genital mucosa. Immunotherapy targeting HPV-derived tumor antigens (TAs) has been widely studied in animal models and in patients. Because the female genital tract is a portal for the entry of HPV and a highly compartmentalized system, the development of topical vaginal immunotherapy in an orthotopic cancer model would provide an ideal therapeutic. Thus, we examined whether flagellin, a potent mucosal immunomodulator, could be used as an adjuvant for a topical therapeutic vaccine for female genital cancer. Intravaginal (IVAG) co-administration of the E6/E7 peptides with flagellin resulted in tumor suppression and long-term survival of tumor-bearing mice. In contrast to IVAG vaccination, intranasal (IN) or subcutaneous (SC) immunization did not induce significant tumor suppression in the same model. The vaginal adjuvant effect of the flagellin was completely abolished in Toll-like receptor-5 (TLR5) knock-out mice. IVAG immunization with the E6/E7 peptides plus flagellin induced the accumulation of CD4+ and CD8+ cells and the expression of T cell activation-related genes in the draining genital lymph nodes (gLNs). The co-administered flagellin elicited antigen-specific IFNγ production in the gLNs and spleen. The intravaginally administered flagellin was found in association with CD11c+ cells in the gLNs. Moreover, after immunization with a flagellin and the E6/E7 peptides, the TLR5 expression in gLN cells was significantly upregulated. These results suggest that flagellin serves as a potent vaginal adjuvant for a therapeutic peptide cancer vaccine through the activation of TLR5 signaling.
RESUMEN
Cisplatin is an effective antineoplastic drug that is widely used to treat various cancers; however, it causes side effects such as ototoxicity via the induction of apoptosis of hair cells in the cochlea. Alpha-lipoic acid (ALA) has been reported to exert a protective effect against both antibiotic-induced and cisplatin-induced hearing loss. Therefore, this study was conducted to (1) elucidate the mechanism of the protective effects of ALA against cisplatin-induced ototoxicity using in vitro and ex vivo culture systems of HEI-OC1 auditory cells and rat cochlear explants and (2) to gain additional insight into the apoptotic mechanism of cisplatin-induced ototoxicity. ALA pretreatment significantly reduced apoptotic cell death of the inner and outer hair cells in cisplatin-treated organ of Corti explants and attenuated ototoxicity via marked inhibition of the increase in the expression of IL-1ß and IL-6, the phosphorylation of ERK and p38, the degradation of IκBα, the increase in intracellular levels of ROS, and the activation of caspase-3 in cisplatin-treated HEI-OC1 cells. This study represents the first histological evaluation of the organ of Corti following treatment with ALA, and these results indicate that the protective effects of ALA against cisplatin-induced ototoxicity are mediated via the regulation of MAPKs and proinflammatory cytokines.
Asunto(s)
Cisplatino/antagonistas & inhibidores , Cisplatino/toxicidad , Citocinas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , Ácido Tióctico/farmacología , Animales , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular , Expresión Génica/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Proteínas I-kappa B/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Inhibidor NF-kappaB alfa , Órgano Espiral/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.
Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Artemisia/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Fase G1/efectos de los fármacos , Células HCT116 , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Interleucina-6/metabolismo , Janus Quinasa 2/metabolismo , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Survivin , Transcripción Genética/efectos de los fármacosRESUMEN
Multidrug resistance is the phenomenon by which, after exposure to a single chemotherapeutic agent, cancer cells evade the agent's cytotoxic effects as well as become resistant to several classes of diverse drugs. ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via a n ATP - dependent drug efflux pump. P-glycoprotein (P-gp) is a prominent ABC superfamily protein encoded by the mdr gene which has the ability to mediate the cellular extrusion of xenobiotics and anticancer drugs from tumor cells. Exclusively expressed P-gp cells from the human colon cancer HCT15/DOX line showed resistance to doxorubicin while parental HCT15 cells treated with doxorubicin displayed typical signs of apoptosis. In order to verify the hypothesis that expression of MDR is controlled in part, by protein kinase C (PKC), expression patterns of different PKC isoforms were examined in both cell lines. Of the PKC isoforms evaluated, the membrane translocation and expression levels of PKCα were strikingly increased in HCT15/DOX cells. PKCα reversed doxorubicin-induced apoptosis through the scavenging of ROS as well as inhibition of PARP cleavage. In addition, inhibition of PKCα with Go6976, a specific inhibitor of classical PKC, led to reduced MDR expression and increased doxorubicin-induced apoptosis. Knockdown of PKCα by siRNA diminished the protective effects of PKCα for doxorubicin-induced apoptosis. These results suggested that over-expression and activity of PKCα is closely associated with the regulation of the MDR phenotype in human colon cancer HCT15 cells and provided insight into a new strategy for inhibiting doxorubicin resistance in human cancers.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Proteína Quinasa C-alfa/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Carbazoles/farmacología , Línea Celular Tumoral , Neoplasias del Colon , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Estrés Oxidativo , Proteína Quinasa C-alfa/antagonistas & inhibidores , Proteína Quinasa C-alfa/genética , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The regional lymph nodal status is the most powerful independent predictor of survival for patients with clinical N0 primary cutaneous malignant melanoma. OBJECTIVE: We wanted to evaluate the feasibility and morbidity of the sentinel lymph node biopsy (SLNB) staging using a multidisciplinary team approach, in cooperation with other surgical departments, at a university hospital setting. METHODS: Twenty two patients with cutaneous melanoma and who were treated at Kyungpook National University Hospital were included in this study. They all received SLNB, which was done by the Departments of Dermatology and General Surgery. We evaluated the feasibility and side effects of SLNB. RESULTS: Pathologically-positive sentinel nodes were found in 7 of the 22 cases (31.8%) and all 7 patients were consequently upstaged. The whole process involved in SLNB was well tolerated by nearly all the patients, with only mild and transient complications being observed. CONCLUSION: We suggest that in a Korean setting, utilizing SLNB with a multi-disciplinary team approach is a technically feasible procedure that is able to detect occult nodal metastasis with low morbidity rates in patients with cutaneous malignant melanoma.
RESUMEN
The need for beneficial use of sedatives in oncologic patients is increasing. Therefore, in this study, antiproliferative characteristics of herbal and synthetic sedatives were examined in vitro in SNU-C4 human colorectal adenocarcinoma cells. Apigenin (50% inhibition concentration, IC(50) = 1.8 +/- 0.5 microM) and diazepam (IC(50) = 7.0 +/- 0.5 microM) showed concentration-dependent inhibition of SNU-C4 cancer cell survival. Efficacy of cancer cell survival inhibition by apigenin and diazepam was much lower than that of 5-fluorouracil (5-FU), a known chemotherapeutic drug. However, 10(-6) M concentration of apigenin and diazepam potentiated 5-FU-induced cytotoxicity. In SNU-C4 cells, 10(-6) M concentrations of diazepam, flumazenil (Ro15-1788), Ro5-4864, or PK11195, all ligands for central- or peripheral-type benzodiazepine (BZD) receptors, inhibited cell survival like the flavonoid apigenin (4',5,7-trihydroxyflavone) and fisetin (3,7,3',4'-tetrahydroxyflavone). Also like the plant flavonoids, treatment with 10(-6) M concentration of diazepam for 3 days hardly affect the peripheral-type BZD receptor (PBR) messenger RNA (mRNA) expression and inhibited glucose utilization of SNU-C4 cells. Treatment with flavonoids or diazepam for 6 days upregulated PBR mRNA expression and cell cytotoxicity of SNU-C4 cells. Furthermore, treatment with 10(-6) M concentration of apigenin, a natural sedative material originating from traditional herbs, positively modulated BZD-induced antiproliferative cytotoxicity in SNU-C4 cells. Overall, the in vitro antiproliferative activity on SNU-C4 cancer cells of herbal sedatives, such as apigenin, plus additive enhancement of synthetic BZD- and 5-FU-induced antiproliferative activities, were shown. In conclusion, this study provides experimental basis for advanced trial in the future.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Hipnóticos y Sedantes/farmacología , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apigenina/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Diazepam/administración & dosificación , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Flavonoides/administración & dosificación , Flavonoles , Fluorouracilo/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hipnóticos y Sedantes/administración & dosificación , Concentración 50 Inhibidora , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismoRESUMEN
Focal cerebral ischemia, known as stroke, is caused by a sudden interruption in the blood supply to the brain. We attempted to identify peptides that can home to ischemic stroke tissue and detect the apoptosis of cells. A phage library displaying random peptides was screened for homing peptides to ischemic stroke tissue in a rat transient middle cerebral artery (MCA) occlusion model. After three rounds of in vivo screening, a phage clone displaying the most frequently occurring CLEVSRKNC sequence was selected. The CLEVSRKNC-phage preferentially homed to ischemic stroke tissue after intravenous administration into the MCA occlusion rats. The fluorescein-labeled synthetic CLEVSRKNC peptide, but not a scrambled control peptide, homed to ischemic stroke tissue with a lack of homing to non-ischemic brain tissue. The CLEVSRKNC peptide co-localized with a portion of neuronal cells, rather than with astrocytes, undergoing apoptosis at the penumbra region of stroke lesions. In autoradiographic studies, the uptake of the (131)I-labeled CLEVSRKNC peptide into an ischemic lesion increased at the first day and peaked at the third day after the injury. These results demonstrate that the CLEVSRKNC peptide can home to ischemic stroke tissue, while detecting apoptotic neuronal cells, and suggest it has applications as a targeting moiety for molecular imaging and selective drug delivery to stroke tissue.
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Apoptosis , Isquemia Encefálica/etiología , Isquemia Encefálica/fisiopatología , Oligopéptidos/administración & dosificación , Biblioteca de Péptidos , Animales , Autorradiografía , Bacteriófago T7/genética , Vectores Genéticos , Masculino , Oligopéptidos/metabolismo , Radioisótopos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
This study examined the comparative anticancer effects of flavonoids and diazepam in the cultured cancer cells. In the SNU-C4 colorectal and MDA-MB-231 breast adenocarcinoma cells, apigenin and fisetin, flavonoids, and diazepam inhibited cancer cell survival concentration and incubation-time dependently. Diazepam consistently inhibited FAS activity, a known anticancer mechanism of flavonoids, in a concentration dependent manner. Unlike diazepam, in highly aggressive breast MDA-MB-231 cells known to have a nuclear/perinuclear located PBR, PK11195, a specific PBR ligand enhanced the proliferation of cells, and the proliferative effect of PK11195 was reversed by an addition of lovastatin, a HMG-CoA reductase inhibitor. Diazepam- and flavonoids-induced cytotoxic activity in both cancer cell lines was not reduced by the addition of 5-fluorouracil (5-FU), a chemotherapeutic agent. Like flavonoids, diazepam inhibited the release of vascular endothelial growth factor (VEGF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) into supernatants of cultured in the SNU-C4 and MDA-MB-231 cells. In conclusion, this study provided in vitro information on the safe use of sedative in oncologic patients.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antineoplásicos , Diazepam/farmacología , Flavonoides/farmacología , Hipnóticos y Sedantes/farmacología , Antimetabolitos Antineoplásicos/toxicidad , Apigenina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ácido Graso Sintasas/antagonistas & inhibidores , Inhibidores de la Síntesis de Ácidos Grasos/farmacología , Flavonoles , Fluorouracilo/toxicidad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Isoquinolinas/farmacología , Lovastatina/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Ectopic thyroid is a rare entity and can occur at any location in the midline position. A role for the ectopic thyroid in the pathogenesis of hypothyroidism and nongoitrous cretinism has been emphasized. OBJECTIVE: To assess the clinical characteristics of an ectopic thyroid by analyzing 49 cases reported in Korea. DESIGN: This study was a retrospective review of 19 cases who were diagnosed by thyroid scan at our institutions together with 30 cases reported in the Korean medical literature, found using KoreaMed. MAIN OUTCOMES: Most cases of ectopic thyroid were diagnosed in patients aged between 1 and 29 years; it was more common in females (43 patients). A lingual thyroid was found in 23 patients, a sublingual thyroid in 17 patients, combined type in 7 patients, a prelaryngeal thyroid in 1 patient, and an intratracheal thyroid in 1 patient. Only four cases had the thyroid gland in the normal position. The chief complaints at presentation were palpable mass in 20 patients, growth retardation in 10 patients, and a lump sensation in the throat in 6 patients. Twenty-six of 42 patients (61.9%) had hypothyroidism, and 16 patients (38.1%) had euthyroidism. As for the treatment modalities, 18 of 26 patients with hypothyroidism and 4 of 16 patients with normal thyroid function received thyroid hormone medication; 3 of 26 patients with hypothyroidism and 8 of 16 patients with euthyroidism underwent resection of the ectopic thyroid. CONCLUSION: Our study suggests that radionuclide thyroid scanning and function testing may be useful not only for the diagnosis of an ectopic thyroid but also before deciding on the therapeutic modality; patients should be followed up to detect changes in thyroid function and malignant transformation.
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Coristoma , Glándula Tiroides , Adolescente , Adulto , Niño , Coristoma/diagnóstico por imagen , Coristoma/epidemiología , Femenino , Humanos , Corea (Geográfico)/epidemiología , Tiroides Lingual/diagnóstico por imagen , Tiroides Lingual/epidemiología , Masculino , Persona de Mediana Edad , Cintigrafía , Estudios Retrospectivos , Glándula Tiroides/diagnóstico por imagenRESUMEN
To investigate the putative mediation of peripheral benzodiazepine receptor (PBR) in the cytotoxicity of flavonoids, in this study, modulatory effects of several flavonoids on the lipid peroxide (LPO) production and PBR mRNA expression of human neuroblastoma cells were observed. Elevated levels of peroxidated products in cancer cells may activate pro-apoptotic and anti-proliferative signaling pathways. Treatment of 10(-6) M 4'-chlorodiazepam and PK 11195 ligands of the PBR for 6 days enhanced the generation of LPO of the human neuroblastoma cells. Several flavonoids, well-known cytotoxic substances, potentiated the enhancement of LPO production by PBR ligands. Treatment of 10(-6) M flavonoids for 6 days elevated the expression of PBR mRNA in cells. These findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their PBR-inducing properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and anti-neoplastic effects.
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Antineoplásicos Fitogénicos/farmacología , Benzodiazepinonas/metabolismo , Flavonoides/farmacología , Fitoterapia , Plantas Medicinales , Regulación hacia Arriba/efectos de los fármacos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Benzodiazepinonas/agonistas , Benzodiazepinonas/farmacología , Línea Celular Tumoral/efectos de los fármacos , Cartilla de ADN , Flavonoides/administración & dosificación , Flavonoides/uso terapéutico , Humanos , Peróxidos Lipídicos , Neuroblastoma/patología , ARN Mensajero/análisis , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Fossilia Mastodi OSSIS, which is a skeletal fossil of a Mastodon, an ancient mammal, has been found to have anxiolytic, sedative and anticonvulsant activities in Oriental medicine. In this study, in vivo characterization of the sedative activities of Fossilia Mastodi OSSIS was performed in order to obtain basic information for the development of a putative natural sedative. The 80% methanol extract of Fossilia Mastodi OSSIS given per os at a dose of 3 g/kg in mice showed anxiolysis, potentiation of pentobarbital sleeping time, reduced locomotor activity, and anticonvulsive activity. Fossilia elicited GABA(A) receptor-mediated anxiolysis. The data obtained suggest that the 80% methanol extract of Fossilia Mastodi OSSIS contains some biologically active principles with sedative activity.
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Fósiles , Hipnóticos y Sedantes/farmacología , Sueño/efectos de los fármacos , Sueño/fisiología , Extractos de Tejidos/farmacología , Animales , Diazepam/farmacología , Masculino , Mamíferos , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Pentobarbital , Picrotoxina/toxicidad , Convulsiones/inducido químicamenteRESUMEN
Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [-1263A>G, -905T>G, -712C>T and -293_-275delCGTGAGGTCAGTGCGGGGA (-293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the -1263 AA genotype or combined -1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42-0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46-0.97, P=0.01, respectively]. For the -712C>T polymorphism, individuals with at least one -712T allele were at a significantly increased risk of lung cancer compared with those harboring the -712 CC genotype (adjusted OR=1.42, 95% CI=1.06-1.89, P=0.02). Consistent with the results of genotype analyses, the -1263G/-712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47-0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45-0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17-0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; P(trend)<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the -1263G/-712T and -1263A/-712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.
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Caspasas/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Anciano , Estudios de Casos y Controles , Caspasa 9 , Femenino , Haplotipos , Humanos , Corea (Geográfico) , Masculino , Persona de Mediana Edad , FumarRESUMEN
BACKGROUND: The MDR1 gene encodes P-glycoprotein (PGP), which plays an important role in mediating multidrug resistance to chemotherapeutic agents. Polymorphisms in the MDR1 gene may have an impact on the expression and function of PGP, thereby influencing the response to chemotherapy. METHODS: We investigated the potential association of MDR1 polymorphisms (2677G>T at exon 21 and 3435C>T at exon 26) and their haplotypes with chemotherapy response in 54 small cell lung cancer (SCLC) patients who received a combination chemotherapy of etoposide-cisplatin. RESULTS: The 3435 CC genotype was associated with a significantly better chemotherapy response compared with the combined 3435 CT and TT genotype (P = 0.025). The 2677 GG genotype was also associated with a better chemotherapy response compared with the combined 2677 GT and TT genotype, although it was not statistically significant. Consistent with the results of genotyping analyses, patients harboring the 2677G-3435C haplotype had a statistically significant better response to chemotherapy compared with those with the other haplotypes combined (P = 0.015). CONCLUSIONS: Our findings suggest that the MDR1 2677G>T and 3435C>T polymorphisms can be used for predicting treatment response to etoposide-cisplatin chemotherapy in SCLC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Genes MDR , Neoplasias Pulmonares/tratamiento farmacológico , Polimorfismo Genético , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Femenino , Predicción , Genotipo , Haplotipos , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana EdadRESUMEN
Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (-449G-->C, -371G-->A, -27G-->C, Val499Arg, PAT-/+, IVS11-5C-->A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined -27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the -27GG genotype (adjusted OR = 1.97, 95% CI 1.22-3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the -371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined -371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09-4.00, p = 0.03). The PAT-/+, IVS11-5C-->A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29-0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36-1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35-0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37-0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the -27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41-5.87, p = 0.004 and Bonferroni-corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.
Asunto(s)
Reparación del ADN , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo Genético , Anciano , Estudios de Casos y Controles , Daño del ADN , Femenino , Genotipo , Haplotipos , Humanos , Corea (Geográfico)/epidemiología , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/efectos adversos , TransglutaminasasRESUMEN
The modulatory effects of behavioral stress on [(3)H]flunitrazepam, an agonist for the central-type benzodiazepine receptor binding to the GABA(A)-benzodiazepine receptor complex, in borderline hypertensive rats (BHR) were examined. In repeatedly immobilized (for 2 weeks, for 2 h/d) BHR, enhancement of [(3)H]flunitrazepam binding to the receptor was observed to be potentiated. The percent enhancement of [(3)H]flunitrazepam binding in BHR was higher than that in normotensive control Wistar-Kyoto rats. Pregnanolone, a neuroactive steroid that has been reported to be a putative endogenous modulator in the stress response, concentration dependently enhanced [(3)H]flunitrazepam binding to the receptor. Enhancement of [(3)H]flunitrazepam binding was observed to be potentiated by the same immobilized stress, and the EC(50) values of pregnanolone in BHR was significantly lower than those in controls and E(max) values were higher. From the above results, it can be concluded that neural modulation to behavioral stress, especially in GABAergic neurotransmission, is exaggerated in BHR. We propose strain-specific differences of stress reactivity as an important pathogenetic factor in psychosomatic disorders including stress-induced hypertension. This is supported by reports showing exaggerated cardiovascular and symathoadrenal responses to stress in BHR.