BACKGROUND: We examined plasma microRNA (miRNA) concentrations from patients with gastric cancers (GCs) to assess their clinical application for diagnosing and monitoring diseases. METHODS: We initially investigated the appropriateness of plasma miRNA assay, and then compared plasma miRNA results with the expressions in cancer tissues from eight GC patients, and also compared plasma miRNAs between pre-and post-operative paired samples from 10 GC patients. Then, plasma miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b and let-7a) were analysed in 69 GC patients and 30 healthy volunteers in total. RESULTS: The initial analysis showed that miRNAs were stable and detectable in all plasma samples, and the plasma miRNA levels reflected the tumour miRNAs in most cases. The levels of these miRNAs were significantly reduced in post-operative samples. In large-scale analysis, the plasma concentrations of miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b) were significantly higher in GC patients than controls (P ¼ 0.05, 0.006, 0.008 and o0.001 respectively), whereas let-7a was lower in GC patients (P ¼ 0.002). The values of the area under the receiver-operating characteristic curve were 0.721 for the miR-106b assay and 0.879 for the miR-106a/ let-7a ratio assay. CONCLUSION: Detection of circulating miRNAs might provide new complementary tumour markers for GC.
Background:Several recent studies demonstrated that microRNAs (miRNAs) are stably detectable in plasma/serum. We hypothesised that plasma miRNAs concentrations contributed to potential biomarkers in patients with oesophageal squamous cell carcinoma (ESCC).Methods:We selected three oncogenic miRNAs (miR-21, miR-184, miR-221) and one tumour suppressive miRNA (miR-375), which are frequently reported in squamous cell carcinoma, as candidate targets for this plasma miRNA assay. This study was divided into three steps: (1) Determination of appropriate plasma miRNAs in preliminary tests. (2) Evaluation of whether the plasma miRNA assays could monitor tumour dynamics. (3) Validation study on the clinical application of plasma miRNA assays in 50 ESCC patients and 20 healthy volunteers.Results:(1) In preliminary tests, the plasma level of miR-21 was significantly higher (P=0.0218) and that of miR-375 (P=0.0052) was significantly lower in ESCC patients than controls. (2) The high plasma miR-21 levels reflected tumour levels in all cases (100%). The plasma level of miR-21 was significantly reduced in postoperative samples (P=0.0058). (3) On validation analysis, the plasma level of miR-21 tended to be higher in ESCC patients (P=0.0649), while that of miR-375 was significantly lower (P<0.0001) and the miR-21/miR-375 ratio was significantly higher (P<0.0001) in ESCC patients than in controls. The value of the area under the receiver-operating characteristic curve (AUC) was 0.816 for the miR-21/miR-375 ratio assay. Patients with a high plasma level of miR-21 tended to have greater vascular invasion (P=0.1554) and to show a high correlation with recurrence (P=0.0164).Conclusion:Detection of circulating miRNAs might provide new complementary tumour markers for ESCC.
Background:Several recent studies demonstrated that microRNAs are stably detectable in plasma/serum. We tested whether miR-18a, which is located in the miR-17-92 cluster and reported to be highly expressed in tissues of oesophageal squamous cell carcinoma (ESCC), served as a plasma biomarker in patients with ESCC.Methods:This study was divided into three steps: (1) confirmation of higher miR-18a levels in primary ESCC tissues and cell lines than normal ESCC tissues and a human fibroblast cell line. (2) Evaluation of the plasma miR-18a assay using quantitative RT–PCR by comparing results from 106 consecutive patients with ESCC and 54 healthy volunteers. (3) Evaluation of the assay for monitoring tumour dynamics in patients with ESCC.Results:(1) Expression of miR-18a was significantly higher in ESCC tissues (P=0.0020) and ESCC cell lines (P=0.0121) than normal tissues and fibroblasts. (2) Plasma concentrations of miR-18a were significantly higher in ESCC patients than healthy volunteers (P<0.0001; ESCC patients vs healthy volunteers (mean±s.d.): 11.77±13.45 vs 0.73±0.54 amol μl−1). The value of the area under the receiver-operating characteristic (ROC) curve (AUC) was 0.9449. Furthermore, the ROC curves to detect early ESCC such as pTis-1 and pStage0-I showed AUCs of 0.9479 and 0.9642, respectively. (3) Plasma levels of miR-18a were significantly lower in postoperative samples than preoperative samples (P=0.0076).Conclusion:Plasma miR-18a may be a very useful biomarker for cancer detection and the monitoring of tumour dynamics in patients with ESCC.
The study was conducted to clarify the cytocidal effect of combination therapy consisting of administration of acridine orange (AO), which is a photosensitizer, and radiation therapy using in vitro and in vivo mouse osteosarcoma models. The results revealed that AO combined with low-dose X-ray irradiation of about 1–5 Gy had a strong cytocidal effect on the cultured mouse osteosarcoma cells regardless of their chemosensitivity, and that this combination therapy inhibited growth of the in vivo mouse osteosarcoma by induction of tumor necrosis. This effect was inhibited by L-histidine, but not by mannitol. These findings suggested that AO might be excited by X-rays and kill osteosarcoma cells through the release of singlet oxygen, which is toxic to living cells. This mechanism is similar to that of photodynamic therapy with AO.
Overcoming multidrug resistance (MDR) is an urgent issue to improve the prognosis of osteosarcoma patients. In this study, we undertook to clarify the effect of photodynamic therapy (PDT) with acridine orange (AO) on the MDR mouse osteosarcoma (MOS/ADR1) cell line, by comparing the outcome with the effect on a chemosensitive osteosarcoma (MOS) cell line. Cultured cells of MOS and MOS/ADR1 cell lines were exposed to AO at various concentrations for various times, followed by long-or short-term (10 or 1 min) illumination with blue light (466.5 nm) for excitation. Key words: Multidrug resistance -Osteosarcoma -Acridine orange -Photodynamic therapyThere is no doubt that chemotherapy is the most important treatment for improving the prognosis of patients with osteosarcoma. However, about 30% of these patients have been found to be resistant to chemotherapy.1-3) Therefore, overcoming multidrug resistance (MDR) is an urgent issue in the management of osteosarcomas. There have been many studies conducted on the modification of MDR in various tumor cell lines, [4][5][6][7][8][9][10] but none is clinically applicable at present. Recently, we have found that photodynamic therapy (PDT) with acridine orange (AO) has a strong cytocidal effect on a chemosensitive mouse osteosarcoma cell line. We conducted the present study to clarify the effect of PDT with AO (AO-PDT) on an MDR mouse osteosarcoma cell line, in comparison with the effect on the chemosensitive cell line. MATERIALS AND METHODS AO-PDT with mouse osteosarcoma cellsThe MDR mouse osteosarcoma cell line (MOS/ADR1) 11) was used in this study. This cell line was established from a radiationinduced mouse osteosarcoma cell line (MOS) 12) by single cell culture after exposure to six-pulsed, stepwise increments of doxorubicin (DOX) concentration ranging from 0.01 to 1 µg/ml. The MOS cells were chemosensitive to most anticancer agents, but the MOS/ADR1 cells showed a classical MDR phenotype with overexpression of P-glycoprotein; they were resistant to DOX, vincristine, vinblastine, etoposide, mitomycin C, and actinomycin D. 11)DOX binding assay demonstrated that more than 90% of the MOS/ADR1 cells were negative for nuclear DOX fluorescence. 11)We cultured 2×10 5 MOS/ADR1 cells and MOS cells in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal calf serum (FCS) at 37°C under a 5% CO 2 atmosphere, using 6-well plates. At 24 h, in a preconfluent cell growth condition, the medium of the wells was replaced with 0.025, 0.05, 0.1, 1.0, or 2.0 µg/ml AO containing DMEM. After 15-min exposure to AO, 1400 lx blue light selected through an interference filter (466.5 nm) from a 150-W halogen lamp source (Nikon Fibertrans 2; Nikon, Tokyo) was employed to illuminate the cell surface, to excite AO bound to the cells, using a double fiber tube system (PDT with AO: AO-PDT). This blue light has low energy and does not generate heat. In the continuous AO exposure study, after illumination for 10 min, both tumor cell groups were further cultured in an AO-containing medium. In the fl...
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