Jug-PLGA-NPs, a New Form of Juglone with Enhanced Efficiency and Reduced Toxicity on Melanoma.

OBJECTIVE: To verrify the anti-tumor efficacy and toxicity between juglone (Jug) and Jug-loaded PLGA nanoparticles (Jug-PLGA-NPs). METHODS: Jug-PLGA-NPs were prepared by ultrasonic emulsification. The anti-tumor activity of Jug (2, 3, 4 µg/mL) and Jug-PLGA-NPs (Jug: 2, 3, 4 µg/mL) in vitro was measured by MTT assay and cell apoptosis analysis. The distribution, anti-tumor effect and biological safety in vivo was evaluated on A375 nude mice. RESULTS: With the advantage of good penetration and targeting properties, Jug-PLGA-NPs significantly inhibited proliferation and migration of melanoma cells both in vitro and in vivo (P<0.05 or P<0.01) with acceptable biocompatibility. CONCLUSIONS: Jug can inhibit the growth of melanoma but is highly toxic. With the advantage of sustained release, tumor targeting, anti-tumor activity and acceptable biological safety, Jug-PLGA-NPs provide a new pharmaceutical form for future application of Jug.

Phase I clinical study of personalized peptide vaccination combined with radiotherapy for advanced hepatocellular carcinoma.

AIM: To assess the efficacy and safety of a new treatment modality, cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, for treating advanced hepatocellular carcinoma (HCC). METHODS: A total of nine patients with advanced HCC were enrolled. Multidisciplinary consultation confirmed that all the patients definitely had no opportunity of surgery, because four patients had multiple liver metastases (the number of liver lesions > 3), one patient had liver metastases and portal vein tumor thrombosis, one patient had lung and bone metastases, two patients had liver and lung metastases and one patient had liver metastasis and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV-DC-CTL. RESULTS: Following radiotherapy and one to three cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in six patients and imaging assessment of the lesions showed a partial response (PR) in three patients and stable disease in the other three patients. The response rate was 33% and disease control rate was 66%. This regimen was found to be safe and well tolerated. None of the patients developed liver or kidney side effects. Only one patient developed grade II bone marrow suppression and the remaining patients had no significant hematological side effects. CONCLUSION: Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced HCC, which is well tolerated, safe, feasible and effective.

Multidisciplinary collaboration in gallbladder carcinoma treatment: A case report and literature review.

Gallbladder carcinoma (GBC) is a rare and highly aggressive disease. The diagnosis of this cancer is difficult due to its occult onset. Hence, GBC is often detected late and at an advanced stage. Although physicians and researchers are continually working to improve the treatment for advanced-stage disease, GBC is usually associated with short survival times. The present study describes a case of GBC that was first diagnosed with accompanying cholecystolithiasis at the time of cholecystectomy. Cancer relapse occurred 1.5 years after the cholecystectomy. Multidisciplinary collaboration was involved in the decision-making process for the treatment of this aggressive recurrence, and the survival time was successfully extended to 26 months. Importantly, high-grade intraepithelial neoplasia and positive margins had previously been detected post-cholecystectomy at a different institution, but were ignored. Relapse may have been preventable had the cancer been diagnosed when it was initially observed. Taken together, these findings suggest that multidisciplinary collaboration should be considered for the management of advanced GBC, whereby patients will benefit from improved survival times. Furthermore, it is recommended that samples obtained from patients undergoing cholecystectomy should more carefully analyzed for evidence of cancerous or precancerous tissues.

Circulating tumour cells predict survival in gastric cancer patients: a meta-analysis.

AIM OF THE STUDY: The prognostic value of the detection of circulating tumour cells (CTCs) in gastric cancer has been studied intensely in recent years. However, the application of different technologies led to inconsistent results between the studies. Here, we performed a meta-analysis of published studies to summarise the evidence. MATERIAL AND METHODS: Medline and ISI Web of Knowledge were searched up to March 2013 using "circulating tumor cells" and "gastric cancer" as search terms. Hazard ratio (HR) with 95% confidence intervals (CIs) for prognostic outcomes and clinical characteristics were extracted from each study. Pooled hazard ratios (HR) and odds ratios (OR) were calculated using random or fixed-effects models. RESULTS: Twelve studies enrolling 774 patients were included. The combined HR estimate for overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were 1.41 (95% CI: 1.28-1.62), 2.99 (95% CI: 2.01-4.45) and 1.64 (95% CI: 1.02-2.62), respectively. Subgroup analysis concerning detection methods and sampling time showed that results of RT-PCR for the OS group and RT-PCR for the DFS group suggest a prognostic significance of CTC detection (pooled HR [95% CI]: 1.45 [1.28-1.65], I(2) = 38%, p = 0.13; 2.99 [2.01-4.45], I(2) = 0%, p = 0.32). In addition, results of the baseline CTC detection group also indicated a significant prognostic value to predict OS and DFS (pooled HR [95% CI]: 1.47 [1.19-1.82], I(2) = 38%, p = 0.14; 2.99 [2.01-4.45], I(2) = 0%, p = 0.32). We simultaneously found that the detection of CTCs correlated with pathological stage (pooled OR [95% CI]: 2.95 [1.65-5.28], I(2) = 56%, p = 0.03), lymph node status (pooled OR [95% CI]: 2.26 [1.50-3.41], I(2) = 37%, p = 0.09), the depth of invasion (pooled OR [95% CI]: 3.21 [1.38-7.43], I(2) = 72%, p = 0.002), and distant metastasis (pooled OR [95% CI]: 2.68 [1.25-5.73], I(2) = 43%, p = 0.15). CONCLUSIONS: Detection of CTCs is associated with poorer prognosis in gastric cancer patients.

Enhancement of anticancer efficacy of chemotherapeutics by gambogic acid against gastric cancer cells.

Gambogic acid (GA), the main active component of gamboge, is well known for its marked antitumor effect in vitro and in vivo. The aim of this study was to assess the natural interaction between GA and chemotherapeutic agents, 5-fluorouracil (5-FU), oxaliplatin (Oxa), and docetaxel (Doc), which are widely used in gastric cancer treatment. This study also investigated the effect of GA on cell apoptosis and drug-associated gene expression for further mechanism research. Synergistic interaction on human gastric cancer BGC-823 cells and MKN-28 cells was evaluated using the combination index (CI) method. The double staining method with Annexin-V-FITC and PI was employed to distinguish the apoptotic cells from others. Expression of drug-associated genes, that is, thymidylate synthase (TS), excision repair cross-complementing (ERCC1), BRCA1, tau, and ß-tubulin III, was measured by real-time quantitative RT-PCR. This study found that GA had a synergistic effect on the cytotoxity of chemotherapeutic agents against both cell lines. The combination of GA and chemotherapeutic agents could also induce apoptosis in a synergistic manner. The mRNA levels of TS, ERCC1, BRCA1, tau, and ß-tubulin III were suppressed at 0.009, 0.075, 0.140, 0.267, and 0.624-fold, respectively, when cells were exposed to GA at the concentration of 0.25 µM. These data suggest that GA has a promising role in enhancing the efficacy of 5-FU, Oxa, and Doc in the treatment of gastric cancer. The potential mechanism would be their synergistic effects on apoptosis induction and the downregulation of chemotherapeutic agent-associated genes.

[Relationship between BRCA1 mRNA expression in tumor cells from malignant effusions and chemosensitivity to cisplatin in patients with metastatic malignant effusions].

OBJECTIVE: To explore the mRNA expression of breast cancer susceptibility gene 1 (BRCA1) in tumor cells isolated from malignant pleural and peritoneal effusions, and the predictive role of BRCA1 related to the efficacy of cisplatin-based chemotherapy. METHODS: Tumor cells were isolated from malignant pleural and peritoneal effusions of 31 cancer patients. The response of these tumor cells to cisplatin was determined by CCK8 assay. Real time quantitative RT-PCR was used to examine the BRCA1 mRNA level in the primary culture cancer cells. RESULTS: The expression level of BRCA1 mRNA was 0.618 (0.014 - 18.063) in primary culture tumor cells. The IC(50) of DDP was 2.809 µg/ml in the primary culture tumor cells (0.118 - 19.439 µg/ml). Both BRCA1 mRNA expression and the tumor cells IC(50) of DDP were not significantly related with patient age, gender, the type of primary tumor, whether to accept the chemotherapy and effusion type (P > 0.05). The level of BRCA1 mRNA was negatively correlated with the chemosensitivity in terms of IC(50) of cisplatin (P < 0.001). CONCLUSION: Assessment of expression level of BRCA1 mRNA may be useful in predicting the efficacy of cisplatin-based chemotherapy in patients with metastatic malignant effusions.

[Prognostic significance of ERCC1 mRNA expression in patients with non-small cell lung cancer receiving platinum-based chemotherapy].

OBJECTIVE: To investigate the correlation of the mRNA expression level of excision repair cross-complementing group 1 (ERCC1) gene with clinicopathological parameters and clinical outcome in patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy. METHODS: The mRNA expression of ERCC1 in formalin-fixed paraffin-embedded primary tumor specimens was measured by real-time quantitative reverse transcriptase polymerase chain reaction. The association between ERCC1 expression levels and clinicopathological parameters in NSCLC patients was analyzed. RESULTS: The median value of ERCC1 mRNA expression level compared with beta-actin in tumor specimens of 61 NSCLC patients was 0.48. There was no correlation between ERCC1 expression and clinicopathological parameters. Patients with low expression of ERCC1 mRNA (less than 0.35, 0.28, respectively) had a significantly longer median time to progression (TTP) (14.3 vs. 8.0 months, P = 0.028) and overall survival (OS) (28.4 vs. 12.9 months, P = 0.0064) than those with high expression. Multivariate analysis showed that a low ERCC1 mRNA expression was an independent factor for OS. CONCLUSION: Our findings suggest that intratumoral ERCC1 mRNA expression level, although is uncorrelated with clinicopathological parameters, is an independent predictive marker for survival of the patients with NSCLC receiving platinum-based chemotherapy, and may provide critical information for personalized chemotherapy.

[Inhibitory effect of oxaliplatin in combination with hyperthermia on angiogenesis].

OBJECTIVE: To study the effect of oxaliplatin in combination with hyperthermia on angiogenesis in vitro and in vivo. METHODS: MTT method was used to observe the influence of oxaliplatin on the proliferation of human umbilical vein endothelial cells (HUVEC) or human colon cancer cells (LOVO). The influence of oxaliplatin on HUVEC migration was evaluated by Transwell. Chick embryo chorioallantoic membrane (CAM) model was used to check whether the neovascularization of CAM could be suppressed in vivo. RESULTS: The survival rate of HUVEC was 80.1% - 42.5% within a range of 0.5 - 16 microg/ml and was negatively correlated with the concentration (correlation coefficient was - 0. 943, P = 0.005). The survival rate of LOVO cells within those doses was more than that of HUVEC. There was a synergistic antiangiogenic effect when a combination of oxaliplatin (0.5 microg/ml, 1 microg/ml and 16 microg/ml) with hyperthermia was used while additional effect was shown by the combinatioin of oxaliplatin (2 microg/ml, 4 microg/ml and 8 microg/ml) and hyperthermia in vitro. Oxaliplatin inhibited migration of HUVEC in vitro at low doses (0.25 - 2 microg/ml), and also suppressed angiogenesis of CAM in vivo at doses of 1 -4 microg/ml. CONCLUSION: The results of this experiment showed that low dose of oxaliplatin has anti-angiogenic effect in vitro, while in combination with hyperthermia has additional effect both in vivo and in vitro.

[Effect of arsenic trioxide on drug transporting molecules in acute promyelocytic leukemia cell line].

OBJECTIVE: To study the effect of arsenic trioxide (As2O3) on expression of drug transporting molecules in APL MR2 cell line. METHODS: MR2 resistant to all-trans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 was used in this in vitro study. Expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) was detected by immunocytochemical assay. RESULTS: The expression of Pgp was significantly higher in MR2 (30%-40%) than in NB4 (10%-20%) (P < 0.001), and that of MRP was also higher in MR2 (56.9 +/- 3.4-21.2 +/- 1.1) than in NB4 (20.6 +/- 5.3-16.7 +/- 1.2) (P < 0.001). As2O3 at concentrations ranging from 0.5 approximately 2.0 micromol/L could significantly decrease the expression of Pgp and MRP, but not that of LRP. The decrease in the expression of Pgp and MRP in MR2 cell line was negatively correlated with the dose and duration of action of As2O3. CONCLUSION: Pgp and MRP, but not LRP, may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.