Protective effect of Shouwu Yizhi decoction against vascular dementia by promoting angiogenesis.

Shouwu is a traditional Chinese medicine (TCM) with neuroprotective effect. Shouwu Yizhi decoction (SYD) was designed based on TCM theory. However, little is known about the roles of SYD in Vascular dementia (VaD). The present study aimed to evaluate the potential effects of SYD on the vascular cognitive impairment and explore the underlying mechanism by establishing focal cerebral ischemia/reperfusion (I/R) rat model to induce VaD. SYD administration (54 mg·kg-1) for 40 days obviously improved the vascular cognitive impairment in the middle cerebral artery occlusion (MCAO) rats as evidenced by the declined neurological deficit score and shortened escape latency via neurological deficit assessment and Morris water maze test. Moreover, SYD decreased neuron damage-induced cell death and ameliorated the ultrastructure of endothelial cells in the MCAO rats, thereby alleviating VaD. Mechanistically, SYD caused increases in the expression of vascular endothelial growth factor (VEGF), CD34 and CD31, compared with the MCAO rats in coronal hippocampus. Simultaneously, the expression level of miR-210 was elevated significantly after SYD administration, compared with the vehicle rats (P < 0.01). The expression of Notch 4 at both mRNA and protein levels was upregulated remarkably along with the notably downregulated DLL4 expression under SYD administration compared with the vehicle rats (P < 0.05). Overall, the above results indicated that SYD promoted angiogenesis by upregulating VEGF-induced miR210 expression to activate Notch pathway, and further alleviated neuron damage and ameliorated the ultrastructure of endothelial cells in the MCAO rats, ultimately enhancing the cognition and memory of MCAO rats. Therefore, our findings preliminarily identified the effect and the mechanism of action for SYD on VaD in rats. SYD could be a potential candidate in treatment of VaD.

[Effect of Peimine on ERCC1 mRNA and LRP Expressions of A549/DDP Multidrug Resistance Cell Line].

OBJECTIVE: To explore the effect of peimine on excision repair cross-complementation 1 (ERCC1) mRNA and lung resistant protein (LRP) expressions in A549/cisplatin (DDP) multidrug resistance (MDR) cell line. METHODS: Lung cancer A549/DDP cells were cultured in vitro.Cells at logarithmic growth phase were divided into 4 groups, i.e., the blank control group, the DDP group, the ligustrazine group (DDP+ligustrazine), the peimine group (DDP + peimine). After 48-h drug action, ERCC1 mRNA expression was detected by RT-PCR and LRP expression detected by cell immunofluorescence. RESULTS: There was no statistical difference in expression levels of ERCC1 mRNA and LRP between the DDP group and the blank control group (P > 0.05). Compared with the DDP group, expression levels of ERCC1 mRNA and LRP obviously decreased in the ligustrazine group and the peimine group (P < 0.05). They were obviously lower in the peimine group than in the ligustrazine group (P < 0.05). CONCLUSIONS: Peimine could reverse MDR of A549/DDP cell line. Its mechanism might be associated with down-regulating ERCC1 mRNA and LRP expression levels.

Cervical cancer gene therapy by gene loaded PEG-PLA nanomedicine.

BACKGROUND AND AIMS: Advances in the treatment of cervical cancer over the last decade have predominantly involved the development of genes directed at molecular targets. Gene therapy is recognized to be a novel method for the treatment of cervical cancer. Genes can be administered into target cells via nanocarriers. This study aimed to develop systemically administrable nano-vectors. Floate (Fa) containing gene loaded nanoparticles (NPs) could target HeLa human cervical cancer cells through combination with receptors on the cells to increase the nuclear uptake of genetic materials. METHODS: Fa was linked onto Poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PLA) to form Fa-PEG-PLA, and the resulting material was used to load plasmids of enhanced green fluorescence protein (pEGFP) to obtain gene loaded nanoparticles (Fa-NPs/DNA). Physical-chemical characteristics, in vitro release and cytotoxicity of Fa-NPs/DNA were evaluated. The in vitro transfection efficiency of Fa-NPs/ DNA was evaluated in HeLa cells and human umbilical vein endothelial cells (HUVEC). PEG-PLA without Fa was used to load pEGFP from NPs/DNA as a control. RESULTS: Fa-NPs/DNA has a particle size of 183 nm and a gene loading quantity of 92%. After 72h of transfection, Fa-NPs/DNA displayed over 20% higher transfection efficiency than NPs/DNA and 40% higher than naked DNA in HeLa cells. However, in HUVECs, no significant difference appeared between Fa-NPs/DNA and NPs/DNA. CONCLUSIONS: Fa-PEG-PLA NPs could function as excellent materials for gene loading. This nano-approach could be used as tumor cell targeted medicine for the treatment of cervical cancer.

Pemetrexed plus dendritic cells as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer who had treatment with TKI.

The aim of this study was to determine the efficacy and toxicity of pemetrexed plus dendritic cells (DCs) in patients suffering from stage IIIB or IV lung adenocarcinoma, who had undergone maintenance treatment with gefitinib or erlotinib. Patients who had failed gefitinib or erlotinib maintenance treatment had ECOG performance statuses ranging from 0 to 2.27 patients received pemetrexed plus DCs as second-line treatment. Dosage: 500 mg/m(2) pemetrexed was administered on day 1 of a 21-day cycle. DCs were given for one cycle of 21 days. Three patients (11.1 %) experienced a partial response and 14 patients (51.9 %) showed stable disease. Ten patients (37.0 %) had progressive disease. The median time to progression-free survival (PFS) was 4.8 months [95 % confidence interval (CI) 4.4-5.2], and the median overall survival was 10.7 months (95 % CI 10.3-11.2). In the subgroup analysis, PFS had a significant difference between the low ratio of CD4/CD8 and normal ratio of CD4/CD8, with 4.5 months (95 % CI 4.2-4.9) and 5.0 months (95 % CI 4.5-5.7), (Log Rank = 0.039), respectively. No one patient experienced grade 4 toxicity. A regimen of pemetrexed combined with DCs is marginally effective and well tolerated in patients with stage IIIB or IV lung adenocarcinoma who had received gefitinib or erlotinib first-line treatment.

Overexpressed FOXC2 in ovarian cancer enhances the epithelial-to-mesenchymal transition and invasion of ovarian cancer cells.

Ovarian cancer is a highly invasive and metastatic disease with poor prognosis, particularly if this disease is diagnosed at an advanced stage, which is often the case. Researchers have argued that ovarian cancer cells that have undergone epithelial­to­mesenchymal transition (EMT) acquire aggressive malignant properties; however, the relevant molecular mechanisms in this setting are poorly understood. In cancer cases, the transcription factor forkhead box protein C2 (FOXC2) has been detected, but the function of this factor in ovarian cancer tumorigenesis remains unclear. In the present study, FOXC2 was overexpressed in invasive ovarian cancer cell lines and tissues. The invasive potential of ovarian cancer cells was significantly increased by ectopic FOXC2 expression but it was significantly decreased by RNA interference targeting FOXC2. E­cadherin and vimentin expression levels were modulated by FOXC2. These results indicated that FOXC2 was required for the maintenance of the mesenchymal phenotype after TGF­ß1 induced EMT in human ovarian cancer cells. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies. These therapies can then be performed to treat invasive ovarian tumor.

Efficacy of erlotinib plus dendritic cells and cytokine-induced killer cells in maintenance therapy of advanced non-small cell lung cancer.

The aim of this study was to evaluate the safety and effectiveness of erlotinib plus DC/CIK in maintenance therapy of advanced non-small cell lung cancer. After 4 cycles of the 2-drug regimen treatment with platinum, the 54 patients with non-small cell lung cancer in phase IIIb or IV reached stable or beyond stable stages. The patients were then randomly divided into 2 groups. One group was treated with erlotinib therapy (erlotinib group), and the other was treated with DC/CIK plus erlotinib (DC/CIK plus erlotinib group). The progression-free survival of the erlotinib group and the DC/CIK plus erlotinib group was 3.98 months (95% CI, 3.56-4.40) and 5.02 months (95% CI, 4.32-5.72) (P=0.002), respectively. The median overall survival of the erlotinib group and the DC/CIK plus erlotinib group was 9.9 months (95% CI, 9.1-10.6) and 10.5 months (95% CI, 9.6-11.4) (P=0.29), respectively. The levels of CD3, CD4, and CD8 were significantly different before and after the treatment in the DC/CIK plus erlotinib group, but not in the erlotinib group. There was no significant difference in toxicity between the 2 groups. In conclusion, there was no statistically significant difference in overall survival between DC/CIK plus erlotinib and erlotinib as maintenance therapy. DC/CIK plus erlotinib was well tolerated with a manageable safety profile.

S-1 plus CIK as second-line treatment for advanced pancreatic cancer.

This study aimed to evaluate the efficacy and tolerability of S-1 (Tegafur, Gimeracil, and Oteracil Potassium Capsules) plus CIK (Cytokine-induced killer cells) in patients with advanced pancreatic cancer who had previously received gemcitabine-based therapy. In this prospective study, fifty-eight patients were randomly divided into two groups. One group (CT group) was given S-1 alone, and the other group (immuno-CT group) was given S-1 plus CIK. S-1 was administered orally twice a day at 80 mg/m(2)/day on days 1-21 of a 28-day cycle till disease progression or unacceptable toxicity occurred. CIK was given for one cycle of 28 days. The disease control rate for S-1 and CIK was 40.0 and 53.6%, respectively (p = 0.621). The serum CA19-9 level decreased for more than 25% was significantly different (33.3 and 60.7 % in CT group and immuno-CT group, respectively, p = 0.037). The median time to progression was 2.5 (95% CI 2.3-2.8) and 2.9 (95% CI 2.6-3.2) months (p = 0.037) for CT group and immuno-CT group, respectively. The median overall survival was 6.1 (95% CI 5.7-6.5) and 6.6 (95% CI 6.1-7.1) months (p = 0.09) for CT group and immuno-CT group, respectively. The difference in hematological toxicity, including leukocytopenia, anemia, and neutropenia, was insignificant between the two groups. In contrast, the differences in non-hematological toxicity, fatigue, and non-infective fever were significantly different between the two groups (p < 0.05). The S-1 plus CIK regimen was well tolerated in a second-line setting in patients with gemcitabine-refractory and advanced pancreatic cancer.

[Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer].

OBJECTIVE: This study investigates the efficacy and tolerability of capecitabine plus thalidomide in patients with advanced pancreatic cancer who previously underwent gemcitabine-based therapy. METHODS: Sixty-one patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen were enrolled. The patients were randomly divided into two groups. One group (31 patients) was treated with capecitabine alone, and another group was treated with capecitabine plus thalidomide. Capecitabine was administered orally twice a day at a dose of 1, 250 mg/m(2) for 14-day followed by 7-day rest and oral thalidomide 100 mg was given daily without interruption until disease progression or occurrence of unacceptable toxicity. RESULTS: The PFS was 2.8 months (95%CI 2.4 - 3.2) vs. 3.1 months (95%CI 2.6-3.6, P < 0.05) and the OS was 6.1 months (95%CI 5.3 - 6.9) vs. 6.3 months (95%CI 5.2 - 7.4, P = 0.426). In the capecitabine alone group, one patient experienced a partial response (PR), 10 patients showed stable disease (SD) and 20 patients had progressive disease (PD). The another group, two patients experienced a partial response (PR), 11 patients SD, and 17 patients PD. The disease control rates were 35.5% and 43.3%, respectively. The major adverse reaction in the two groups was grade 3 diarrhea. CONCLUSION: Capecitabine plus thalidomide regimen is marginally effective and well tolerated in the second-line setting in patients with gemcitabine-refractory advanced pancreatic cancer.

Treatment of stage IIIb/IV non-small cell lung cancer with Pemetrexed plus Oxaliplatin after failure of Erlotinib as second-line treatment.

To determine the efficacy and toxicity of Pemetrexed plus Oxaliplatin in patients suffering from stage IIIb or IV lung adenocarcinoma and being treated with Erlotinib as second-line treatment, a total of 45 patients were randomly divided into two groups. One group was treated with 500 mg/m(2) Pemetrexed plus 100 mg/m(2) Oxaliplatin, and the other was treated with 500 mg/m(2) Pemetrexed plus 75 mg/m(2) Cisplatin. All drugs were administered on day one of a 21-day cycle. In the Oxaliplatin group, 3 patients (13.6 %) experienced partial response (PR), 9 patients (41.0 %) showed stable disease (SD), and 10 patients (45.5 %) had progressive disease (PD). In the Cisplatin group, 2 patients (8.7 %) experienced PR, 7 patients (30.4 %) showed SD, and 14 patients (60.9 %) had PD. The PFS of the Oxaliplatin group and the Cisplatin group was 4.45 months (95 % CI 4.10-4.80) and 3.96 months (95 % CI 3.68-4.24) (P = 0.03), respectively. The median overall survival (OS) was 10.8 months (95 % CI 10.2-11.5) and 10.7 months (95 % CI 10.2-11.3) (P = 0.72), respectively. There was no statistically significant difference in the occurrence rate of grades 3 and 4 myelotoxicity between the two groups. However, there was a significant difference in the occurrence rate of grades 3 and 4 gastrointestinal reactions and peripheral neurotoxicity between the two groups (P < 0.05). A regime combining Pemetrexed and Oxaliplatin was marginally effective and well tolerated in patients with stage IIIb or IV lung adenocarcinoma who have received Erlotinib as second-line treatment.

Phase II trial of capecitabine combined with thalidomide in second-line treatment of advanced pancreatic cancer.

BACKGROUND: To evaluate the efficacy and tolerability of capecitabine combined with thalidomide in patients with advanced pancreatic cancer (APC) who have previously received gemcitabine-based therapy. METHODS: A total of 31 patients were recruited prospectively in Shandong Tumor Hospital from May 2007 to April 2009. Capecitabine was offered to patients twice a day at a dose of 1250 mg/m(2) for 14-day then followed by 7-day rest. Thalidomide was administered 100 mg/day without interruption until disease progression or occurrence of unacceptable toxicity. RESULTS: Two patients presented partial response (PR), 11 patients showed stable disease (SD) and eighteen patients presented progressive disease (PD). The median progression-free survival (PFS) was 2.7 months (95% confidence interval (CI), 2.4-3.3) and the median overall survival (OS) was 6.1 months (95% CI, 5.3-6.9). In the subgroup analysis, PFS had a significant difference between the serum CA19-9 level decreasing >25% and decreasing <25%, with 3.0 months (95% CI, 2.5-3.6) and 2.5 months (95% CI, 1.8-3.2), (Log Rank = 0.02), respectively. Hematological toxicity included leukocytopenia, anemia and neutropenia. Non-hematological toxicities included diarrhea, skin rash, nausea/vomiting, hand-foot syndrome, fatigue, dizziness, drowsiness and constipation. CONCLUSION: Capecitabine combined with thalidomide is a well-tolerated second-line regimen, in patients with APC refractory to gemcitabine.

Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer.

AIMS AND BACKGROUND: The incidence and development of cancer are closely related to dysfunction of immune function. The immune system cannot identify and remove malignant and mutant cells, which cause tumor cells to escape from surveillance and clearance of the immune system. Immunobiological cancer therapy plays an important role in strengthening body immunological surveillance function and killing remaining tumor cells in the body. We investigated the role of DC/CIK (dendritic cell/cytokine-induced killer cells) immunobiological cancer therapy in maintenance therapy of advanced non-small cell lung cancer. METHODS: When 60 cases of non-small cell lung cancer patients in stage IIIb and IV reached stable disease after treatment with 4 cycles of a two-drug regimen with platinum, they were randomly divided into two groups. One group was treated with DC/CIK immunobiological cancer therapy, and the other was taken as a control group. Finally, cancer progression time and toxicity reaction of the two groups were evaluated. RESULTS: DC/CIK treatment prolongs progression-free survival (3.20 months [95% CI, 2.94-3.50] vs 2.56 months [95% CI, 2.39-2.73]; P <0.05). In the treatment group, the proportion of NK cells, T-cell subgroups CD3+, CD4+ and CD8+ had a significant change before and after treatment. Liver and kidney function and blood tests of the treatment group were within the normal range before and after treatment. In the treatment group, 1 case suffered from chest distress, 3 cases suffered from acratia, and 4 cases suffered from pyrexia. CONCLUSIONS: DC/CIK treatment had potential benefit for patients with advanced non-small cell lung cancer compared with the control group and had no obvious side effects. DC/CIK treatment is a safe and effective method for maintenance therapy of advanced non-small cell lung cancer.