A candidate for lung cancer treatment: arsenic trioxide.

Arsenic trioxide (ATO), a highly effective drug in treating acute promyelocytic leukemia with low toxicity, demonstrates a significant effect on lung cancer. The anti-cancer mechanisms of ATO include inhibition of cancer stem-like cells, induction of apoptosis, anti-angiogenesis, sensitization of chemotherapy and radiotherapy, anti-cancer effects of hypoxia, and immunoregulation properties. In addition, some studies have reported that different lung cancers respond differently to ATO. It was concluded on numerous studies that the rational combination of administration and encapsulation of ATO have promising potentials in increasing drug efficacy and decreasing adverse drug effects. We reviewed the efficacy of ATO in the treatment of lung cancer in recent years to provide some views for further study.

Comparative efficacy of whole-brain radiotherapy with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma.

PURPOSE: We explored and compared the clinical effects of whole-brain radiotherapy (wbrt) with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma (nsclc). METHODS: We retrospectively analyzed 62 patients with multiple brain metastases from nsclc who received wbrt (30 Gy in 10 fractions) at Shengjing Hospital of China Medical University from January 2012 to May 2013. In 30 patients, elemene liposomes (400 mg) were injected intravenously via a peripherally inserted central catheter for 21 consecutive days from the first day of radiotherapy. Overall survival (os) and nervous system progression-free survival (npfs) for the two groups were compared by Kaplan-Meier analysis. Factors influencing npfs were examined by Cox regression analysis. Chi-square or Fisher exact tests were used for group comparisons. RESULTS: The median os was 9.0 months in the wbrt plus elemene group and 7.8 months in the wbrt-alone group (p = 0.581); the equivalent median npfs durations were 5.2 months and 3.7 months (p = 0.005). Patient treatment plan was an independent factor associated with npfs (p = 0.002). Tumour response and disease-control rates in the wbrt plus elemene group were 26.67% and 76.67% respectively; they were 18.75% and 62.5% in the wbrt group (p = 0.452). Compared with the patients in the wbrt-alone group, significantly fewer patients in the wbrt plus elemene group developed headaches (p = 0.04); quality of life was also significantly higher in the wbrt plus elemene group both at 1 month and at 2 months (p = 0.021 and p = 0.001 respectively). CONCLUSIONS: The addition of elemene liposomes to wbrt might prolong npfs in patients with multiple brain metastases from nsclc, while also reducing the incidence of headache and improving patient quality of life.

Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study.

PURPOSE: Median survival of patients with brain metastases from non-small cell lung cancer is poor. This study was to investigate the radiation-enhancing effect of sodium glycididazole combined with whole-brain radiotherapy of multiple brain metastases from non-small cell lung cancer. PATIENTS AND METHODS: Sixty-four patients with multiple brain metastases from non-small cell lung cancer were included: the study group (n=32) received whole-brain radiotherapy combined with sodium glycididazole at a dose of 700mg/m(2) intravenous infusion 30minutes before radiotherapy, three times a week; the control group (n=32) only received whole-brain radiotherapy. The primary end point was central nervous system (CNS) progression-free survival and overall survival. The treatment-related toxicity was also recorded. RESULTS: The CNS disease control rate was better (90.6% vs 65.6%, P=0.016) in the study group than in the control group at 3 month of follow-up. The median CNS progression-free survival time was longer in the study group than in the control group (7.0 months vs 4.0 months, P=0.038). There was no significant difference of the median overall survival time between the study group and the control group (11.0 months vs 9.0 months, P=0.418). On the other hand, the treatment-related toxicity showed no statistically significant difference between these two groups (P>0.05). CONCLUSIONS: The study indicated that sodium glycididazole was an effective, promising radiation-enhancing agent that improved CNS disease control rate, extended the median CNS progression-free survival time and was well tolerated in patients suffering from non-small cell lung cancer with multiple brain metastases.

Serum C-reactive protein predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.

BACKGROUND: We aimed to evaluate the association of serum C-reactive protein (crp) with prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. METHODS: We retrospectively reviewed 79 patients with locoregionally advanced nasopharyngeal carcinoma (cT3-4N0-3M0) treated with chemoradiotherapy. Chemoradiotherapy consisted of external-beam radiotherapy to the nasopharynx (70-80 Gy), the lymph node-positive area (60-70 Gy), and the lymph node-negative area (50-60 Gy) combined with 3 cycles of various platinum-based regimens delivered at 3-week intervals. Elevated crp was defined as more than 8 mg/L. The survival rate was calculated using the Kaplan-Meier method, and univariate and multivariate analyses (Cox proportional hazards model) were used to identify factors significantly associated with prognosis. RESULTS: During the median follow-up of 3.9 years (range: 1-5.5 years), 23 patients died from nasopharyngeal cancer. The 5-year cancer-specific survival (css) rate was 62.90%. Before chemoradiotherapy, 18 patients had high serum crp; the css rate in that subgroup was significantly worse than the rate in the remaining patients (p = 0.0002). Multivariate analysis showed that crp was an independent prognostic indicator of css, with a hazard ratio of 3.04 (95% confidence interval: 1.22 to 7.55; p = 0.017). Among the 18 patients with elevated serum crp, 9 achieved normal serum crp after chemoradiotherapy, of whom 5 remained living with no evidence of recurrence or metastasis during follow-up. By contrast, the remaining 9 patients in whom serum crp did not normalize after chemoradiotherapy died within 4.2 years. CONCLUSIONS: Elevated serum crp before treatment predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.

Serum levels of selenium in patients with brain metastases from non-small cell lung cancer before and after radiotherapy.

PURPOSE: This study was to evaluate the influence of radiotherapy on the selenium serum levels of non-small cell cancer patients with brain metastases. PATIENTS AND METHODS: This prospective study included 95 non-small cell cancer patients with brain metastases treated by radiotherapy from December 2007 until November 2010. Plasma selenium levels were determined before and at the end of the radiotherapy. Age, body mass index (BMI), prior chemotherapy, pathological type and personal habits (smoking and alcoholism) were recorded for each patient. RESULTS: The mean age was 63 years; the mean BMI was 27.6. Seventy-six patients (80%) were non-smokers. Sixty-two patients (65.3%) showed no drinking habits and 8 (8.4%) have no prior chemotherapy. Thirty-nine patients (41.1%) were adenocarcinoma, 51 (53.7%) were squamous cell carcinoma and five (5.3%) were large cell carcinoma. At the beginning of radiotherapy, the mean selenium level for all patients was 90.4 µg/l and after radiation this value dropped to 56.3 µg/l. Multivariate analysis showed statistically significant difference in the plasma selenium concentration before and after radiotherapy for age (P<0.001), BMI (P<0.001), smoking (P<0.001), alcoholism (P<0.001), prior chemotherapy (P<0.001) and pathological type (P<0.001). CONCLUSION: Significant reduction in plasma levels of selenium was recorded in patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents.

Safety and radiation-enhancing effect of sodium glycididazole in locoregionally advanced laryngeal cancers previously treated with platinum-containing chemotherapy regimens: A preliminary report.

PURPOSE: To determine the safety and radiation-enhancing effect of sodium glycididazole in laryngeal squamous cell carcinoma (stage T3-4,N0-3,M0) with conventional radiotherapy. PATIENTS AND METHODS: Patients with locoregional advanced laryngeal cancer (stage T3-4,N0-3,M0) were included: group 1(control, n=30)were not administered of sodium glycididazole; group 2 (test, n=30) received sodium glycididazole at a dose of 700 mg/m(2) intravenous infusion 30 minutes before radiotherapy three times a week. Surrogate end-points of efficacy were tumor and nodal size. Safety parameters were vomiting, nausea, mucositis, laryngeal edema, esophagus and skin reaction, dysphagia, dyspnea, neurological deficit. Patients were evaluated weekly during treatment for 7 weeks and thereafter monthly for 3 months. RESULTS: In the test, the overall response rate was 88.89% (95%CI, 71.00-97.00%) at 7 weeks and 92.59% (95%CI, 76.00 to 99.00%) at 1 month of follow-up. In the control, the overall response rate was 62.5% (95%CI, 41.00 to 81.00%) at 7 weeks and 58.33% (95%CI, 37.00 to 78.00%) at 1 month of follow-up. The short-term locoregional response rate was better in the test group at 7 weeks (p=0.027) and at 1 month (p=0.005) of follow-up. The test group had significantly more nausea and vomiting in weeks 1 (p=0.047), 2 (p=0.007), and 3 (p=0.01) of treatment. CONCLUSIONS: The study indicates sodium glycididazole is an effective radiation-enhancing agent that improves short-term locoregional control and is well tolerated in patients with locoregionally advanced laryngeal cancer.

HIV-1 infected mononuclear phagocyte secretory products affect neuronal physiology leading to cellular demise: relevance for HIV-1-associated dementia.

Viral and cellular products from HIV-1-infected and/or immune competent mononuclear phagocytes (MP) (brain macrophages and microglia) affect neuronal function during HIV-1-associated dementia (HAD). Neurotoxic MP factors include, but are not limited to, pro-inflammatory cytokines, chemokines, platelet activating factor, arachidonic acid and its metabolites, nitric oxide, progeny virions and viral structural and regulatory proteins. The mechanisms for immune-mediated neural injury in HAD, only now, are being unraveled. In this regard, we reviewed the current knowledge of how postmitotic neurons, which can neither divide nor be replaced, are damaged by MP secretory activities. Linking neuronal function with brain MP activation was made possible by placing viral and/or immune products onto neurons and measuring cell signaling events or through ex vivo electrophysiological tests on MP-treated brain slices. Such linkages are shown, in this report, by select demonstrations of MP factors which cause neuronal dysfunction in HAD.

Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: a mechanism for cognitive dysfunction in HIV-1-associated dementia.

It is generally accepted that viral and cellular products from immune competent mononuclear phagocytes (MP) (brain macrophages and microglia) underlie the neuropathogenesis of HIV-1-associated dementia (HAD). What remains unanswered, however, is the composition of and mechanisms for such MP-induced neurological dysfunctions. In attempts to address these issues culture fluids from HIV-1ADA-infected monocyte-derived macrophages (MDMs) (depleted or enriched with progeny virus) were placed onto the CA1 area of rat hippocampal brain slices (the site of mammalian learning and memory) and neuronal long-term potentiation (LTP) assayed. LTP was induced by high frequency stimulation (HFS). Lipopolysaccharide (LPS) served as a surrogate macrophage activator. Synaptic strength was assayed by the initial slope of evoked field excitatory postsynaptic potentials (EPSPs). Synaptic potentiation following HFS was observed in slices incubated with uninfected (control) MDM culture fluids. The magnitude of the LTP response was 150.2 +/- 21.10% compared to basal levels (n=6). Synaptic strength was enhanced in virus-infected (135.7+/-28.9%, n=8) and LPS-activated MDM (123.3+/-5.1%, n=7) but at lower levels than controls. The lowest levels of LTP were in brain slices incubated with virus-infected and LPS-activated MDM fluids at (109.5+/-9.9% n=12). Interestingly, bath application of progeny HIV-1 virions showed minimal LTP effects. Virus-infected, LPS-activated MDM fluids, with progenyvirus, reduced synaptic strength but were not statistically different than replicate culture fluids depleted of virus. In contrast, IL-1beta and quinolinic acid, significantly diminished synaptic strength. These results, taken together, suggest that soluble HIV-1-infected MDM secretory products, but not virus per se, significantly affect LTP. This electrophysiological system, which monitors neuronal function following cell exposure to HIV-1 infected materials could provide a novel testing ground for therapeutics designed to protect brain function in HAD.

Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia.

The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1alpha (SDF-1alpha), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1alpha, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1alpha/beta was detected predominantly in astrocytes and at low levels in MDM. SDF-1beta/beta was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1beta induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD.

Opposite modulation of 4-aminopyridine and hypoxic hyperexcitability by A1 and A2 adenosine receptor ligands in rat hippocampal slices.

The effects of the adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), and of the adenosine agonists N6-cyclopentyladenosine (CPA), N6-(2-phenylisopropyl)adenosine (R-PIA), and 2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) were investigated on the hyperexcitability induced in the CA1 area of rat hippocampal slices by hypoxia or the epileptogenic agent 4-aminopiridine. Slice perfusion with the mixed adenosine receptor agonist R-PIA (0.2 microM) significantly (P < 0.05) decreased: (i) the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period; (ii) the duration of the hypoxia-induced epileptiform bursting. Conversely, slice perfusion with the selective A1 adenosine receptor antagonists DPCPX (0.2 microM) or with the selective A2 adenosine receptor agonist CGS 21680 significantly (P < 0.05) increased the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period but did not affect the duration of the hypoxia-induced epileptiform bursting. Neither drug significantly affected the number of slices showing functional recovery after hypoxia. Slice perfusion with DPCPX (0.2 microM) also significantly increased (P < 0.05) the number of slices showing a persistent CA1 epileptiform bursting during the reoxygenation period, while the other drugs failed to affect it. Slice perfusion with the selective A1 adenosine receptor agonist CPA (2 microM) or R-PIA (5 microM) significantly (P < 0.05) decreased the duration of the CA1 epileptiform bursting induced by 100 microM 4-aminopyridine. CGS 21680 (5 microM) perfused together with CPA (2 microM) significantly (P < 0.05) counteracted the inhibitory effects of the A1 adenosine receptor agonist on 4-aminopyridine epileptiform bursting, while it failed by itself to directly affect the 4-aminopyridine epileptiform bursting duration. The results produce evidence for a selective opposite modulation by A1 and A2 adenosine agonists in the control of hippocampal hyperexcitability induced by hypoxia or 4-aminopyridine but not in the post-hypoxic functional recovery.

Highly ouabain-sensitive alpha 3 isoform of Na+,K(+)-ATPase in human brain.

The Na+,K(+)-ATPase alpha 3 isoform has recently been demonstrated immunochemically in human brain. Conclusive biochemical evidence, however, is still lacking. In this study, a unique 50-kDa polypeptide, which is known to be specific to the rat alpha 3 isoform, has been found in human brainstem Na+,K(+)-ATPase following formic acid treatment of the purified alpha isoform proteins. Human alpha 3 Na+,K(+)-ATPase is also highly sensitive to ouabain inhibition, with a 50% ouabain inhibition value of 1.0 x 10(-7) M. These results provide clear and direct evidence for the existence of the alpha 3 isoform in human brain.

Effects of adenosinergic drugs on hypoxia-induced electrophysiological changes in rat hippocampal slices.

The effects of adenosinergic antagonists caffeine and DPCPX, and of the adenosinergic agonists L-PIA, CPA and CGS 21680 were investigated on fully and partially reversible hypoxia-induced electrophysiological changes in rat hippocampal slices. The influence of a high potassium solution and of the N-methyl-D-aspartate antagonist dizocilpine (MK 801) was also tested. The latency to obtain a 50% decrease in the amplitude of the CA1 population spike (CA1 PS) during a short- (5-10 min) lasting hypoxic period was significantly increased (P less than 0.01) by slice perfusion with caffeine (50 microM), DPCPX (0.2 microM), and by increasing (from 3 to 4 mM) the potassium concentration in the medium bathing the hippocampal slices. The latency was significantly decreased (P less than 0.01) by slice perfusion with L-PIA (0.2 microM) and CPA (0.05 microM). It was not significantly modified by CGS 21680 (5 microM). The incidence of reappearance of the CA1 PS during reoxygenation after long- (45 min) lasting hypoxia was significantly increased (P less than 0.05) by slice perfusion with MK 801 (50 microM), while it was not significantly affected by slice perfusion with caffeine (50 microM) or DPCPX (0.2 microM) or L-PIA (0.2 microM) or CPA (0.05 microM) or CGS 21680 (5 microM). The results indicate a prevalent involvement of the A1 adenosine receptors in the early mechanisms underlying hypoxia-induced reversible changes. Adenosine seems to have a limited role in the late mechanisms occurring after a long-lasting hypoxic period.