Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study

BACKGROUND: Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. METHODS: Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. RESULTS: The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively. CONCLUSIONS: The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported (AU)

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Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors.

In this study, we investigated the safety and efficacy in cancer patients of a single intra-tumor injection of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene (AdV/TK) followed by systemic administration of ganciclovir (GCV). In 18 patients with malignant tumors refractory to standard treatment, AdV/TK was injected on day 1 with dose escalation from 2.5 x 10(11) to 1 x 10(12) virus particles (VP), and GCV (5 mg kg(-1)) was delivered intravenously every 12 h from days 2 to 15. The most common treatment-related toxicities were transient fever (10/18) and local injection site reaction (10/18), and most adverse events were WHO grade I/II. Anti-adenovirus antibody levels increased continuously during treatment, but anti-HSV antibody levels remained stable. One patient had a PR at the injection site but PD was found in the primary site (lung cancer), one patient with fibrosarcoma of the neck had an MR, five patients had SD, and 10 patients had PD. In conclusion, AdV/TK followed by GCV can be administered safely to Chinese cancer patients, and achieved a local response with few environmental effects. Because the response was localized, single regional tumor relapse, especially after radiation, may be an indication for this suicide gene therapy.

Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology.

Down-regulation of protein phosphatase 2A (PP2A) is thought to play a critical role in tau hyperphosphorylation in Alzheimer's disease (AD). In vitro phosphorylation of PP2A catalytic subunit at Y307 efficiently inactivates PP2A. A specific antibody against phosphorylated (p) PP2A (Y307) (PP2Ac-Yp307) was used to investigate possible PP2A down-regulation by known pathophysiological changes associated with AD, such as Abeta accumulation and oestrogen deficiency. Immunohistochemistry and immunofluorescence confocal microscopy showed an aberrant accumulation of PP2Ac-Yp307 in neurons that bear pretangles or tangles in the susceptible brain regions, such as the entorhinal cortical cortex and the hippocampus. Experimentally, increased PP2Ac-Yp307 was observed in mouse N2a neuroblastoma cells that stably express the human amyloid precursor protein with Swedish mutation (APPswe) compared with wild-type, and in the brains of transgenic APPswe/ presenilin (PS1, A246E) mice, which corresponded to the increased tau phosphorylation. Treating N2a cells with Abeta25-35 mimicked the changes of PP2Ac-Yp307 and tau phosphorylation in N2a APPswe cells. Knockout of oestrogen receptor (ER) alpha or ERbeta gave similar changes of PP2Ac-Yp307 level and tau phosphorylation in the mouse brain. Taken together, these findings suggest that increased PP2A phosphorylation (Y307) can be mediated by Abeta deposition or oestrogen deficiency in the AD brain, and consequently compromise dephosphorylation of abnormally hyperphosphorylated tau, and lead to neurofibrillary tangle formation.

Pharmacokinetic and pharmacodynamic study of intratumoral injection of an adenovirus encoding endostatin in patients with advanced tumors.

Angiogenesis plays a pivotal role in tumor growth, tissue invasion and metastasis. Endostatin is an angiogenesis inhibitor and has been shown to reduce tumor growth in animal models. However, therapy with recombinant endostatin protein was hampered by its short half-life and very-low yield of bioactive protein. We performed a phase I dose-escalation clinical trial using intratumoral injection of an adenovirus containing human endostatin gene (Ad-rhE; E10A; 10(10)-10(12) virus particles (vp)) in 15 patients with advanced solid tumors. We observed intratumoral injections of E10A without dose-limiting toxicity. Most frequently reported E10A-related adverse events were transient fever and local response. Distribution studies revealed that the vector was detected in the blood, throat and injection site, but rarely in the urine and stool. An increased endostatin expression was detected using enzyme immunoassay in serum in 13 of 14 treated patients throughout the period of treatment despite the presence of neutralizing antiadenovirus antibody. Median serum basic fibroblast growth factor levels decreased from 32.4 pg ml(-1) at baseline to 24.9 pg ml(-1) after 28 days of first treatment. Thus, direct intratumoral injection of up to 10(12) vp of E10A to patients is well tolerated and further studies are necessary to define and increase clinical efficacy.

Postnatal upregulation of alpha4 and alpha3 nicotinic receptor subunits in the brain of alpha7 nicotinic receptor-deficient mice.

The nicotinic receptor subtypes are important for several physiological functions in brain and may therefore play a critical role in brain development. The alpha7 nicotinic receptors which have high Ca2+ permeability are important for cognitive, neuroprotective and trophic functions. In this study, the brain development and the expression of alpha4, alpha3, alpha7, alpha5 and beta2 nicotinic receptors were investigated in the brains of alpha7 deficient (alpha7 -/-), alpha7 heterozygous null (alpha7 +/-) and alpha7 wild-type (alpha7 +/+) mice from postnatal days (P) 7-84. The specific binding of [3H] cytisine and [3H] epibatidine, as well as the expressions of alpha4 and alpha3 nicotinic receptor subunits at mRNA and protein levels, were significantly increased in the cortex and hippocampus of alpha7 -/- and alpha7 +/- mice compared with alpha7 +/+ mice. Furthermore, the alpha4 and alpha3 nicotinic acetylcholine receptor (nAChR) subunits appeared to co-assemble with the alpha5 nAChR subunit in these above brain regions of these mice. No significant change in synaptophysin level was observed. These data suggest that increased levels of alpha4, alpha3-containing nAChRs, co-assembled with the alpha5 nAChR subunit, may contribute to the normal brain development of alpha7 -/- and alpha7 +/- mice.

Protein and mRNA levels of nicotinic receptors in brain of tobacco using controls and patients with Alzheimer's disease.

The neuronal nicotinic receptors (nAChRs) are involved in several processes in brain including nicotine dependence and cognitive disorders. While the number of nAChRs in the brain of tobacco smokers is up-regulated, the receptors are reduced in the brain of patients with Alzheimer's disease (AD). The aim of this study was to investigate nAChR mRNA and protein levels in brain of smoking and non-smoking controls and AD patients. Western blotting and RT-PCR techniques were used to quantify different nAChR subunits in autopsy brain. The alpha4 and alpha7 but not the alpha3 nAChR protein levels were significantly increased in the temporal cortex of smoking (SC) compared with non-smoking controls (NSC). The alpha4-protein level was significantly higher in the temporal cortex of smoking AD (SAD) patients compared with non-smoking AD (NSAD). No changes in the alpha3, alpha4 or alpha7 subunits protein level were found in the hippocampus in any of the smoking groups. For both SADs and NSADs the protein levels for the alpha3 and alpha4 in temporal cortex and hippocampus and alpha7 in the hippocampus were significantly lower compared with non-smoking controls. No significant differences in alpha4 and alpha7 mRNA levels were detected in the hippocampus or temporal cortex of smokers compared with non-smokers. In conclusion this study showed an increased level of alpha4 and alpha7 nAChRs subunits in the temporal cortex of SC compared with NSC. This up-regulation was also seen in SAD although the protein levels of nAChR subunits were still lower in smoking AD brain compared with the NSC. The up-regulation of nAChRs in smoking groups and the loss of these receptors in AD patients were not correlated to any changes at the mRNA level suggesting that these changes may reflect post-transcriptional events.