Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic ...resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties.
Summary
Background
Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC).
Aim
To determine the maximum tolerated dose (MTD) of the oral ...mTOR inhibitor everolimus in advanced HCC patients.
Methods
Patients with locally advanced or metastatic HCC (Child‐Pugh class A or B) were enrolled in an open‐label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose‐escalation design. MTD was based on the rate of dose‐limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified.
Results
Thirty‐nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)‐seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg‐seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively.
Conclusions
The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti‐viral therapy should be mandatory for HBsAg‐seropositive patients (ClinicalTrials.gov NCT00390195).
Summary
Background: Radiographic measurements do not always reflect the biological response of hepatocellular carcinoma to drug therapy.
Aims: To evaluate the clinical implications of tumour marker ...(α‐fetoprotein) response in advanced hepatocellular carcinoma patients with thalidomide treatment.
Patients and methods: Forty‐two advanced hepatocellular carcinoma patients with baseline α‐fetoprotein levels above 200 ng/mL and thalidomide therapy were included. Serum α‐fetoprotein levels were measured every 4 weeks. α‐fetoprotein response was defined as a 50% or greater reduction of α‐fetoprotein levels for 4 or more weeks during treatment. Radiographic response was assessed by World Health Organization criteria; survivals were estimated by Kaplan–Meier method and prognostic factors were assessed by Cox's proportional hazard model.
Results: With intention‐to‐treat analysis, radiographic response and α‐fetoprotein response were obtained in 7% (three of 42, 95% confidence interval: 0–15) and 24% (10 of 42, 95% CI: 10–38) of patients, respectively. All radiographic response was observed in α‐fetoprotein responders. Multivariate analyses showed α‐fetoprotein response was independent prognostic factor for both progression‐free survival (relative risk = 0.394, 95% CI: 0.189–0.820, P = 0.013) and overall survival (relative risk = 0.241, 95% CI: 0.096–0.606, P =0.003), whereas radiographic response was not.
Conclusion: α‐fetoprotein response can more accurately reflect the biological response of advanced hepatocellular carcinoma to thalidomide therapy than radiographic response.
Quality of life (QOL) was studied in gastric cancer patients treated on a randomised, controlled trial comparing D1 (level 1) with D3 (levels 1, 2 and 3) lymphadenectomy. A total of 221 patients were ...randomly assigned to D1 (n=110) and D3 (n=111) surgery. Quality-of-life assessments included functional outcomes (a 14-item survey about treatment-specific symptoms) and health perception (Spitzer QOL Index) was performed before and after surgery at disease-free status. Patients suffered from irrelative events such as loss of partners was excluded thereafter. Main analyses were done by intention-to-treat. Thus, 214 D1 (106/110=96.4%) and D3 (108/111=97.3%) R0 patients were assessed. Longitudinal analysis showed that functional outcomes decreased at 6 months after surgery and increased over time thereafter, while health perceptions increased over time in general. On the basis of linear mixed model analyses, patients having total gastrectomy, advanced cancer and hemipancreaticosplenectomy, but not complications had poorer QOL than those without. D1 and D3 patients showed no significant difference in QOL. The results suggest that changes of QOL were largely due to scope of gastric resection, disease status and distal pancreaticosplenectomy, rather than the extent of lymph node dissection. This indicates that nodal dissection can be performed for a potentially curable gastric cancer.
Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. ...This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.
This study examined whether mesenchymal stem cells (MSCs), which are stem cells originated from embryonic mesoderm, are able to differentiate into functional hepatocyte‐like cells in vitro. MSCs were ...isolated from human bone marrow and umbilical cord blood, and the surface phenotype and the mesodermal multilineage differentiation potentials of these cells were characterized and tested. To effectively induce hepatic differentiation, we designed a novel 2‐step protocol with the use of hepatocyte growth factor and oncostatin M. After 4 weeks of induction, cuboidal morphology, which is characteristic of hepatocytes, was observed, and cells also expressed marker genes specific of liver cells in a time‐dependent manner. Differentiated cells further demonstrated in vitro functions characteristic of liver cells, including albumin production, glycogen storage, urea secretion, uptake of low‐density lipoprotein, and phenobarbital‐inducible cytochrome P450 activity. In conclusion, human MSCs from different sources are able to differentiate into functional hepatocyte‐like cells and, hence, may serve as a cell source for tissue engineering and cell therapy of hepatic tissues. Furthermore, the broad differentiation potential of MSCs indicates that a revision of the definition may be required. (HEPATOLOGY 2004;40:1275–1284.)
Two overlapping cDNA clones encoding human DNA topoisomerase II were identified by two independent methods. In one, a human cDNA library in phage λ was screened by hybridization with a mixed ...oligonucleotide probe encoding a stretch of seven amino acids found in yeast and Drosophila DNA topoisomerase II; in the other, a different human cDNA library in a λ gt11 expression vector was screened for the expression of antigenic determinants that are recognized by rabbit antibodies specific to human DNA topoisomerase II. The entire coding sequences of the human DNA topoisomerase II gene were determined from these and several additional clones, identified through the use of the cloned human TOP2 gene sequences as probes. Hybridization between the cloned sequences and mRNA and genomic DNA indicates that the human enzyme is encoded by a single-copy gene. The location of the gene was mapped to chromosome 17q21-22 by in situ hybridization of a cloned fragment to metaphase chromosomes and by hybridization analysis with a panel of mouse-human hybrid cell lines, each retaining a subset of human chromosomes.
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