E1B-55 kDa-defective adenoviruses activate p53 in mesothelioma and enhance cytotoxicity of anticancer agents.

INTRODUCTION: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.

Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners.

INTRODUCTION: We examined whether zoledronic acid (ZOL), the third generation of bisphosphonates, produced cytotoxic effects on human mesothelioma cells in vitro and in vivo, and investigated a possible involvement of p53, Ras, and extracellular signal-regulated kinase1/2 (ERK1/2) pathways. METHODS: Cytotoxicity and cell cycles were assessed with a colorimetric assay and flow cytometry, respectively. Expression levels of apoptosis-linked proteins and prenylation of small guanine-nucleotide-binding regulatory proteins were tested with p53-small interfering RNA, an ERK kinase1/2-inhibitor, and prenyl alcohols. The antitumor activity was examined in an orthotopic animal model. RESULTS: ZOL treatments suppressed growth of mesothelioma cells bearing the wild-type p53 gene through apoptosis induction accompanied by activation of caspases, or S-phase arrest by up-regulated cyclin A and B1. ZOL induced p53 phosphorylation and subsequent activation of the downstream pathways. Down-regulated p53 expression with the small interfering RNA, however, showed that both apoptosis and S-phase arrest were irrelevant to the p53 activation. Geranylgeranyl but not farnesyl pyrophosphate inhibited ZOL-induced apoptosis and S-phase arrest, and the geranylgeraniol supplement decreased ZOL-mediated Rap1A but not Ras unprenylation. Inhibition of ERK1/2 pathways suppressed ZOL-induced apoptosis but not S-phase arrest. We further demonstrated that ZOL, administrated intrapleurally, inhibited the tumor growth in the pleural cavity. CONCLUSIONS: These data indicate that ZOL induces apoptosis or S-phase arrest, both of which are independent of p53 activation and Ras unprenylation, and suggest that ZOL is a possible therapeutic agent to mesothelioma partly through non-Ras- and ERK1/2-mediated pathways.

Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma.

Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and therefore novel therapies are required. We previously reported that overexpression of the FUSE-binding protein-interacting repressor (FIR), a c-myc transcriptional repressor, induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/ΔF/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/ΔF/FIR and a fusion gene deleted non-transmissible Sendai virus vector encoding green fluorescent protein (SeV/ΔF/GFP) were prepared. The transduction efficiency of these agents in terms of dose-dependent cytotoxicity and/or apoptosis induction was then assessed in a few HMPM cells. Combination therapy with SeV/ΔF/FIR plus cisplatin was evaluated in vitro and in a mouse model. SeV/ΔF/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/ΔF/FIR cytotoxicity was partly due to apoptosis induction via c-Myc suppression. In addition, SeV/ΔF/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H. Moreover, combination therapy with SeV/ΔF/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model. Combination therapy with SeV/ΔF/FIR plus cisplatin has therapeutic potential against HMPM. SeV/ΔF/FIR plus cisplatin will be an attractive modality against HMPM in the future.

[Case of disseminated tuberculosis complicated with tuberculous meningitis while investigating an abdominal lymphadenopathy].

In February 2005, a 33-year-old man visited A hospital complaining of fever. The blood screening test revealed the liver dysfunction, then computed tomography showed swelling of abdominal lymph nodes. In April, headache and disorientation appeared. He was diagnosed as disseminated tuberculosis and tuberculous meningitis based on chest X-ray and computed tomography findings and examination of cerebrospinal fluid. After admission to our hospital, anti-tuberculous drugs were prescribed, but the cerebral infarction happened. The disturbance of consciousness and the left half of his body paralysis appeared. They did not improve and hydrocephalus was complicated in August, though he was treated by steroids. He needed all helps because of the left half of his body paralysis and an advanced sequelae was left. It was thought that the abdominal lymph adenopathy preceded as one of symptoms of the disseminated tuberculosis in this case. It is said to be rare that abdominal lymph node swelling is seen in the early stage of disseminated tuberculosis. But, we think that it is necessary to keep in mind that the possibility of disseminated tuberculosis as one of the diseases in differential diagnosis, when we examine enlargement of abdominal lymph nodes with symptoms suggesting the presence of infection such as fever.

[Clinical review of patients with pulmonary tuberculosis who were detected by the screening of homeless persons admitted in the shelter facilities].

PURPOSE AND METHODS: There has been a recent increase in the number of non-profit facilities that provide shelter for the homeless. These social service facilities aim to assist the social rehabilitation of homeless persons. The Public Health Center of Chiba City screened 1,054 residents of these homeless shelters between November 2002 and August 2004 and found 17 individuals (1.6%) with active pulmonary tuberculosis. We clinically reviewed these cases. RESULTS: All 17 individuals were male, and their ages ranged from 44 to 70 years (mean 54.9 years). Four cases were smear positive and three cases were smear negative but culture positive by sputum examination for acid-fast bacilli. Nine cases had cavitary lesions on chest X-ray. There were three cases complicated with hepatitis C, two cases with diabetes mellitus and two cases with past history of gastrectomy. Of the 17 individuals, 13 were treated as inpatients, and four as outpatients. The mean hospitalization duration was 146.7 days excluding two patients who were discharged by themselves. Of the 11 inpatients, four remained hospitalized until the completion of treatment. Final outcome of the treatment was the following; 12 patients were cured, while five patients dropped out or discontinued treatment. CONCLUSION: The screening performed by the Public Health Center of Chiba City revealed a very high prevalence of tuberculosis among shelter residents. Thus, in the future, public health centers and medical institutions must work in collaboration to actively screen and provide treatment for residents of homeless shelters. This study also revealed that in spite of recommended hospitalization or long-term treatment, patients often self-discharged or discontinued regular outpatient treatment. Health centers and other public agencies must therefore work in close cooperation to help the homeless to continue hospitalization and subsequent medication and treatment even after their discharge from hospital.