Reemerging murine typhus, Japan.
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Antibodies, Bacterial↗
Biomedical subjects
Saburo Sone
Publications and source records attributed to Saburo Sone.
[Molecule based diagnosis].
Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.
Antineoplastic Agents↗
[Anti angiogenesis].
Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets. Further development of new strategies involving such novel cancer therapies requires wide reaching development of translational research abilities. However, for moving new therapies into the clinic same rigorous criteria need to be applied as is done for traditional therapies. Angiogenesis appear to be a critical factor for development of prostate, gastric, lung and breast cancers. Development of new anti-angiogenic treatment modalities might become very important in these diseases. A critical requirement for the successful clinical development will be the development of imaging techniques that can help evaluate the effect on blood vessel functionality. Such surrogate markers of anti-angiogenic effect will be essential for optimising molecules and doses.
Angiogenesis Inhibitors↗
[Molecular-target drug].
Cancer metastasis involves the complicated steps of tumor growth, angiogenesis, invasion and adhesion. At present new drugs targeting particular molecule (s) responsible for such cancer progression and metastasis have been developed in clinics. Major endpoints for cancer treatment should be prolongation of survival and maintenance of QOL. However, clinical development of such molecular-target based drugs is associated with difficulties in evaluating the efficacy in phase I/II studies prior to entering phase III study, because many of the targeted drugs seem cytostatic rather than cytocidal to tumors. New approaches incorporating technologies of genomics and proteomics may provide an expanding repertoire of molecular targeted therapeutics for clinical evaluation. In this review, the significance and problems of biomarkers available for clinical evaluation of molecular targeted drugs are discussed.
Angiogenesis Inhibitors↗
Combined therapy with a new bisphosphonate, minodronate (YM529), and chemotherapy for multiple organ metastases of small cell lung cancer cells in severe combined immunodeficient mice.
PURPOSE: Lung cancer in the advanced stage frequently metastasizes to multiple organs, including the liver, lungs, lymph nodes, and bone. Bisphosphonates have been widely used to treat osteolytic bone metastasis in the past years; however, many studies have implicated that a single use of bisphosphonates could not prolong the survival of patients. In the present study, using a multiple-organ metastasis model of human lung cancer cells, we examined the effect of combined therapy with a new bisphosphonate (YM529) and etoposide (VP-16). EXPERIMENTAL DESIGN: Human small cell lung cancer (SBC-5) cells i.v. inoculated into natural killer cell-depleted severe combined immunodeficient mice metastasized to multiple organs, including the lungs, liver, kidneys, lymph nodes, and bone. SBC-5-bearing mice were treated with YM529 and/or VP-16 and sacrificed 5 weeks after tumor cell inoculation. Bone metastasis was assessed by X-ray photographs, and visceral metastasis was evaluated macroscopically. The number of osteoclasts in the bone lesions was examined by tartrate-resistant acid phosphatase staining. RESULTS: Monotherapy with YM529 suppressed the production of bone metastases, but not visceral metastasis. Histological analyses revealed that the number of osteoclasts in bone lesions was lower in YM526-treated mice, compared with control mice. VP-16 inhibited both bone metastasis and visceral (lung and liver) metastasis. However, neither YM529 alone nor VP-16 alone significantly prolonged the survival of SBC-5-bearing mice. Combined use of YM529 and VP-16 further inhibited the production of bone metastasis and significantly prolonged survival. CONCLUSIONS: Combined therapy with bisphosphonate and chemotherapy may be useful for small cell lung cancer patients with multiple organ metastases including bone metastasis.
Animals↗
CD13/aminopeptidase N in collagen vascular diseases.
To determine the significance of CD13/aminopeptidase N in collagen vascular diseases (CVD), we examined its activity and expression in sera and disease sites of patients with CVD. Significantly higher aminopeptidase activity was detected in bronchoalveolar lavage fluid from patients with interstitial lung diseases due to rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), systemic sclerosis (SSc), and Sjögren's syndrome than from control subjects. Increased aminopeptidase activity and increased expression of CD13/aminopeptidase N protein were found in alveolar macrophages from CVD patients with interstitial lung diseases. Significantly higher aminopeptidase activity was detected in pleural effusions from patients with systemic lupus erythematosus (SLE) than in transudate effusions. The mean aminopeptidase activity in synovial fluids from RA patients was significantly higher than from patients with osteoarthritis. The mean value of serum aminopeptidase activity was significantly higher in patients with SLE, RA, SSc, and PM/DM than in normal subjects. This study suggests that the activity of CD13/aminopeptidase N, locally produced in the disease site, is a useful marker for CVD and that CD13/aminopeptidase N may have an important role in the pathogenesis of CVD.
Adult↗
Stimulation of human bronchial epithelial cells by IgE-dependent histamine-releasing factor.
An IgE-dependent histamine-releasing factor (HRF p23; also known as translationally controlled tumor protein or p23) stimulates the release of histamine, IL-4, and IL-13 from a subpopulation of highly allergic donor basophils. It has also been shown to act as a chemoattractant for eosinophils. To elucidate novel functions of HRF p23 in airway inflammation, we examined the effects of human recombinant HRF p23 (hrHRF) on bronchial epithelium and found that hrHRF stimulated the secretions of IL-8 and granulocyte/macrophage colony-stimulating factor by both primary cultures of human bronchial epithelial cells and BEAS-2B cells. In response to hrHRF, these cells induced IL-8 mRNA expression within 4 h. H2O2, but not IL-1 beta or tumor necrosis factor-alpha, stimulated secretion of HRF p23 by BEAS-2B cells, suggesting that oxidative stress may trigger the release of HRF p23 from bronchial epithelial cells. Bronchoalveolar lavage (BAL) from healthy volunteers contained only trivial or undetectable amounts of HRF p23. Significantly higher amounts of HRF p23 were recovered from BAL fluid taken from asthmatic patients, and the amounts of HRF p23 were further elevated in patients with idiopathic eosinophilic pneumonia. Our results demonstrate for the first time that HRF p23 can stimulate nonimmune epithelium. HRF p23 derived from bronchial epithelial cells may regulate complex cytokine networks in eosinophil-dependent inflammation of the human airway.
Biomarkers, Tumor↗
[Non-small cell lung cancer: 1) Molecular-target therapy].
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Antibodies, Monoclonal↗
[Bridging between molecular biology and clinical aspect of respiratory tract diseases: discussion].
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Biomarkers↗
A peptide mimetic of human interferon (IFN)-beta.
Type I interferons (IFNs) are cytokines that are used clinically as antiviral and antitumour agents. The interaction of IFNs with their heterodimeric type I IFN receptor comprised of IFNAR1 and IFNAR2 is a first step to inducing biological actions. Here, we describe the successful mimicry of IFN-beta by a peptide isolated by phage-display screening using a neutralizing anti-IFN-beta monoclonal antibody. The 15-mer peptide, designated SYR6, was shown to compete with IFN-beta for binding to type I IFN receptor in a concentration-dependent manner, and was shown to elicit antiviral activity on cultured cells. This antiviral activity was not eliminated in the presence of neutralizing monoclonal antibodies to IFN-alpha, -beta and -gamma, and a low concentration of soluble type I IFN receptor, suggesting that it was not due to IFN contamination or the induction of endogenous IFNs by SYR6. This peptide might be a potent agonist to provide a mechanism of activating heterodimeric cytokine receptors.
Amino Acid Sequence↗
A third-generation matrix metalloproteinase (MMP) inhibitor (ONO-4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP-expressing tumor cells in nude mice.
The lung is the common target organ of hematogenous metastasis that restricts the prognosis of cancer patients. MMPs play a pivotal role in metastasis by promoting tumor invasion and angiogenesis; therefore, a large number of MMPIs have been developed. Our purpose was to determine the therapeutic efficacy of a selective-spectrum MMPI, ONO-4817 (inhibits MMP-2 and MMP-9 but not MMP-1), against established lung micrometastasis in combination with a cytotoxic anticancer drug, DOC, in a nude mouse model. Human non-small cell lung cancer PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells, expressing MMP-2, MMP-9 and/or MMP-1, were injected i.v. into nude mice on day 0. Mice received a single injection of DOC on day 7 (after establishment of micrometastasis) and/or ONO-4817 mixed with food from day 7 to the end of experiments. Monotherapy with ONO-4817 or DOC inhibited formation of lung metastasis by PC14PE6 and H226 cells. In addition, combined use of ONO-4817 with DOC significantly suppressed the tumor burden of H226 and PC14PE6 cells in the lung and prolonged the survival of PC14PE6-bearing mice compared to ONO-4817 or DOC alone. These therapies did not affect the body weight or food intake of tumor-bearing mice. FIZ revealed that lung lesions, but not nontumor parenchyma of the lung, expressed gelatinolytic activity and that treatment with ONO-4817 abrogated the gelatinolytic activity in lung lesions. These results suggest that the combined use of MMPIs with cytotoxic anticancer drugs may be helpful in the control of established lung micrometastasis by tumor cells expressing MMPs.
Adenocarcinoma↗
[Molecular targetting therapy for non-small-cell lung neoplasms with EGF-R inhibitors].
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Antibodies, Monoclonal↗
A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice.
In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung, liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529 after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesions in vivo, but had no effect on the proliferation or cytokine production of SBC-5 cells in vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day 1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging the survival of small-cell lung cancer patients with multiple-organ metastasis.
Animals↗
Increased macrophage inflammatory protein-1alpha and -1beta in BAL fluid of bronchiolitis obliterans organizing pneumonia.
OBJECTIVE: CC chemokines are mainly chemotactic for monocytes and lymphocytes. The aim of this study was to evaluate the involvement of the CC chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in the pathogenesis of bronchiolitis obliterans organizing pneumonia (BOOP). METHODOLOGY: The concentrations of MIP-1alpha and MIP-1beta in BAL fluid (BALF) obtained from patients with BOOP (n = 13) and control patients (CP, n= 18) were measured by enzyme-linked immunosorbent assay. RESULTS: MIP-1alpha in BALF was significantly higher in patients with BOOP (mean +/- SD; 123.8 +/- 98.0 pg/mL) than in CP (62.5 +/- 46.1 pg/mL). Significantly higher MIP-1beta was also detected in patients with BOOP (51.6 +/- 72.5 pg/mL) than in CP (6.4 +/- 3.7 pg/mL). The concentration of MIP-1alpha significantly correlated with the percentage of lymphocytes in BALF, and the concentration of MIP-1beta significantly correlated with the numbers of lymphocytes, neutrophils and eosinophils in BALF. Both MIP-1alpha and MIP-1beta in BALF were decreased after corticosteroid therapy and this was accompanied by decreased lymphocytes in BALF. CONCLUSION: This study suggests that MIP-1alpha and MIP-1beta may play important roles in the recruitment of immuno-inflammatory cells into the lungs, and may contribute to the pathogenesis of BOOP.
Adrenal Cortex Hormones↗
Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules.
We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.
Angiogenesis Inducing Agents↗
Soluble Fas in malignant pleural effusion and its expression in lung cancer cells.
Soluble Fas (sFas) has the ability to block Fas-mediated apoptosis, suggesting that sFas at tumor sites might inhibit tumor cell-killing by immune effector cells. We examined the sFas level in pleural effusion associated with lung cancer. The level of sFas in malignant pleural effusion was significantly higher than those in transudate and tuberculous pleural effusion. There was no significant difference in the sFas concentration among various histological types of lung cancer. The cytotoxicity mediated by anti-Fas agonistic antibody against Jurkat cells was inhibited by the addition of malignant pleural effusion, being inversely correlated with the sFas concentration. When Fas expression was examined using flow cytometry, eight of ten (80%) lung cancer cell lines expressed cell surface Fas. On the other hand, sFas protein and mRNA were detected in six of ten (60%) lung cancer cell lines, but there was no correlation between Fas and sFas expression. Furthermore, although the expressions of Fas and sFas were clearly detected in tumor cells derived from malignant effusion, the sFas expression was down-regulated in an in vitro culture. These results suggest that sFas in malignant pleural effusion is at least in part produced by lung cancer cells, and might play a role in local immunosuppression by tumor cells.
Actins↗
A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ("Iressa").
Bronchioloalveolar carcinoma (BAC), a form of pulmonary adenocarcinoma, presents unique clinical features, such as endobronchial spread and bronchorrhea in advanced stages. The prognosis for BAC patients in advanced stages is poor, as is the case for patients with other non-small-cell lung cancer (NSCLC) types, because of low susceptibility to conventional chemotherapy. Recently, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), ZD1839 ("Iressa"), has been investigated in phase II clinical studies (IDEAL 1 and IDEAL 2) as monotherapy against chemotherapy-refractory NSCLC, and provided clinically significant antitumor activity. In this study, we examined the therapeutic efficiency of ZD1839 in chemotherapy-refractory BAC patients with bronchorrhea. Two female BAC patients with bronchorrhea were treated once daily with ZD1839 (250 mg/day). In both cases, serous sputum production was dramatically reduced within 3 days of starting the treatment, and hypoxia and radiographic signs of bilateral lung consolidation were visibly improved within 7 days. Following more than 8 months of treatment, no evidence of recurrence or severe adverse events has been observed. These results suggest that this selective EGFR-TKI, ZD1839, may be a powerful agent for treatment of chemotherapy-refractory BAC patients with bronchorrhea.
Adenocarcinoma, Bronchiolo-Alveolar↗
Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules.
Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in preclinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.
Angiogenesis Inhibitors↗