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Biomedical subjects

Makoto Maemondo

Publications and source records attributed to Makoto Maemondo.

At least 19 recordsLinked to original sources
PubMed2006

Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations.

PURPOSE: This study was undertaken to investigate the efficacy and the feasibility of gefitinib for chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: The EGFR gene status in various tumor samples obtained from chemotherapy-naïve advanced NSCLC patients was examined by DNA sequencing of EGFR exons 18 to 23. Patients harboring EGFR mutations received gefitinib (250 mg/d) alone. The response rate, progression-free survival (PFS), and toxicity profile were assessed prospectively. RESULTS: Between June 2004 and October 2005, 75 patients were examined for the EGFR status, and 25 patients (33%) harbored EGFR mutations. EGFR mutations were significantly frequent in females (P < .01) and never or light smokers (P < .001). Sixteen patients with EGFR mutations were enrolled onto the study. The overall response rate in these patients was 75% (95% CI, 54% to 96%), and the disease control rate was 88% (95% CI, 71% to 100%). The median PFS time of these patients was 9.7 months (95% CI, 7.4 to 9.9 months). No life-threatening toxicity was observed. CONCLUSION: Treatment with gefitinib alone for chemotherapy-naïve NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity. To assess the proper timing of gefitinib in such patients, a subsequent randomized trial comparing gefitinib with standard chemotherapy is warranted.

Adult↗
PubMed2006

Acute-onset sarcoidosis with erythema nodosum and polyarthralgia (Löfgren's syndrome) in Japan: a case report and a review of the literature.

Löfgren's syndrome is an acute form of sarcoidosis that is characterized by erythema nodosum (EN), bilateral hilar lymphadenopathy (BHL), and polyarthralgia or polyarthritis. This syndrome is common among white people, but is considered rare among Japanese people. We present the case of a 26-year-old Japanese woman with Löfgren's syndrome. The patient complained of polyarthritis and EN of the lower extremities that lasted for 3 months. A chest radiograph revealed BHL and nodular shadows. The angiotensin-converting enzyme (ACE) level was within the normal range. Transbronchial lung biopsy revealed a noncaseating granuloma with giant cells. Six Japanese cases of Löfgren's syndrome have been reported previously. Five of the seven Japanese patients with Löfgren's syndrome had normal ACE levels; all of them exhibited BHL. Löfgren's syndrome should be considered as a possibility when examining a patient with EN and articular symptoms, even if the patient is Japanese.

Adult↗
PubMed2006

[A case of pulmonary Langerhans cell histiocytosis discovered by CT mass screening and followed by bronchoalveolar lavage].

A 42-year-old woman who had a cigarette index of 420 had many cavitary lesions predominantly in the upper areas of both lungs. The lesions were detected on a health examination using CT. Analysis with bronchofiberscopy showed increased CD1a positive cells in bronchoalveolar fluid (BALF). Histological examination by video-associated lung biopsy demonstrated that both S-100 and vimentin-positive cells were present in the peribronchial fibrotic lesions. From these data, this disease was diagnosed as pulmonary Langerhans cell histiocytosis (PLCH). Three months after the cessation of smoking, the cavity lesions disappeared. As the image findings improved, CD1a positive cells in BALF decreased (4.9% --> 1.8%) and the CD4/CD8 ratio in BALF increased (1.66 --> 6.16). So far, there is no report describing the time course of both CD1a positive cells and CD4/CD8 ratio in BALF after cessation of smoking in PLCH. These findings attract our interest on the PLCH.

Adult↗
PubMed2005

Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice.

NK4, a 4-kringle fragment of hepatocyte growth factor (HGF), is an HGF antagonist that also acts as an angiogenesis inhibitor. NK4 strongly inhibits the infiltration, metastasis, and tumor growth of pancreatic cancer. The aim of our study was to evaluate the antitumor effect of adenovirus-mediated NK4 gene transfer to the liver on hepatic metastasis of pancreatic cancer in vivo. We constructed recombinant adenoviral NK4 (Ad-NK4), which encodes a secreted form of human NK4. Intrasplenic injection of Ad-NK4 induced high and relatively maintained expression of NK4 protein in the liver and suppressed the number and growth of metastatic foci in the liver in a nude mouse model. Microscopically, central necrosis was found even in small metastatic foci in Ad-NK4 treated mice. Immunohistochemical analysis of metastatic tumors showed a remarkable decrease in microvessel density and an increase in the number of apoptotic tumor cells after treatment with Ad-NK4. These results indicate that intraportal injection of Ad-NK4 may be a useful therapeutic modality for the clinical control of hepatic metastasis in pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells.

Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.

Animals↗
PubMed2005

Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis.

We examined therapeutic gene transfer of human hepatocyte growth factor (hHGF) to alveolar septa in mouse bleomycin-induced lung fibrosis using macroaggregated albumin-polyethylenimine complex (MAA-PEI). Intravenous administration of MAA-PEI along with 1 microg pCAG.hHGF to C57BL/6 mice increased the uptake of plasmids into alveolar capillary endothelial cells and epithelial cells, prolonged hHGF expression in the lung, and induced a level of hHGF expression equal to that seen with 10 microg of hHGF-expression plasmids alone. The exogenous source of hHGF gene expression increased the endogenous mouse HGF in the lungs and significantly decreased TNF-alpha, IL-6, and collagen synthesis after bleomycin injury. Because GFP-labeled bone marrow-derived stem cells after bleomycin injury were reduced in number by HGF, the primary mechanism of HGF is likely to be the prevention of apoptosis, as has been suggested by in vitro experiments. This novel HGF gene transfer method to alveolar septa with nonstimulatory MAA-PEI conjugates may have promising clinical applications.

Albumins↗
PubMed2005

Suppression of peritoneal implantation of gastric cancer cells by adenovirus vector-mediated NK4 expression.

Peritoneal dissemination is the most common mode of metastasis in gastric cancer. We previously reported the importance of milky spots (MS), peritoneal lymphoid tissues, as selective sites of cancer implantation in peritoneal dissemination. In the present study, we first demonstrated that intraperitoneal injection of adenovirus vector encoding the GFP gene into tumor-free nude mice resulted in GFP expression at omental and mesenteric MS; MS macrophages were target cells for adenovirus infection. We confirmed that intraperitoneal injection of adenovirus vector encoding the NK4 gene (AdNK4) resulted in NK4 production localized to the peritoneal cavity, especially the omentum. Adenovirus vector-mediated MS-selective transgene expression was markedly impaired in tumor-bearing mice whose MS had already been replaced by infiltrating cancer cells. However, prior injection of AdNK4 successfully inhibited MS-selective cancer cell implantation, resulting in suppression of peritoneal dissemination and prolongation of survival. Adenovirus vector-mediated MS-selective delivery of a therapeutic gene may prevent peritoneal dissemination of gastric cancer.

Adenoviridae↗
PubMed2004

Gene therapy with secretory leukoprotease inhibitor promoter-controlled replication-competent adenovirus for non-small cell lung cancer.

Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLCs), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPI.E1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the cytomegalovirus (CMV) promoter that can selectively replicate only in NSCLC cells. Infection with AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a >100-fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24 cells). In contrast, neither E1A protein nor replication was detected in non-SLPI-producing HepG2 cells. Treatment with AdSLPI.E1AdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose-dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared with controls (A549, 57%, P < 0.02; H358, 67%, P < 0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMV.NK4 encoding NK4 protein, which has strong antiangiogenic activity. E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMV.NK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted in a more striking reduction of tumor growth compared with single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMV.NK4 may be a more effective gene therapy for NSCLC.

Adenoviridae↗
PubMed2004

Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts.

OX40 ligand (OX40L), the ligand for OX40 on activated CD4+ T cells, has adjuvant properties for establishing effective T-cell immunity, a potent effector arm of the immune system against cancer. The hypothesis of this study is that in vivo genetic engineering of tumor cells to express OX40L will stimulate tumor-specific T cells by the OX40L-OX40 engagement, leading to an induction of systemic antitumor immunity. To investigate this hypothesis, s.c. established tumors of three different mouse cancer cells (B16 melanoma, H-2b; Lewis lung carcinoma, H-2b; and Colon-26 colon adenocarcinoma, H-2d) were treated with intratumoral injection of a recombinant adenovirus vector expressing mouse OX40L (AdOX40L). In all tumor models tested, treatment of tumor-bearing mice with AdOX40L induced a significant suppression of tumor growth along with survival advantages in the treated mice. The in vivo AdOX40L modification of tumors evoked tumor-specific cytotoxic T lymphocytes in the treated host correlated with in vivo priming of T helper 1 immune responses in a tumor-specific manner. Consistent with the finding, the antitumor effect provided by intratumoral injection of AdOX40L was completely abrogated in a CD4+ T cell-deficient or CD8+ T cell-deficient condition. In addition, ex vivo AdOX40L-transduced B16 cells also elicited B16-specific cytotoxic T lymphocyte responses, and significantly suppressed the B16 tumor growth in the immunization-challenge experiment. All of these results support the concept that genetic modification of tumor cells with a recombinant OX40L adenovirus vector may be of benefit in cancer immunotherapy protocols.

Adenoviridae↗
PubMed2004

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model.

Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GB-d1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n=4, P<.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.

Adenoviridae↗
PubMed2003

N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers.

Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (deltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing deltaN Bax, and investigated the effects of the deltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell lines. deltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the deltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that deltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing deltaN Bax into A549 tumors in Balb/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that deltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.

Adenoviridae↗
PubMed2003

Severe acute interstitial pneumonia and gefitinib.

Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.

Adult↗
PubMed2002

Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor, and naive dendritic cells.

NK4, a 4-kringle antagonist of hepatocyte growth factor (HGF), is a potent inhibitor of tumor angiogenesis and functions independently of its HGF-antagonistic activity. We have shown previously that in vivo genetic modification of tumors with an adenovirus vector that expresses NK4 (AdNK4) restrains tumor angiogenesis and slows the rate of tumor growth in vivo. In the present study, we investigated the hypothesis that this can be made more efficient by also administering bone marrow-generated dendritic cells (DCs) to the tumor. The data show that the growth of mouse subcutaneous tumors is significantly suppressed by direct administration of DCs into established tumors that had been pretreated with AdNK4 3 days previously. The synergistic antitumor effect produced by the combination therapy of AdNK4 with DCs correlated with the in vivo priming of tumor-specific cytotoxic T lymphocytes. Analysis of mice treated with fluorescence-labeled DCs suggested that DCs injected into the flank tumor could migrate to lymphoid organs in vivo for activation of immune-relevant processes. Knockout mice experiments demonstrated that the tumor regression produced by this combination therapy depends on both major histocompatibility complex (MHC) class I antigen presentation of DCs injected into the tumors and CD8(+) T cells of the treated host. Finally, a mechanism for this synergism was suggested by the histological observation that tumor necrosis and apoptosis were induced by genetic engineering of the tumors to express NK4. These findings should be useful in designing novel strategies that use a combination of 2 monotherapies directed against the vascular and immune systems for cancer therapy.

Adenoviridae↗
PubMed2002

Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction.

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Angiogenesis Inducing Agents↗
PubMed2002

Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth.

Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H(2), which is immediately converted to bioactive prostanoids including PGE(2), PGD(2), thromboxane (TX)A(2) and PGI(2). To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA(2) synthase cDNA or PGI(2) synthase cDNA to colon-26 adenocarcinoma cells and subsequently inoculated each transformant to syngeneic BALB/c mice. Tumors derived from TXA(2) synthase transformants grew faster (280%, day 8, versus null-vector control; P < 0.05) and showed more abundant vasculature (204%, versus null-vector control; P < 0.01), whereas tumors from PGI(2) synthase transformants presented opposite effects. These effects by the transgenes were reversed by administration of specific inhibitors. These results suggest that the profile of downstream metabolites of cyclooxygenase in cancer cells can be a determinant for tumor development.

Adenocarcinoma↗
PubMed2002

Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy.

Hepatocyte growth factor (HGF) affects tumor growth/invasion and tumor neovascularization. A proposed HGF antagonist, NK4 (an amino-terminal kringle-domain peptide of HGF), inhibits tumor growth/invasion through the competition of HGF binding to its receptor, c-Met, and acts as an angiogenesis inhibitor. To investigate the in vivo effect of NK4 gene transfer, we constructed an adenovirus vector expressing human NK4 (AdCMV.NK4). Human lung cancer cell lines (A549 and H358) infected in vitro with AdCMV.NK4 yielded NK4 protein without a change in the cell growth rate. In contrast, direct injection of AdCMV.NK4 (1 x 10(9) pfu, twice) into established subcutaneous tumors in BALB/c nu/nu mice resulted in suppression of the tumors by 64% for A549 or by 91% for H358 compared with controls (P<0.02 or P<0.01, respectively). Counting of the tumor vessels revealed suppressed vascularity by 57% in H358 tumors when using AdCMV.NK4 (P<0.0001). Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P<0.032), subcutaneous tumor growth in vivo (by 65% for H358, P<0.001), and hematogenous lung metastases without obvious side effects. These results indicate that NK4 elicits tumor-growth suppression in vivo through its anti-angiogenic activity and anti-HGF activity and that NK4 gene transfer can be an effective tool in the treatment of cancer.

Adenoviridae↗
PubMed2002

Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas.

Hepatocyte growth factor (HGF) is involved in malignant behavior of cancers as a mediator of tumor-stromal interactions, facilitating tumor invasion and metastasis. We have investigated whether a blockade of HGF using recombinant NK4, an HGF antagonist, would lead to growth inhibition of the human gastric carcinoma cell line, TMK1. To evaluate the function of endogenous NK4 and investigate its potential inhibitory effect, TMK1 cells were transfected with NK4 plasmid. After selection, NK4-expressing cells (T11) were obtained, and cell growth was evaluated. Significant growth inhibition was observed in the T11-group compared to the control both in vitro and in vivo. Moreover, we investigated the effect of exogenous NK4 transferred by an adenovirus vector (AdCMV.NK4). Cell proliferation of AdCMV.NK4 infected TMK1 cells was significantly inhibited compared with the control group. We also assessed the in vivo tumor suppression effect of AdCMV.NK4. The tumor volume following treatment with AdCMV.NK4 was significantly inhibited compared to that of the control group. These findings indicate that NK4 gene expression has a potential role in controlling proliferation of cancer cells. In conclusion, NK4 is a promising therapeutic agent and its gene delivery may be a new approach to treating patients with advanced gastric cancer.

Adenoviridae↗