Cytokines and molecular therapy最新文献_第5页

Formulation and antitumor efficacy of liposomal-caprylated-TNF-SAM2. 脂质体-巯基化- tnf - sam2的制备及抗肿瘤疗效。

Cytokines and molecular therapy Pub Date : 1995-09-01

K Akimaru, E Auzenne, Y Akimaru, M E Leroux, A C Hayman, T Utsumi, G Soma, J Klostergaard

{"title":"Formulation and antitumor efficacy of liposomal-caprylated-TNF-SAM2.","authors":"K Akimaru, E Auzenne, Y Akimaru, M E Leroux, A C Hayman, T Utsumi, G Soma, J Klostergaard","doi":"","DOIUrl":"","url":null,"abstract":"The tumor necrosis factor (TNF) mutant TNF-SAM2 has previously been shown to have a therapeutic profile superior to parental TNF. To initially evaluate the characteristics of liposomal formulations of TNF-SAM2, it was modified with the N-hydroxysuccinimide ester of caprylic acid to increase its hydrophobic binding to multilamellar and small unilamellar vesicles (MLVs and SUVs). Native PAGE and fluorescamine analysis of acetylated parental TNF and TNF-SAM2 indicated that these proteins both displayed trimeric structures based on crosslinking/SDS-PAGE analysis and behaved similarly with respect to reactivity of their amino functions. Limited N-terminal sequencing analysis of partially acetylated (approx 3 acetyl groups per trimer) TNF-SAM2 indicated that the N-terminal Val was not modified; this was also concluded based on HPLC/mass spectrometric (LC-MS) analysis of Glu C digests. LC-MS analysis of tryptic digests of the acetylated TNF-SAM2 indicated that Lys-98 was unreactive. Molecular ions corresponding to acetylated Lys-containing peptides for all five other Lys residues could be detected; none appeared hyperreactive, but Lys-11 appeared hyporeactive. MLVs composed of DMPC/DMPG (7:3) and SUVs composed of DPPC/DSPC (1:1) displayed high capacity for binding to caprylated TNF-SAM2. These formulations of caprylated TNF-SAM2 displayed tumor necrotizing and growth-inhibitory activity in a syngeneic tumor model, and may be candidates for clinical development.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"197-210"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of vindesine and doxorubicin resistance in multidrug-resistant pleural mesothelioma cells by tumor necrosis factor-alpha. 肿瘤坏死因子- α调节多药耐药胸膜间皮瘤细胞的长春地西和阿霉素耐药。

Cytokines and molecular therapy Pub Date : 1995-06-01

T Licht, M Lübbert, C Martens, K J Bross, H H Fiebig, R Mertelsmann, F Herrmann

{"title":"Modulation of vindesine and doxorubicin resistance in multidrug-resistant pleural mesothelioma cells by tumor necrosis factor-alpha.","authors":"T Licht, M Lübbert, C Martens, K J Bross, H H Fiebig, R Mertelsmann, F Herrmann","doi":"","DOIUrl":"","url":null,"abstract":"Tumor necrosis factor-alpha (TNF-alpha) has been shown to enhance the cytotoxicity of a variety of antineoplastic agents. To examine whether multidrug-resistant cells are targets of TNF-alpha, and whether TNF-alpha is capable of modulating chemoresistance of these cells, a pleural mesothelioma cell line (PXF1118L) and two multidrug-resistant sublines thereof were used as experimental models. Drug resistance of these cells was due to P-glycoprotein expression, as confirmed by (1) staining with a monoclonal antibody (MRK16) specific for human P-glycoprotein, (2) decreased accumulation of [3H]vinblastine that was reversed by verapamil, and (3) enhanced cytotoxicity of vindesine in the presence of verapamil. Parental and multidrug-resistant cells exhibited little but comparable sensitivity to TNF-alpha alone. Combining TNF-alpha with vindesine or, to a lesser extent, with doxorubicin, but not with cisplatin, resulted in greater cytotoxicity towards multidrug-resistant cells than seen for each compound alone, indicating a synergism. In contrast, TNF-alpha failed to modulate vindesine or doxorubicin cytotoxicity in parental cells. [3H]Vinblastine accumulation was unaffected by TNF-alpha, and chemoresistance was reduced by TNF-alpha also in the presence of verapamil (10 microM), indicating that TNF-alpha was acting in a way different from calcium-channel blockers. Though the molecular mechanism by which TNF-alpha was enhancing vindesine and doxorubicin cytotoxicity remained undefined in this study, the numbers of TNF-alpha binding sites on parental and on multidrug-resistant cells were similar, and P-glycoprotein expression was unmodulated during the entire 48 h incubation period. In conclusion, we show that TNF-alpha increases the cytotoxicity of anticancer drugs in multidrug-resistant tumor cells by a mechanism that differs from most chemosensitizing agents, including verapamil. Further studies will be needed to clarify the mechanism by which TNF-alpha synergizes with anticancer drugs.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 2","pages":"123-32"},"PeriodicalIF":0.0,"publicationDate":"1995-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The TNF ligand superfamily and its relevance for human diseases. TNF配体超家族及其与人类疾病的相关性

Cytokines and molecular therapy Pub Date : 1995-06-01

H J Gruss, S K Dower

{"title":"The TNF ligand superfamily and its relevance for human diseases.","authors":"H J Gruss, S K Dower","doi":"","DOIUrl":"","url":null,"abstract":"The tumor necrosis factor (TNF) receptor superfamily comprises 10 different members of type I integral membrane glycoproteins with characteristic limited sequence homology for the extracellular cysteine-rich repeats. A parallel existing TNF ligand superfamily has been discovered by cloning of ligands for all of the TNF receptor superfamily members. These molecules are type II membrane glycoproteins, with the exception of LT-alpha, which is the only secreted protein of the family. TNF and CD95L also exist in biologically active shed soluble form. The TNF ligand superfamily presently contains nine different proteins. In addition, the NGFR p75 binds to a second family of proteins. These NGF-like dimeric soluble molecules are basic neurotrophic factors, and the five members are not related to the TNF superfamily ligands. The TNF-like ligands share some common biological activities, but other activities appear to be shared only by some ligands or are unique. The diverse biological effects mediated through the interaction of the members of the TNF receptor and ligand superfamilies have provided information on the regulation of cellular activation, including the involvement of T-cell-dependent immune responses as well as associations with human diseases.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 2","pages":"75-105"},"PeriodicalIF":0.0,"publicationDate":"1995-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine-receptor therapy. 抗细胞因子和抗细胞因子受体治疗对实验性癌症恶病质的抑制作用。

Cytokines and molecular therapy Pub Date : 1995-06-01

G Strassmann, T Kambayashi

引用次数: 0

Clinical and immunological follow-up of patients with AIDS-associated Kaposi's sarcoma treated with an anti-IL-6 monoclonal antibody. 抗il -6单克隆抗体治疗艾滋病相关卡波西肉瘤患者的临床和免疫随访

Cytokines and molecular therapy Pub Date : 1995-06-01

E Racadot, B Audhuy, H Duvernoy, A Thyss, J M Lang, J Wijdenes, P Hervé

{"title":"Clinical and immunological follow-up of patients with AIDS-associated Kaposi's sarcoma treated with an anti-IL-6 monoclonal antibody.","authors":"E Racadot, B Audhuy, H Duvernoy, A Thyss, J M Lang, J Wijdenes, P Hervé","doi":"","DOIUrl":"","url":null,"abstract":"Ten AIDS patients with Kaposi's sarcoma (four in stage II A, four in stage III A, one in stage III B and one in stage IV of the disease) were treated for 14 days with B-E8, an anti-IL-6 monoclonal antibody (IgG1), at a daily dose of 10 mg. No side-effects were observed, but no patients experienced a complete or partial response. No modification was noted in the analysis of lymphocyte subsets, except for a transient decline in the number of cells expressing CD56, accompanied by altered NK activity in four of the seven evaluable patients. Anti-IL-6 mAb prevented the binding of IL-6 to its cell membrane receptor, as documented by the decline in C reactive protein levels. However, anti-IL-6 mAb induced the circulation of significant amounts of IL-6, probably in the form of monomeric immune complexes. The sera, analysed on B9 cell line, demonstrated a stimulating activity, indicating that hypersensitive cells were able to cleave these complexes. This observation, together with the clinical inefficacy of the treatment, should prompt us to be careful with the use of unmanipulated single monoclonal antibodies, especially in cancer patients.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 2","pages":"133-8"},"PeriodicalIF":0.0,"publicationDate":"1995-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation. 干扰素- α和白细胞介素-2治疗异基因骨髓移植后白血病复发。

Cytokines and molecular therapy Pub Date : 1995-06-01

S Giralt, S O'Brien, M Talpaz, K Van Besien, K W Chan, G Rondón, B Andersson, R Mehra, I Khouri, E Estey

{"title":"Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation.","authors":"S Giralt, S O'Brien, M Talpaz, K Van Besien, K W Chan, G Rondón, B Andersson, R Mehra, I Khouri, E Estey","doi":"","DOIUrl":"","url":null,"abstract":"We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 2","pages":"115-22"},"PeriodicalIF":0.0,"publicationDate":"1995-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic changes in gene expression during in vitro differentiation of mouse embryonic stem cells. 小鼠胚胎干细胞体外分化过程中基因表达的动态变化。

Cytokines and molecular therapy Pub Date : 1995-06-01

M Messerle, M Follo, M Nehls, H Eggert, T Boehm

引用次数: 0

The use of cytokines to improve gene transfer to human hematopoietic stem cells. 利用细胞因子改善基因向人类造血干细胞的转移。

Cytokines and molecular therapy Pub Date : 1995-03-01

M K Brenner

引用次数: 0

IL-2 gene-transduced human HLA-A2 melanoma cells can generate a specific antitumor cytotoxic T-lymphocyte response. IL-2基因转导的人HLA-A2黑色素瘤细胞可以产生特异性的抗肿瘤细胞毒性t淋巴细胞反应。

Cytokines and molecular therapy Pub Date : 1995-03-01

A Guarini, B Gansbacher, K Cronin, M T Fierro, R Foa

{"title":"IL-2 gene-transduced human HLA-A2 melanoma cells can generate a specific antitumor cytotoxic T-lymphocyte response.","authors":"A Guarini, B Gansbacher, K Cronin, M T Fierro, R Foa","doi":"","DOIUrl":"","url":null,"abstract":"This study was designed to assess whether transfer of the interleukin-2 (IL-2) gene into human tumor cells could generate cytotoxic T lymphocytes (CTL) directed specifically against the autologous tumor. Two HLA class I+ melanoma cell lines, one (TOM) A2+ and the other (CLB-M) A2-, obtained from living patients were transduced with the IL-2 gene. The patients' peripheral blood lymphocytes (PBL) were incubated with irradiated IL-2 gene-transduced autologous tumor cells for up to four weeks. After seven days, PBL from both patients showed non-specific cytotoxic activity against the K562 cell line. When the co-culture incubation time was prolonged to 28 days, PBL from patient TOM (A2+) developed a lytic activity directed specifically against the autologous tumor cells. In contrast, after 28 days of incubation, PBL from CLB-M (A2-) displayed only non-specific cytotoxic activity. Inhibition experiments demonstrated that the specific lytic function observed with TOM cells transduced with the IL-2 gene could be reversed following incubation with monoclonal antibodies directed against HLA class I and CD8. The evidence that K562 cells were incapable of blocking the PBL killing capacity in a cold-target inhibition assay further confirmed that engineered TOM cells induced the generation of specific CTL. This study indicates that retroviral vector mediated transfer of the IL-2 gene into human melanoma cell lines can lead to the amplification of the autologous cytotoxic compartment and to the generation of specific antitumor CTL, and that the A2 allele may play an important role in the process of tumor recognition.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 1","pages":"57-64"},"PeriodicalIF":0.0,"publicationDate":"1995-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20316528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transfer of the MDR1 (multidrug resistance) gene: protection of hematopoietic cells from cytotoxic chemotherapy, and selection of transduced cells in vivo. MDR1(多药耐药)基因的转移:造血细胞免受细胞毒性化疗的保护，以及体内转导细胞的选择。

Cytokines and molecular therapy Pub Date : 1995-03-01

T Licht, M M Gottesman, I Pastan

{"title":"Transfer of the MDR1 (multidrug resistance) gene: protection of hematopoietic cells from cytotoxic chemotherapy, and selection of transduced cells in vivo.","authors":"T Licht, M M Gottesman, I Pastan","doi":"","DOIUrl":"","url":null,"abstract":"Expression of the drug efflux pump P-glycoprotein, encoded by the multidrug resistance (MDR1) gene, has been identified as an impediment to successful chemotherapy of neoplastic diseases. More recently, its potential use for gene therapy has been analyzed. Expression of a full-length MDR1 cDNA in hematopoietic cells renders them resistant to various anticancer drugs, as first shown in a transgenic mouse model. Similarly, mouse hematopoietic progenitor cells in bone marrow or peripheral blood are protected from the toxicity of anticancer chemotherapy by retroviral transduction of the MDR1 gene. Furthermore, cells engineered to express P-glycoprotein survived after the administration of cytotoxic drugs, indicating that the gene could function as a selectable marker in vivo. Recently, MDR1 transduction into isolated pluripotent hematopoietic stem cells has been demonstrated. Clinical studies on MDR1 gene transfer into hematopoietic cells of cancer patients are being planned. Transfer of the MDR1 gene into hematopoietic precursor cells may allow the introduction and selection of otherwise non-selectable genes in bone marrow. The ability to select transduced cells can circumvent the low transduction efficiency that has hampered efficient gene therapy. Recently, fusion genes in which the MDR1 cDNA is fused to genes that correct genetic disorders have been constructed to facilitate gene therapy of inherited metabolic disorders.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 1","pages":"11-20"},"PeriodicalIF":0.0,"publicationDate":"1995-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20316523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0