共查询到11条相似文献,搜索用时 0 毫秒
1.
Kazuyoshi Yanagihara Masaru Tsumuraya Misato Takigahira Keichiro Mihara Takanori Kubo Kazuo Ohuchi Toshio Seyama 《International journal of cancer. Journal international du cancer》2010,126(12):2835-2846
Human malignant pleural mesothelioma (HMPM) is an aggressive neoplasm that is highly resistant to conventional therapies. We established 3 HMPM cell lines (TCC‐MESO‐1, TCC‐MESO‐2 and TCC‐MESO‐3) from Japanese patients; the first 2 from the primary and metastatic tumors of a patient with the epithelioid type of HMPM, and the third from a patient with biphasic characteristics of the tumor (epithelioid and sarcomatous phenotypes). The 3 cell lines resembled the original HMPMs in their morphological and biological features, including the genetic alterations such as lack of p16 expression and mutation of p53. Their tumorigenicity was determined in SCID mice by orthotopic implantation (20–46%). The tumorigenicity of the HMPM cell lines, which was relatively low, was enhanced by repeated subcultures and orthotopic implantations, and 3 competent tumorigenic sublines were produced (Me1Tu, Me2Tu and Me3Tu sublines from the TCC‐MESO‐1, TCC‐MESO‐2 and TCC‐MESO‐3 cell lines, respectively). The resultant HMPM sublines efficiently generated tumors in the SCID mice (100%) following orthotopic implantation. SCID mice implanted with the competent sublines, into one of which the luciferase gene was introduced, displayed quantitative fluctuation of the bioluminescence for the tumor volume in vivo. Oral administration of S‐1, an anticancer agent, suppressed the proliferation of the luciferase gene‐expressing Me1Tu subline in the mouse models in vivo, with a treated‐to‐control ratio of the mean tumor volume of 0.2. The orthotopic implantation mouse model proved to be useful for quantitative evaluation of the efficacy of novel anticancer drugs and also for studying the biology of HMPMs in vivo. 相似文献
2.
Joanna Napp Christian Dullin Friedemann Müller Kerstin Uhland Jean Bernhard Petri Andreas van de Locht Torsten Steinmetzer Frauke Alves 《International journal of cancer. Journal international du cancer》2010,127(8):1958-1974
Proteolytic enzymes expressed on the surface of tumor cells, and thus easily accessible to external interventions, represent useful targets for anticancer and antimetastatic therapies. In our study, we thoroughly evaluated matriptase, a trypsin‐like transmembrane serine protease, as potential target for novel inhibitor‐based tumor therapies. We applied time‐domain near infrared fluorescence (NIRF) imaging to characterize expression and activity of matriptase in vivo in an orthotopic AsPC‐1 pancreatic tumor model in nude mice. We show strong and tumor‐specific binding of intravenously injected Cy5.5 labeled antimatriptase antibody (MT‐Ab*Cy5.5) only to primary AsPC‐1 tumors and their metastases over time within living mice, taking into account fluorescence intensities and fluorescence lifetimes of the applied probes. Specific binding of MT‐Ab*Cy5.5 to tumor sites was confirmed by ex vivo NIRF imaging of tumor tissue, NIRF microscopy and by coregistration of the in vivo acquired NIRF intensity maps to anatomical structures visualized by flat‐panel volume computed tomography (fpVCT) in living mice. Moreover, using an activatable synthetic substrate S*DY‐681 we could clearly demonstrate that matriptase is proteolytically active in vitro as well as in vivo in tumor‐bearing mice, and that application of synthetic active‐site inhibitors having high affinity and selectivity toward matriptase can efficiently inhibit its proteolytic activity for at least 24 hr. We thus successfully applied NIRF imaging in combination with fpVCT to characterize matriptase as a promising molecular target for inhibitor‐based cancer therapies. 相似文献
3.
Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3‐kinase dual inhibitor 下载免费PDF全文
Ken Saijo Hiroo Imai Sonoko Chikamatsu Koichi Narita Tadashi Katoh Chikashi Ishioka 《Cancer science》2017,108(7):1469-1475
Histone deacetylase (HDAC)/phosphatidylinositol 3‐kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK‐A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK‐A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK‐A11 showed in vivo antitumor activity by both i.v. and i.p. administration in a dose‐dependent manner. In both xenograft models, FK‐A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti‐cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK‐A11 in mice. These findings will be essential for guiding further preclinical and clinical studies. 相似文献
4.
5.
Estefanía Martino‐Echarri Rubén Fernández‐Rodríguez Francisco Javier Rodríguez‐Baena Antonio Barrientos‐Durán Antoni X. Torres‐Collado María del Carmen Plaza‐Calonge Suyapa Amador‐Cubero Javier Cortés Louise E. Reynolds Kairbaan M. Hodivala‐Dilke Juan Carlos Rodríguez‐Manzaneque 《International journal of cancer. Journal international du cancer》2013,133(10):2315-2324
The extracellular protease ADAMTS1 (A disintegrin and metalloprotease with thrombospondin repeats 1) has been described as an anti‐angiogenic molecule and its role as a putative tumor protective molecule has also been suggested. Here, we have used a tumor xenograft model to determine the role of ADAMTS1 in tumor growth and angiogenesis. Increasing levels of the protease led to the complete inhibition of tumor growth. In an attempt to elucidate the mechanism of action of this protease, we focused our attention on its proteolytic activity on nidogens, one of the main components of the vascular basement membrane. The increased expression of ADAMTS1 was accompanied by increased proteolysis of nidogen‐1 and ‐2 and their almost complete removal from vascular structures, together with major morphological alterations of tumor blood vessels and a decreased vessel density. The clinical relevance of this work is supported by our observations that ADAMTS1 expression is decreased in breast tumor specimens when compared with healthy tissue. Our studies also reveal that the cleavage of nidogen‐1 and ‐2 is partially inhibited in human tumor samples. Moreover, the deposition of both nidogens surrounding vascular structures is drastically altered, implying a possible reduction in the maintenance of vessel integrity. Our studies reflect the requirement to explore the functional interactions between proteases and specific substrates in cancer biology. 相似文献
6.
Naoko Takahashi‐Makise Shinya Suzu Masateru Hiyoshi Takeo Ohsugi Harutaka Katano Kazuo Umezawa Seiji Okada 《International journal of cancer. Journal international du cancer》2009,125(6):1464-1472
Primary effusion lymphoma (PEL) is a unique and recently identified non‐Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma‐associated herpes virus (KSHV/HHV‐8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)‐ κ B pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL‐1, TY‐1 and RM‐P1), in vitro and in vivo. An methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1–10 μg/ml). CEP also inhibited NF‐ κ B activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL‐1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL‐1 without significant systemic toxicity in this model. These results indicate that NF‐ κ B could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. © 2009 UICC 相似文献
7.
8.
Maximilian Bockhorn Jussuf T. Kaifi Sabrina Thieltges Cenap Güngör Katharina E. Effenberger Andrea Strelow Uta Reichelt Guido Sauter Klaus Pantel Jakob R. Izbicki Emre F. Yekebas 《International journal of cancer. Journal international du cancer》2010,127(8):1931-1940
Insulin‐like growth factor‐1 receptor (IGF‐1R) and human epidermal growth factor receptor‐2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF‐1R in esophageal cancer and to determine the effect of IGF‐1R and HER2 targeting with α‐IR3 and Herceptin? antibodies on the proliferation of esophageal cancer cells in vitro. IGF‐1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin? and α‐IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF‐1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF‐1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2‐positive tumors, 93.1% showed concordant overexpression for IGF‐1R. IGF‐1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin? and α‐IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF‐1R protein levels and suppression of Akt‐ and MAP kinase phosphorylation. IGF‐1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF‐1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma. 相似文献
9.
Live imaging of transforming growth factor‐β activated kinase 1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyinosinic:polycytidylic acid 下载免费PDF全文
Saori Takaoka Yuji Kamioka Kanako Takakura Ai Baba Hiroaki Shime Tsukasa Seya Michiyuki Matsuda 《Cancer science》2016,107(5):644-652
Transforming growth factor‐β activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live‐imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the s.c. tissue of syngeneic C57BL/6 mice and treated with polyinosinic:polycytidylic acid (PolyI:C). First, we developed and characterized a Förster resonance energy transfer‐based biosensor for TAK1 activity. The TAK1 biosensor, named Eevee‐TAK1, responded to stress‐inducing reagents such as anisomycin, tumor necrosis factor‐α, and interleukin1‐β. The anisomycin‐induced increase in Förster resonance energy transfer was abolished by the TAK1 inhibitor (5z)‐7‐oxozeaenol. Activity of TAK1 in 3LL cells was markedly increased by PolyI:C in the presence of macrophages. 3LL cells expressing Eevee‐TAK1 were implanted into mice and observed through imaging window by two‐photon excitation microscopy. During the growth of tumor, the 3LL cells at the periphery of the tumor showed higher TAK1 activity than the 3LL cells located at the center of the tumor, suggesting that cells at the periphery of the tumor mass were under stronger stress. Injection of PolyI:C, which is known to induce regression of the implanted tumors, induced marked and homogenous TAK1 activation within the tumor tissues. The effect of PolyI:C faded within 4 days. These observations suggest that Eevee‐TAK1 is a versatile tool to monitor cellular stress in cancer tissues. 相似文献
10.
Mark A ROSENTHAL Peter DAVIDSON Frederic ROLLAND Mario CAMPONE Lingling XUE Tae H HAN Anish MEHTA Yuliya BERD Weili HE Antonio LOMBARDI 《Asia-Pacific Journal of Clinical Oncology》2010,6(1):42-48
Aim: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an ανβ3 integrin inhibitor on bone turnover and disease activity in men with hormone‐refractory prostate cancer (HRPC) and bone metastases. Methods: A total of 21 patients with bone metastases and HRPC were randomized to receive MK‐0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. Results: Nausea was the most common adverse event: one (200‐mg group) and 11 (1600‐mg group) patients. At 4 weeks, mean AUC0–12 h was 210 mmol*h (200‐mg group) and 673 mmol*h (1600‐mg group); mean Cmax values were 42 mmol/L (200‐mg group) and 154 mmol/L (1600‐mg group). Urinary cross‐linked N‐telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of ?43.4 percent (200‐mg group) and ?34.1 percent (1600‐mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200‐mg group) and 44.5 percent (1600‐mg group). Conclusion: MK‐0429 was generally well tolerated, with the most common side‐effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study. 相似文献
11.
Muthusamy Thangaraju PhD Senthil K. Karunakaran BTech Shiro Itagaki PhD Elangovan Gopal PhD Selvakumar Elangovan PhD Puttur D. Prasad PhD Vadivel Ganapathy PhD 《Cancer》2009,115(20):4655-4666