bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice
Authors: Zaki Mohamed H. , Nemeth Jeffrey A. , Trikha Mohit 
Published: May 2004

AbstractIL‐6 is a multifunctional cytokine implicated in several cancers. IL‐6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a human–mouse chimeric MAb to IL‐6 (Kd approx. 10−12 M) that inhibits IL‐6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half‐life of approximately 17 days. Since IL‐6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor‐induced cachexia. We used 2 human tumor‐induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (±7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)–treated animals lost only 1.5% (±1.3%) body weight from day 0 to day 31 (p = 0.023). In the second cachexia model, human prostate tumor cells were injected into male nude mice. By day 29, control treated animals lost 6% (±3.5%) body weight, whereas CNTO 328 (10 mg/kg)–treated animals gained 7% (±4%) body weight (p = 0.01). Since CNTO 328 blocks human IL‐6 but not mouse IL‐6, the data indicate that tumor cell–secreted IL‐6 directly contributes to body weight loss, highlighting the potential role for CNTO 328 as an anticachectic agent. © 2004 Wiley‐Liss, Inc.
Metalloproteinase inhibition augments antitumor efficacy of the anti‐CD30 immunotoxin Ki‐3(scFv)‐ETA′ against human lymphomas in vivo
Authors: Matthey Baerbel , Borchmann Peter , Schnell Roland , Tawadros Samir , Lange Hans , Huhn Michael , Klimka Alexander , Tur Mehmet K. , Barth Stefan , Engert Andreas , Hansen Hinrich P. 
Published: May 2004

AbstractThere is increasing evidence that the shedding of extracellular antigen domains impedes selective immunotherapy. One example is CD30, which is overexpressed on the surface of malignant lymphoma cells and has been identified as a promising target for antibody‐based immunotherapy. However, CD30 is cleaved from the surface of target cells and the resulting soluble ectodomain (sCD30) is protecting the cells from antibody binding. Shedding can be inhibited by hydroxamate inhibitors of metalloproteinases such as BB‐3644. We thus evaluated the influence of BB‐3644 on the efficacy of the anti‐CD30 single‐chain immunotoxin Ki‐3(scFv)‐ETA′. In vitro, the addition of BB‐3644 augmented the antitumor effect of Ki‐3(scFv)‐ETA′ against Hodgkin‐derived L540Cy cells by a factor of 2.75. Severe combined immunodeficiency (SCID) mice challenged with CD30‐positive L540Cy cells were treated with the immunotoxin. One single nontoxic dose of BB‐3644 increased the mean survival time of animals treated concomitantly with Ki‐3(scFv)‐ETA′ to 93 days as compared with 35 days in the control (p = 0.0017). When BB‐3644 was continuously delivered using subcutaneously implanted pumps, this effect was even more pronounced with no observed tumor growth in the animals within 200 days. Thus, concomitant application of metalloproteinase inhibitors might become clinically relevant in antibody‐based immunotherapy against targets known to be shed from tumor cells. © 2004 Wiley‐Liss, Inc.
Expression in bladder transitional cell carcinoma by real‐time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1‐2: Identification of 5 candidates tumor suppressor genes
Authors: Amira Najla , Cancel‐Tassin Géraldine , Bernardini Stéphane , Cochand‐Priollet Béatrix , Bittard Hugues , Mangin Philippe , Fournier Georges , Latil Alain , Cussenot Olivier 
Published: May 2004

AbstractFrequent deletions on 9q34.1‐2 were reported in bladder transitional cell carcinoma. High deletion mapping studies delimited a critical interval between markers D9S61 and D9S66, which is highly susceptible to contain a tumor suppressor gene. Expression level of the 65 genes localized in this region was analyzed by real‐time quantitative RT‐PCR, comparing tumor to normal urothelium. Five genes exhibited a significantly reduced expression level: C9orf9, KIAA0625, ABL1, LAMC3 and KIAA1857‐netrin‐G2, which exhibited the most significant downregulation (p=0.0007). KIAA1857‐netrin‐G2 belongs to the netrins and might then be a tumor suppressor gene in bladder cancer, as netrin1 receptor DCC has been implicated in tumorigenesis. © 2004 Wiley‐Liss, Inc.
Antimetastatic activity of the photodynamic agent hypericin in the dark
Authors: Blank Michael , Lavie Gad , Mandel Mathilda , Hazan Sadick , Orenstein Arie , Meruelo Daniel , Keisari Yona 
Published: May 2004

AbstractA unique property of the photodynamic signal transduction inhibitor hypericin (HY) is high functionality in the dark, which has been shown to result in portfolio of anticancer activities both in vitro and in vivo. Here we show that treatment with HY significantly reduces growth rate of metastases in 2 murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2). Focus on metastases was achieved by resection of primary tumors at stages in which micrometastases exist in lungs. Long‐term animal survival in DA3 tumor‐excised groups increased from 15.6% in controls to 34.5% following supplementary treatment with HY. In mice bearing SQ2 tumor metastases, therapy with HY increased animal survival from 17.7% in controls to 46.1%. Using Laser‐induced fluorescence and multipixel spectral image analyses, we demonstrate that HY has a high tendency to accumulate in primary and metastatic tumors; HY content in lungs bearing metastases was approximately 2‐fold higher than in the lungs of healthy animals. The tendency of HY to preferentially concentrate in lung metastases, combined with its potent antiproliferative activities, may render HY as a useful supplementary modality in the treatment of metastatic cancer irrespective of photoactivation. © 2004 Wiley‐Liss, Inc.
Interleukin‐6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation
Authors: Wang Qingcai , Horiatis Dimitris , Pinski Jacek 
Published: May 2004

AbstractIn vitro, the human prostate cancer (PCA) cell line LNCaP can be permanently transdifferentiated into a quiescent neuroendocrine (NE) phenotype by the cytokine interleukin‐6 (IL‐6). Recently, we have shown that the growth of prostate cancer cells is significantly suppressed when cocultured with NE cells. In order to explore the inhibitory activity of IL‐6 on prostate tumor growth, nude mice bearing xenografts of the PCA cell lines LNCaP and DU‐145 (a line that is incapable of NE transdifferentiation by IL‐6 in vitro) were treated with IL‐6 for 3 weeks, either injected around the tumor or systematically released from implanted minipumps. Both administration forms of IL‐6 inhibited the growth of LNCaP xenografts by more than 75% compared to the control group. In contrast, there was no difference in DU‐145 tumor growth between IL‐6‐treated animals and controls. In comparison to control and DU‐145 tumors, both IL‐6 injected and pump‐infused LNCaP tumors exhibited a significant increase in the expression of the NE markers neuron‐specific enolase (NSE) and βIII tubulin. Serum NSE levels were also significantly elevated in both IL‐6‐treated LNCaP tumor groups when compared to controls. IL‐6 treatment resulted in G0 cell cycle accumulation as evidenced by a loss of Ki‐67 expression in > 90% of LNCaP tumor cells. These combined results demonstrate that IL‐6‐induced NE transdifferentiation of PCA cells has a significant inhibitory effect on tumor growth in mice. Agents, like IL‐6, capable of NE transdifferentiation of PCA cells, should be considered as a new therapeutic approach for the treatment of prostate cancer. © 2004 Wiley‐Liss, Inc.
Role of α4 integrin and its ligand VCAM‐1 in the specific extravasation of a tumor‐specific TH2 clone into tumor tissue that initiates its rejection
Authors: Jin Zhe , Shen Yuan , Fujimoto Shigeyoshi 
Published: May 2004

AbstractThe effectiveness of anticancer immunotherapeutic strategies involving the transfer of tumor‐specific T cells depends on appropriate lymphocyte–endothelial cell interactions that facilitate the migration of lymphocytes into tumor. Here, we investigated the molecular mechanisms underlying the migration of the antigen‐specific Th2 CD4+ T‐cell clone YS1093 into S1509a tumor tissue. YS1093 is specific for the S1509a tumor but does not recognize the S713a tumor. Transfer of YS1093 cells into mice bearing both S1509a and S713a tumors caused only the S1509a tumor to regress. This regression was markedly inhibited by pretreating YS1093 cells with an anti‐α4 integrin MAb and administering an anti‐VCAM‐1 MAb at T‐cell transfer. Since vascular endothelial cells in S1509a tumor tissues express VCAM‐1 and the MHC class II (I‐Ek) molecule restricting YS1093 activity, labeled YS1093 cells migrated specifically into the S1509a tumor, and this migration was also blocked by the anti‐TCRβ F(ab′)2 and anti‐I‐Ek MAbs. Furthermore, in vitro assays revealed that anti‐CD3 MAb–mediated TCR cross‐linkage initiated the binding of α4 integrin on YS1093 cells to VCAM‐1. This adhesive activity was completely blocked by the anti‐α4 integrin MAb. These results strongly suggest that i.v.‐transferred YS1093 cells act in tumor regression by specifically recognizing their tumor antigen peptide in the context of I‐Ek on vascular endothelial cells in the S1509a tumor, which activates the binding of α4 integrin to VCAM‐1 on the endothelial cells, facilitating YS1093 extravasation into the tumor. It is likely that this initial migration of specific CD4+ T cells into tumor tissues promotes the subsequent infiltration into the tumor of other immunocytes that effect tumor destruction. © 2004 Wiley‐Liss, Inc.
Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes
Authors: Tanaka Tomotaka , Tanimoto Keiji , Otani Keiko , Satoh Kenichi , Ohtaki Megu , Yoshida Kazuhiro , Toge Tetsuya , Yahata Hiroshi , Tanaka Shinji , Chayama Kazuaki , Okazaki Yasushi , Hayashizaki Yoshihide , Hiyama Keiko , Nishiyama Masahiko 
Published: May 2004

AbstractWe developed concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5‐FU, CDDP, MMC, DOX, CPT‐11, SN‐38, TXL and TXT), along with individual clinical responses to 5‐FU using expression data of 12 genes. We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes. The correlation significance of each was confirmed using expression data quantified by real‐time RT‐PCR, and finally 12 genes (ABCB1, ABCG2, CYP2C8, CYP3A4, DPYD, GSTP1, MGMT, NQO1, POR, TOP2A, TUBB and TYMS) were selected as more reliable predictors of drug response. Using multiple regression analysis, we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order, to predict the efficacy of the drugs by referring to the value of Akaike's information criterion for each sample. These formulae appeared to accurately predict the in vitro efficacy of the drugs. For the first clinical application model, we fixed prediction formulae for individual clinical response to 5‐FU in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival, time to treatment failure and tumor growth. None of the 12 selected genes alone could predict such clinical responses. © 2004 Wiley‐Liss, Inc.
Omega‐3 fatty acids improve liver and pancreas function in postoperative cancer patients
Authors: Heller Axel R. , Rössel Thomas , Gottschlich Birgit , Tiebel Oliver , Menschikowski Mario , Litz Rainer J. , Zimmermann Thomas , Koch Thea 
Published: May 2004

AbstractEpidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega‐3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5‐lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double‐blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 ± 0.1 vs. 0.5 ± 0.1 mmol/(l · sec)], ALAT [0.9 ± 0.1 vs. 0.6 ± 0.1 mmol/(l · sec)], bilirubin (16.1 ± 5.3 vs. 6.9 ± 0.6 mmol/l), LDH (7.7 ± 0.4 vs. 6.7 ± 0.4 mmol/(l · sec) and lipase (0.6 ± 0.1 vs. 0.4 ± 0.1 μmol/(l · sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL‐6/IL‐10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega‐3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 ± 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients. © 2004 Wiley‐Liss, Inc.
Synergistic effect of alcohol drinking and smoking on in vivo acetaldehyde concentration in saliva
Authors: Salaspuro Ville , Salaspuro Mikko 
Published: May 2004

AbstractAlcohol drinking and smoking are independent risk factors for upper digestive tract cancers. Furthermore, their combined use interacts in a multiplicative way on cancer risk. There is convincing evidence that acetaldehyde, the first metabolite of ethanol and a constituent of tobacco smoke, is a local carcinogen in humans. Therefore, we examined the combined effect of alcohol drinking and tobacco smoking on in vivo acetaldehyde concentration in saliva. Seven smokers and 6 nonsmokers participated in the study. First, to measure the effect of alcohol on salivary acetaldehyde, all volunteers ingested 0.8 g/kg body weight of ethanol and saliva samples were collected every 20 min for 160 min thereafter. After a 3‐day washout period, smokers ingested again the same amount of ethanol and smoked one cigarette every 20 min and saliva samples were collected at 10 min intervals for 160 min. Acetaldehyde and ethanol concentrations were analyzed by headspace gas chromatograph. Firstly, smokers without concomitant smoking during ethanol challenge had 2 times higher in vivo salivary acetaldehyde concentrations than nonsmokers after ethanol ingestion (AUC 114.8 ± 11.5 vs. 54.2 ± 8.7 μM × hr, respectively; p = 0.002). Secondly, smokers with active smoking during ethanol challenge had 7 times higher in vivo salivary acetaldehyde levels than nonsmokers (AUC 369.5 ± 12.2 vs. 54.2 ± 8.7 μM × hr, respectively; p < 0.001). We conclude that this markedly increased exposure of upper digestive tract mucosa to carcinogenic salivary acetaldehyde of smoking and drinking subjects may explain the synergistic and multiplicative risk effect of alcohol drinking and tobacco smoking on upper gastrointestinal tract carcinogenesis. © 2004 Wiley‐Liss, Inc.
Peroxiredoxins, a novel protein family in lung cancer
Authors: Lehtonen Siri T. , Svensk Anne‐Mari , Soini Ylermi , Pääkkö Paavo , Hirvikoski Pasi , Kang Sang Won , Säily Marjaana , Kinnula Vuokko L. 
Published: May 2004

AbstractCigarette smoke, the major risk factor for lung cancer, induces an accumulation of reactive oxygen species. These have multiple effects on cell defense, cell proliferation and cell death. Thus, compounds involved in the regulators of redox balance can be hypothesized to play a fundamental role in both carcinogenesis and tumor progression. Here, we have evaluated the expressions of all 6 peroxiredoxins (Prxs I–VI) in lung carcinomas. Prxs represent a protein family with the capability of breaking down hydrogen peroxide; thus, they can participate in cellular antioxidant defense, regulate cell proliferation and increase drug resistance of cultured cells. Altogether 92 cases were investigated by immunohistochemistry, including 32 adenocarcinomas, 45 squamous cell, 9 small cell and 6 other carcinomas. Additionally, 11 cases with adenocarcinoma or squamous cell carcinoma were studied by Western analysis and/or by RT‐PCR. Prxs I, II, IV and VI were particularly elevated in lung carcinomas as assessed by immunohistochemistry and/or RT‐PCR. Western analysis revealed that Prxs I and IV were significantly elevated in tumors compared to nonmalignant tissue (p = 0.04 and 0.002, respectively). There were remarkable variations in Prx expression in various tumor subtypes, the most striking being Prx IV expression, which was mainly associated with adenocarcinoma. Elevated Prx VI expression was associated with high‐grade squamous cell carcinoma (p = 0.03) and Prx II expression, with advanced tumor stage (p = 0.01). Our results suggest that Prxs may have effects on the progression of lung cancer. © 2004 Wiley‐Liss, Inc.
Aberrant intracellular localization of SET‐CAN fusion protein, associated with a leukemia, disorganizes nuclear export
Authors: Saito Shoko , Miyaji‐Yamaguchi Mary , Nagata Kyosuke 
Published: May 2004

AbstractThe SET‐CAN fusion gene is the product of a chromosomal rearrangement found on 9q34 associated with an acute undifferentiated leukemia. SET‐CAN encodes an almost complete SET protein fused to the C‐terminal two‐thirds of CAN. SET is also known as TAF‐Iβ, a histone chaperone and intracellular inhibitor of protein phosphatase 2A, whereas CAN is identical to Nup214, a nucleoporin protein. To obtain insight into the leukemogenic function of SET/TAF‐Iβ‐CAN/Nup214, we have examined its subcellular localization. Immunofluorescence analyses showed that SET/TAF‐Iβ and CAN/Nup214 are found in the nucleus and the nuclear envelope, respectively, whereas the majority of SET/TAF‐Iβ‐CAN/Nup214 is localized in the nucleus. SET/TAF‐Iβ‐CAN/Nup214 interacted with hCRM1, one of the nuclear export factors, and caused aberrant intracellular localization of hCRM1. In cells expressing SET/TAF‐Iβ‐CAN/Nup214, a protein containing a nuclear export signal accumulated in the nucleus. The export of this protein was partially restored by overexpression of hCRM1. These results suggest that aberrantly localized molecules associated with SET/TAF‐Iβ‐CAN/Nup214 may be involved in oncogenesis. © 2004 Wiley‐Liss, Inc.
Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis
Authors: Sheng Yezhou , Hua Jianyi , Pinney Kevin G. , Garner Charles M. , Kane Robert R. , Prezioso Joseph A. , Chaplin David J. , Edvardsen Klaus 
Published: May 2004

AbstractThe mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5‐T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6–24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1–3 hr, followed by tumor cell necrosis from 6–72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies. © 2004 Wiley‐Liss, Inc.
Effect of exposure to light‐at‐night on life span and spontaneous carcinogenesis in female CBA mice
Authors: Anisimov Vladimir N. , Baturin Dmitri A. , Popovich Irina G. , Zabezhinski Mark A. , Manton Kenneth G. , Semenchenko Anna V. , Yashin Anatoly I. 
Published: May 2004

AbstractThe effect of constant illumination on the development of spontaneous tumors in female CBA mice was investigated. Fifty female CBA mice starting from the age of 2 months were kept under standard light/dark regimen (12 hr light:12hr dark; LD) and 50 CBA mice of similar age were kept under constant illumination (24 hr a day, 2,500 Lux, LL). Exposure to the LL regimen decreased food consumption but did not influence body weight, significantly accelerated age‐related disturbances in estrous function, and was followed by a significant increase in spontaneous tumor incidence in female CBA mice. Tumor incidence as well as the number of total or malignant tumors was significantly increased in the LL group compared to the LD group (p < 0.001). The incidence of lung adenocarcinomas, leukemias and hepatocarcinomas was 7/50; 6/50 and 4/50 in the LL group and 1/50; 0/50 and 0/50 in the LD group. Mice from the LL groups had shorter life spans then those from the LD group. The data demonstrate, for the first time, that exposure to constant illumination was followed by increases in the incidence of spontaneous lung carcinoma, leukemias and hepatocarcinoma in female CBA mice. © 2004 Wiley‐Liss, Inc.