bluuebunny/crossref_metadata_2025_split huggingface dataset:
Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI‐277 on inhibition of MCF‐7 breast cancer cell‐cycle progression
Authors: Doisneau‐Sixou Sophie F. , Cestac Philippe , Faye Jean‐Charles , Favre Gilles , Sutherland Robert L. 
Published: July 2003

AbstractThe efficacy of tamoxifen in the hormonal therapy of breast cancer is well established, but therapeutic resistance is inevitable. FTIs are a new class of anticancer drugs that are in phase III clinical evaluation. Since the mechanisms of action of these 2 classes of drugs are different, we tested the combination of tamoxifen and FTI‐277 on inhibiting proliferation of hormone‐dependent MCF‐7 human breast cancer cells. An additive effect on cell proliferation was demonstrated, accompanied by an additive G0/G1 arrest. The major effect of the combination of the 2 drugs was to maintain p21waf/cip1 at an intermediate level, higher than that observed in the presence of tamoxifen alone. This was associated with an additive effect on inactivation of cyclin E–Cdk2 complexes and decreased phosphorylation of pRb and p130 pocket proteins. These effects were accompanied by increased association of 2 CDIs, p27kip1 and p21waf/cip1, with cyclin E–Cdk2 complexes. These data demonstrate that the additive effect is likely predominantly due to the recruitment of p27kip1 and, to a lesser extent, p21waf/cip1 into the cyclin E–Cdk2 complexes. Together, these results suggest that the combination of FTI and tamoxifen may increase the antitumor effect of either drug alone in breast cancer. © 2003 Wiley‐Liss, Inc.
Promotion of intestinal tumor formation by inulin is associated with an accumulation of cytosolic β‐catenin in Min mice
Authors: Pajari Anne‐Maria , Rajakangas Johanna , Päivärinta Essi , Kosma Veli‐Matti , Rafter Joseph , Mutanen Marja 
Published: July 2003

AbstractInulin, polydisperse β (2‐1) fructan, has been suggested to protect against colon carcinogenesis and is currently used in a number of food applications. However, the data regarding the role of inulin in intestinal carcinogenesis remains controversial since the results of our previous study suggested that inulin promotes intestinal tumor formation in Min mice, an animal model for intestinal cancer with a mutation in the Apc tumor suppressor gene (Carcinogenesis 2000;21:1167–73). In our present study, we further examined the effects of inulin on intestinal tumor formation in Min mice by carefully analyzing β‐catenin expression and cellular localization at 3 different time points during the tumorigenic process. Min mice were fed a high‐fat inulin‐enriched (10% w/w) diet or the high‐fat diet without any added fiber from the age of 6 weeks to the ages of 9, 12 or 15 weeks. The results showed that inulin significantly increased the number (by 20%) and especially the size (by 44%) of adenomas in the small intestine. At week 15, the promotion of tumor development was accompanied by an accumulation of cytosolic β‐catenin in the adenoma tissue. In the normal appearing mucosa, levels of membrane β‐catenin and PCNA were reduced in the inulin‐fed mice, possibly indicating impaired enterocyte migration. These data do not support the earlier suggestions on the cancer preventive effects of inulin and emphasize the need for further research and evaluation where health claims for inulin are concerned. © 2003 Wiley‐Liss, Inc.
Prognostic value ofERBBfamily mRNA expression in breast carcinomas
Authors: Bièche Ivan , Onody Peter , Tozlu Sengül , Driouch Keltouma , Vidaud Michel , Lidereau Rosette 
Published: July 2003

AbstractThe ErbB‐driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials. Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discoveredERBBgenes,ERBB3andERBB4, is unclear. We used a real‐time quantitative RT‐PCR assay to quantifyERBBfamily mRNA copy numbers in a large series of breast tumors from patients with known long‐term outcome.ERBBgene expression varied widely, by more than 2 orders of magnitude forERBB1andERBB3, more than 3 orders forERBB2and more than 4 orders forERBB4. We found a positive correlation betweenERBB3andERBB4mRNA levels, and a negative correlation between the expression of these 2 latter genes and that ofERBB1. Compared to normal breast tissue,ERBB1was underexpressed (82.3% of tumors),ERBB2(16.9%) andERBB3(46.2%) were overexpressed andERBB4was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found betweenERBBstatus on the one hand and Scarff‐Bloom‐Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand. Relapse‐free survival (RFS) was shorter among patients withERBB3‐overexpressing tumors (p=0.0092) and longer among those withERBB4‐underexpressing tumors (p=0.0085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced byERBB1orERBB2mRNA status. OnlyERBB4status retained prognostic significance in Cox multivariate regression analysis (p=0.015). Our results point to the involvement of several ErbB‐specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer. These findings reveal a complex expression pattern ofERBBgene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors. © 2003 Wiley‐Liss, Inc.
Phagocytosis by dendritic cells rather than MHC IIhigh macrophages is associated with skin tumour regression
Authors: Byrne Scott N. , Halliday Gary M. 
Published: July 2003

AbstractDendritic cells (DC) are important for the induction of anti‐tumour immunity and are currently being used in clinical trials. Whether DC in tumours behave the same as DC in normal tissues or whether the tumours subvert DC phenotype and function remains unknown. To address this, we have used a unique animal tumour model to compare the DC infiltrating regressing tumours with the DC infiltrating progressing skin tumours. Compared to progressor tumours, the regressor tumours were infiltrated by greater numbers of DC that were also less mature, based on MHC II expression. Apart from this, the phenotype of DC in both tumours was similar. However, compared to various control DC, they could not be classed as either mature or immature. Similar to terminally maturated DC but in contrast to fresh DC, tumour‐derived DC did not express CCR5 or CXCR4, suggesting that they most closely resembled terminally matured DC. Macrophages that expressed high MHC II levels were found infiltrating progressor but not regressor tumours and in vivo were the major phagocytic cell. In contrast, DC were found to be the major phagocytic cell in regressor tumours. The results show that immune destruction and eventual regression of skin tumours occurs if DC rather than MHC IIhigh macrophages are the major phagocytic cell. © 2003 Wiley‐Liss, Inc.
Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889
Authors: Endo Mika , Miwa Masanori , Eda Hiroyuki , Ura Masako , Tanimura Hiromi , Ishikawa Tohru , Miyazaki‐Nose Taeko , Hattori Kazuo , Shimma Nobuo , Yamada‐Okabe Hisafumi , Ishitsuka Hideo 
Published: July 2003

AbstractCapecitabine is an orally available fluoropyrimidine and is finally converted to 5‐FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD‐overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5‐vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5‐ethynyluracil or 5‐vinyluracil, which inhibited DPD not only in tumor tissues but also in other non‐cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD. © 2003 Wiley‐Liss, Inc.
Energy restriction and the risk of spontaneous mammary tumors in mice: A meta‐analysis
Authors: Dirx Miranda J.M. , Zeegers Maurice P.A. , Dagnelie Pieter C. , van den Bogaard Ton , van den Brandt Piet A. 
Published: July 2003

AbstractOur meta‐analysis was aimed at providing a systematic review of the literature regarding the effect of energy restriction on spontaneous mammary tumors in mice and at providing a more precise pooled (summary) estimate of the risk of mammary tumors. A sensitivity analysis was conducted to obtain insight in potential heterogeneity between the animal studies. A literature search was conducted with the following terms to identify relevant articles: animal studies, mammary tumors, fat restricted, dietary carbohydrates, energy restriction and calorie restriction. A criteria list for the assessment of quality items (i.e., study characteristics) in animal experiments was developed that was intended to quantitatively assess potential factors that underlie heterogeneous results of different animal experiments. Incidence figures were used to calculate the risk difference. The pooled risk difference was calculated by random effects meta regression analysis. Fourteen animal experiments were included in this meta‐analysis. Publication bias could not be identified. The pooled risk difference for the 14 studies was −0.55 with a narrow 95% confidence interval (−0.69; −0.41), implying that the energy‐restricted animal groups developed 55% less mammary tumors than the control groups. No heterogeneity could be detected between the studies based on study characteristics that included the age of mice at the start of intervention, duration of intervention, allocation of the mice, use of ad libitum control group, fertility of the mice and the type of energy‐providing nutrient (fat, carbohydrate or protein). This meta‐analysis confirms that energy restriction in itself consistently protects against the development of mammary tumor in mice, irrespective of the type of restricted nutrient or other study characteristics. © 2003 Wiley‐Liss, Inc.
Human pHyde is not a classical tumor suppressor gene in prostate cancer
Authors: Porkka Kati P. , Nupponen Nina N. , Tammela Teuvo L.J. , Vessella Robert L. , Visakorpi Tapio 
Published: July 2003

AbstractA novel putative tumor suppressor gene, pHyde, was recently cloned from rat prostate. The rat gene has been shown to inhibit prostate cancer cell proliferation both in vitro and in vivo. However, the role of human pHyde in prostate cancer has not been studied before. Here, we analyzed human prostate cancer cell lines (LNCaP, DU145, PC‐3, 22Rv1), xenografts (LuCaP 23.1, 35, 41, 49, 58, 69, 70 and 73) and clinical prostate carcinomas for genetic alterations and expression of pHyde. The expression of pHyde in normal human tissues as well as in prostate cancer was studied by Northern analysis and real‐time quantitative RT‐PCR. It was ubiquitously expressed in all normal tissues analyzed. Although, the expression was significantly (p=0.007) lower in poorly differentiated than in well and moderately differentiated carcinomas, there were no differences in the expression levels between benign prostate hyperplasia, untreated primary and recurrent hormone‐refractory prostate carcinomas (p=0.607). Altogether, missense mutations were detected in 2 out of 68 samples studied (∼3%) by denaturing high‐performance liquid chromatography (DHPLC) and sequencing. One of the samples with the mutation also exhibited a loss of a gene copy by fluorescence in situ hybridization (FISH). This was the only sample that exhibited a genetic alteration in both alleles, suggesting that the human pHyde is not a classical prostate tumor suppressor gene. The reduced expression of the gene found in some tumors warrant further studies. © 2003 Wiley‐Liss, Inc.
Magnetic resonance imaging of the pancreas and pancreatic tumors in a mouse orthotopic model of human cancer
Authors: Grimm Jan , Potthast Andreas , Wunder Andreas , Moore Anna 
Published: July 2003

AbstractPancreatic adenocarcinoma has a rising incidence and a very poor survival rate. To develop new treatment strategies, extensive research is performed on animal models of pancreatic cancer. Orthotopic pancreatic tumors models, where the tumor is implanted into the pancreas, resemble the human disease more closely than subcutaneous tumor models, yet are difficult to monitor. In our study we report a magnetic resonance imaging (MRI) approach to visualize the pancreas in mice and to monitor orthotopically implanted pancreatic tumors. An MRI scanner was used to image normal murine pancreas and the pancreas of mice implanted with a human pancreatic adenocarcinoma cell line. Gadolinium (Gd)‐DTPA‐enhanced T1‐ and T2‐weighted standard sequences were used with the objective to identify the pancreas and to monitor the growth of orthotopic tumors during 30 days. The pancreas as well as the implanted tumors could be easily identified using MRI. On T2‐weighted images, the implanted tumors were easily visualized at the implantation side with high signal intensity. After application of a contrast agent, the tumors showed an enhancement. Heterogeneities within the tumor could be delineated, corresponding to histology, and the size of the tumor could be measured precisely. MR serves as a noninvasive high‐resolution image modality to monitor murine pancreas as well as size, growth and even areas of heterogeneity in orthotopic pancreatic tumors. © 2003 Wiley‐Liss, Inc.
Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis
Authors: Nagata Masaki , Fujita Hajime , Ida Hiroko , Hoshina Hideyuki , Inoue Tatsuo , Seki Yukie , Ohnishi Makoto , Ohyama Tokio , Shingaki Susumu , Kaji Masataka , Saku Takashi , Takagi Ritsuo 
Published: July 2003

AbstractWe surveyed the expression of 557 cancer‐related genes in 15 cases of well‐differentiated OSCC by cDNA microarray analysis. To identify potential biomarkers for lymph node metastasis, all microarray data were compared by the Mann‐Whitney test and the significance analysis of microarrays between OSCCs with and those without lymph node metastasis. The tissues of OSCCs with lymph node metastasis exhibited increased expression levels of MMP‐1, MMP‐3, uPA, integrin‐α3, paxillin, tenascin C and IL‐6 transcripts. All of these genes were included in common clusters on the Cluster/TreeView analysis, implying that functional gene groups of proteolytic enzymes and integrin‐related molecules are involved in cervical lymph node metastasis. The results of RTQ‐PCR for differentially expressed genes were in accord with those of cDNA microarray analyses, suggesting that the data obtained by microarray gene expression analyses were valid. Consistent with cooperative expression patterns, immunohistochemical analyses demonstrated that products of MMP‐1, MMP‐3 and uPA were colocalized to components of the neoplastic stroma, particularly mononuclear inflammatory cells with well‐developed eosinophilic cytoplasm. Our results suggest that expression levels of molecules involved in tissue remodeling and cell–ECM adhesion, especially MMP‐1 and integrin‐α3, can provide an accurate biomarker system for predicting the risk of cervical lymph node metastasis in OSCC. © 2003 Wiley‐Liss, Inc.
Transfection of the genes for interleukin‐12 into the K1735 melanoma and the EMT6 mammary sarcoma murine cell lines reveals distinct mechanisms of antitumor activity
Authors: Moran James P. , Gerber Scott A. , Martin Celeste A. , Frelinger John G. , Lord Edith M. 
Published: July 2003

AbstractInterleukin 12 (IL‐12) is a pleiotropic cytokine with multiple effects on the immune system. The antitumor effects of locally produced IL‐12 were examined in 2 tumor model systems. IL‐12 expressing EMT6 mammary sarcomas (EMT6/IL‐12) grew temporarily and then regressed resulting in mice that were immune to a further challenge of EMT6 cells. Interestingly, the IL‐12 expressing K1735 melanomas (K1735/IL‐12) maintained a lag phase of nonmeasurable growth for several weeks, followed by tumor outgrowth that was associated with a loss of IL‐12 production. Tumor‐infiltrating lymphocytes (TILs) isolated from EMT6/IL‐12 tumors effectively lysed EMT6 target cells, whereas K1735/IL‐12 TILs lacked lytic activity. Both IL‐12 expressing tumors, however, grew progressively in nude mice indicating an important role for T cells in each case. Recombinant murine interferon gamma (rmIFN‐γ) inhibited the growth of EMT6 cells, but not K1735 cells in vitro, and strongly induced the expression of the antiangiogenic chemokine interferon‐inducible protein 10 (IP‐10) by both cell lines. Of interest, only the EMT6 cell line was able to secrete the proangiogenic molecule, vascular endothelial growth factor (VEGF), in response to low oxygen conditions. Fluorescent staining of the vascular endothelium at the tumor injection site provided images depicting early stages of angiogenesis prior to K1735/IL‐12 tumor outgrowth. These results indicate that locally produced IL‐12 likely mediates the rejection of EMT6 tumors through tumor cell lysis by host immune cells, whereas its antiangiogenic potential may be counterbalanced by the strong induction of VEGF by hypoxic tumor cells. In contrast, IL‐12 does not induce protective immunity to K1735 tumors. However, an antiangiogenic mechanism may be responsible for controlling tumor growth. © 2003 Wiley‐Liss, Inc.
Plasma MMP‐9 (92 kDa‐MMP) activity is useful in the follow‐up and in the assessment of prognosis in breast cancer patients
Authors: Ranuncolo Stella Maris , Armanasco Eduardo , Cresta Carlos , Bal de Kier Joffe Elisa , Puricelli Lydia 
Published: July 2003

AbstractPreviously we determined that plasma MMP‐9 activity was significantly elevated in breast cancer patients compared to benign mammary pathologies and healthy controls. Now we analyzed its potential usefulness in the follow‐up and in the prognosis of these patients. MMP‐9 activity was measured by gelatin quantitative zymography in the euglobulin plasma fraction of 46 breast cancer patients in a 38‐month follow‐up study. Blood samples were obtained before surgery (S1), 1 month after (S2) and every 3 months. The relapse‐free survival (RFS) and overall survival (OS) analysis was performed along 56 months in 113 patients using the Kaplan‐Meier curves and Cox analysis. In 63% of the S2 analyzed, MMP‐9 decreased after surgery. In 44 patients evaluated during the adjuvant period who developed a complete response, MMP‐9 decreased compared to their S1, whereas 2 patients showed an enhancement in correlation with lack of response. Further analysis indicated that in all patients who never showed evidence of recurrence, plasma MMP‐9 activity remained low, but it increased 1 to 8 months preceding the clinical detection of progression in those patients who relapsed. Kaplan‐Meier curves indicated that high levels of plasma MMP‐9 activity at the moment of breast cancer diagnosis were associated with a worse OS rate. Cox analysis showed it was not associated with tumor stage or patient's age. Our results, which show a good correlation between plasma MMP‐9 activity and the clinical status of each patient, suggest its usefulness as a marker both in the follow‐up and in the prognosis of breast cancer patients. © 2003 Wiley‐Liss, Inc.
Nitric oxide suppresses apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions
Authors: Wenzel Uwe , Kuntz Sabine , de Sousa Ulrike Jambor , Daniel Hannelore 
Published: July 2003

AbstractIn cells lacking a functional p53 tumor suppressor protein, the endogenous free radical nitric oxide (NO) appears to inhibit apoptosis, and thereby promotes growth of cancer cells. In order to elucidate the underlying mechanisms on a molecular basis, we used HT‐29 human colon carcinoma cells, carrying a p53 loss‐of‐function mutation, and examined the effects of NO on apoptosis when induced either by the flavonoid flavone or by the chemotherapeutic drug camptothecin (CPT), which is able to scavenge NO by superoxide anion production. Caspase‐3 activation as well as nuclear fragmentation, both indicative of apoptosis, were dose dependently inhibited by the NO‐liberating agents sodium nitroprusside (SNP) or S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP) when apoptosis was initiated by flavone with only minor effects on apoptosis when initiated by camptothecin. The transcript levels of 9 apoptosis‐related genes were assessed and NO liberation was shown to completely and specifically prevent the flavone‐induced but not camptothecin‐induced decrease in bcl‐XL mRNA levels. These results were also confirmed at the protein level. The effects of NO on the mitochondrial apoptosis pathway were further evidenced by the scavenging of superoxide anions as produced in mitochondria of cells undergoing apoptosis. Scavenging of mitochondrial superoxide anions by NO prevents the downregulation of bcl‐XL, the depolarization of the mitochondrial membrane potential, the cytochrome c release and finally the activation of caspase‐3. In conclusion, NO effectively inhibits apoptosis by scavenging superoxide anions generated in the mitochondria of p53 mutant cells and thereby prevents the downregulation of the antiapoptotic factor bcl‐XL, which controls the mitochondrial apoptosis pathway. © 2003 Wiley‐Liss, Inc.
Neutrophils influence melanoma adhesion and migration under flow conditions
Authors: Slattery Margaret J. , Dong Cheng 
Published: July 2003

AbstractWe have studied human melanoma cell (C8161) adhesion and migration in response to stimulation by soluble collagen IV (CIV) using a modified Boyden chamber. In this modified chamber, shear flow can be introduced over the cell‐substrate interface, affecting tumor cell chemotactic migration through a microporous filter. A relatively high level of intercellular adhesion molecule‐1 (ICAM‐1) was found on C8161 cells. In contrast, levels of β2‐integrins (e.g., LFA‐1 and Mac‐1), the molecules that would be necessary for C8161 stable adhesion to the endothelium substrate, were found to be very low on these melanoma cells. As a result, C8161 transendothelial migration under a flow condition of 4 dyn/cm2 decreased by 70% as compared to static migration. When human neutrophils (PMNs) were present in the tumor cell suspension, C8161 migration recovered by 85% over C8161 cells alone under the 4 dyn/cm2 flow condition. Blocking ICAM‐1 on C8161 cells or Mac‐1 on PMNs significantly inhibited C8161‐PMN adhesion and subsequent C8161 migration through the endothelium under flow conditions. In addition, increased interleukin‐8 production and Mac‐1 expression by PMNs were detected when they were co‐cultured with C8161 melanoma cells. These results suggest that transmigration of C8161 cells under flow conditions can be influenced by PMNs, mediated by Mac‐1/ICAM‐1 adhesive interactions and enhanced by altered cytokine production. © 2003 Wiley‐Liss, Inc.