bluuebunny/crossref_metadata_2025 huggingface dataset:
A fetal rat urogenital sinus mesenchymal cell line (rUGM): Accelerated growth and conferral of androgen‐induced growth responsiveness upon a human bladder cancer epithelial cell line IN VIVO
Authors: Zhau Haiyen E. , Hong Sung‐Joon , Chung Leland W. K.
Published: February 2007

A cell‐cell interaction model was developed to examine the intercellular communication between mesenchymal and epithelial cells in vivo, and to define the role of androgen and paracrine growth factors in promoting growth and differentiation of the target epithelial cells. Using this model system, we have demonstrated that, in the presence of andrqgenic steroids, a fetal urogenital sinus mesenchymal cell line exhibited androgen‐induced growth responses which resulted in an induction of growth of a non‐androgen target epithelial cell line derived from human urinary bladder. Our results show that: (1) a rat fetal urogenital sinus mesenchyme‐derived cell line (rUGM) accelerated growth and conferred androgen‐induced growth responsiveness upon a non‐androgen target cell line, WH, derived from a human bladder transitional‐cell carcinoma (TCC); this induction of epithelial tumor growth in vivo occurred in a fibroblast‐specific manner; (2) live fetal rUGM cells are required to promote WH tumor growth in vivo, which suggests that continuous production of factors that may serve as mediators for paracrine/autocrine pathways are responsible for androgen stimulation of WH tumor growth in vivo; and (3) although WH tumor growth, mediated by the presence of rUGM cells, was markedly accelerated by the presence of androgen in vivo, androgen and rUGM cells failed to promote the expression of a human prostate‐specific antigen (PSA) by WH tumors in vivo. Our results emphasize the importance of organ‐specific fibroblasts that promote tumor growth and mediate androgen‐induced growth responses; the accelerated growth of the bladder epithelium was not accompanied by the expression of PSA, a known differentiated gene product produced by human prostatic epithelial cells. This report also discusses the potential significance of mesenchymal‐epithelial cellular interaction which mediates androgen action and may play an important role by influencing human prostate tumor growth, progression and differentiation.
Effect of immunomodulators on specific tumor immunity induced by liposome‐encapsulated tumor‐associated antigens
Authors: Bergers Joep J. , Den Otter Willem , Dullens Hub F. J. , De Groot Jan Willem , Steerenberg Peter A. , Filius Margreet P. G. , Crommelin Daan J. A.
Published: February 2007

Reconstituted membranes consist of liposomal structures formed by removal of detergent from solubilized membrane constituents. The membrane‐like configuration of reconstituted membranes makes them attractive as vehicles for presentation of tumor‐associated antigens and induction of immune responses. In this study the potential of immunomodulators was assessed to enhance the specific immune response induced by immunization with reconstituted membranes prepared from SL2 lymphosarcoma cells. Reconstituted membranes containing muramyl tripeptide phosphatidylethanolamine (MTP‐PE) provided better protection against a challenge with SL2 cells than did reconstituted membranes containing alternative immunomodulators. Local administration of IL‐2 at the immunization sites further augmented the protection induced by reconstituted membranes with MTP‐PE, but was ineffective when administered with plain reconstituted membranes. Immunity elicited by the triple modality of reconstituted SL2 membranes with MTP‐PE and IL‐2 was specific for SL2 cells. Systemic immunity was obtained against a challenge with a 100‐fold higher number of SL2 cells than was reached after immunization with reconstituted membranes alone (105 vs. 10 SL2 cells). Macrophages isolated from the peritoneal cavity of immunized mice 5 to 7 days after tumor challenge expressed high In vitro cytotoxicity. However, in contrast to the observed specificity of the systemic immunity, macrophages killed both SL2 cells and non‐related P815 cells. Neither major cytotoxic lymphocyte activity nor substantial cytotoxic antibody tilers were detectable. These results clearly indicate that the approach using reconstituted membranes combined with particular immunomodulators warrants further exploration for the development of safe, well‐characterized cancer vaccines.
RT‐PCR detection of fibronectin EDA+ and EDB+ mRNA isoforms: Molecular markers for hepatocellular carcinoma
Authors: Tavian Daniela , De Petro Giuseppina , Colombi Marina , Portolani Nazario , Giulini Stefano Maria , Gardella Rita , Barlati Sergio
Published: February 2007

Alternative splicing of fibronectin pre‐mRNA has been shown to be independently regulated at the EDA and EOB regions in a tissue and developmental stage‐specific manner. In this study, RT‐PCR approaches were developed for the detection of EDA and EDB FN mRNA isoforms in hepatocarcinoma cells (SK‐Hep‐I) grown in vitro and in human liver biopsies. While EDA+ and EDB+ isoforms were not present in control adult liver, they were detectable in the hepatocarcinoma cells and in fetal liver. The RT‐PCR analysis, extended to biopsies of malignant and non‐malignant hepatic tissues, showed that FN mRNAs containing the EDA and EDB sequences were present in the 14 hepatocelfular carcinomas (HCCs) tested but absent in the non‐tumorous liver tissues (i.e., normal parenchyma, nonspecific reactive and chronic hepatitis, steatosis). The EDB+ FN mRNA isoforms were also detected in 3 cases of benign neoplasm (hepatocellular adenoma, HCA, I; nodular focal hyperplasia, NFH, 2), while the EDA+ was only detectable in I of the 2 cases of NFH. In addition, both EDA+ and EDB+ isoforms were expressed in 5 out of 9 cirrhotic livers surrounding the tumors. This molecular analysis, which can also be performed on small liver biopsies (2 mg), may therefore be a useful additional tool in the diagnosis of HCC.
Expression of mage genes by non‐small‐cell lung carcinomas
Authors: Weynants P. , Lethé B. , Brasseur F. , Marchand M. , Boon T.
Published: February 2007

Human gene MAGE‐1 codes for an antigen that is recognized on melanoma cells by autologous cytolytic T lymphocytes (CTL). This antigen is potentially useful as a target for cancer immunotherapy because gene MAGE‐1 is not expressed in any normal tissues except the testis. We tested 46 surgical samples of non‐small‐cell lung carcinomas and observed MAGE‐1 expression in 16 of them (35%). Genes MAGE‐2 and 3, which are closely related to MAGE‐1, were expressed by a similar proportion of these tumors. Some small‐cell lung tumors also express MAGE genes. The proportion of tumors expressing MAGE‐1 suggests that lung tumor patients may constitute the largest group of patients potentially eligible for pilot studies involving MAGE‐1 immunization.
Retroviral‐mediated transduction of p53 gene increases TGF‐β expression in a human glioblastoma cell line
Authors: Fujiwara Toshiyoshi , Mukhopadhyay Tapas , Cai De Wei , Morris Danna K. , Roth Jack A. , Grimm Elizabeth A.
Published: February 2007

Transforming growth factor‐β (TGF‐β) has been implicated as a potent growth regulator; the degree of responses to it, whether positive or negative, generally correlates with the stage of cell differentiation in various cell types. We examined the effect of the p53 gene, which participates in the control of cell‐cycle progression, on the expression of human TGF‐β. The human glioblastoma cell line SNB‐19, which expresses the latent form of TGF‐β, was transfected with a retroviral vector containing wild‐type p53 (wt‐p53) or p53 with a mutation (mut‐p53) at codon 273. Stable G418‐resistant SNB‐19 clones were isolated. The growth kinetics of wt‐p53 transfectants were suppressed compared with those of parental cells, vector transfectants, or mut‐p53 transfectants, as assayed by growthcurve measurements and H‐thymidine incorporation; how‐, ever, RNA dot blot and Western blot analyses demonstrated that wt‐p53 and mut‐p53 transfectants expressed higher amounts of TGF‐β1 and TGF‐β2 mRNA and intracellular TGF‐β isoform proteins, respectively, than parental cells. By means of the biological assay for active TGF‐β (MvlLu cell‐growth‐inhibition assay), we observed that both transfectants produced active TGF‐β, whereas the parental cells produced only the latent form. These results suggest that, while only the wt‐p53 gene inhibits tumor‐cell progression, both wt‐p53 and codon 273‐mutated p53 can cause increased TGF‐β expression.
Cytotoxicity and characterization of an active metabolite of benzamide riboside, a novel inhibitor of IMP dehydrogenase
Authors: Gharehbaghi Kamran , Paull Kenneth D. , Kelley James A. , Barchi Joseph J. , Marquez Victor E. , Cooney David A. , Monks Anne , Scudiero Dominic , Krohn Karsten , Jayaram Hiremagalur N.
Published: February 2007

Benzamide riboside exhibits significant cytotoxicity against a variety of human tumor cells in culture. On the basis of metabolic studies, the primary target of this drug's action appears to be IMP dehydrogenase (IMPDH). Incubation of human myelogenous leukemia K562 cells with an IC50 concentration of benzamide riboside resulted in an expansion of IMP poofs (5.9‐fold), with a parallel reduction in the concentration of GMP (90%), GDP (63%), GTP (55%) and dGTP (40%). On kinetic grounds, it was deduced that benzamide riboside (whose Ki versus IMPDH is 6.4 mM, while that of its 5′‐monophosphate is 3.9 mM) or its 5′‐monophosphate were unlikely to be responsible for inhibition of this target enzyme, IMPDH, since only micromolar concentrations of benzamide riboside were needed to exert potent inhibition of tumor‐cell growth. Studies on the metabolism of this C‐nucleoside have revealed the presence of a new peak eluting in the nucleoside diphosphate area on HPLC. Treatment of this peak with venom phosphodiesterase degraded it and concurrently nullified its inhibitory activity versus IMPDH; alkaline phosphatase, on the other hand, totally failed to digest the anabolite. These results suggest that the metabolite in question is the phosphodiester, benzamide adenine dinucleotide (BAD). Evidence that the inhibitor was an analog of NAD, wherein the nicotinamide moiety has been replaced by benzamide, was provided by both NMR and mass spectrometric analysis and confirmed by enzymatic synthesis. Further insight into the nature of the active principle was obtained from kinetic studies, which established that BAD competitively inhibited NAD utilization by partially purified IMPDH from K562 cells with a Ki of O.118 μM. In concert, these studies establish that benzamide riboside exhibits potent antiproliferative activity by inhibiting IMPDH through BAD.
Clinical outcome of colorectal cancer patients treated with human monoclonal anti‐idiotypic antibody
Authors: Denton Gavin W. L. , Durrant Lindy G. , Hardcastle Jack D. , Austin Eric B. , Sewell Herb F. , Robins R. Adrian
Published: February 2007

A human monoclonal anti‐idiotypic antibody (105AD7) has been developed which mimics a colorectal‐tumour‐associated antigen and induces cellular anti‐colorectal tumour immune responses in animals. Thirteen patients with advanced colorectal cancer were immunized with 105AD7 and their survival was compared with that of a contemporary group of unimmunized patients with similar disease status. No toxicity related to anti‐idiotype immunization was seen. Cellular responses to anti‐idiotypic immunization were indicated by lymphocyte proliferation to gp72‐positive tumour cells, and production of interleukin‐2; anti‐tumour antibodies were not detected. Median survival following diagnosis of advanced disease of immunized patients was 12 months, compared with 4 months in unimmunized patients. The improved survival of immunized patients in this study without associated toxicity suggests that 105AD7 immunization may have considerable potential for immunotherapy of colorectal cancer. © Wiley‐Liss, Inc.
Invasion depth is the most important prognostic factor for transitional‐cell carcinoma in a prospective trial of radical cystectomy and adjuvant chemotherapy
Authors: Mazzucchelli Luca , Bacchi Marisa , Studer Urs E. , Markwalder Regula , Sonntag Roland W. , Kraft Rainer
Published: February 2007

The aim of this prospective study was to examine the prognostic pathomorphological factors in urothelial cancer of the urinary bladder. Clinical and morphological variables were evaluated by univariate and multivariate analysis in 70 patients with invasive transitional‐cell carcinoma of the bladder (pTI‐pT4a). The patients were treated according to a prospective program consisting of radical cystectomy and pelvic‐node dissection, either alone or followed by adjuvant cisplatinum chemotherapy. Nodal status was pN0 in 89% of the patients. The median follow‐up time was 5.75 years and the 5‐year survival was 58%. Among the morphologic variables, deep invasion of the bladder wall and squamous differentiation indicated a poorer prognosis. Differentiation grade, pattern of growth (infiltrating versus expanding), angioinvasive growth, glandular differentiation and concomitant prostate carcinoma (pT1) were not significative factors for survival. By contrast, a significant reduction in mortality rate was found in patients with concomitant carcinoma in situ. Multivariate analysis confirmed that depth of invasion is an independent prognostic factor of outcome. The results confirm the primary importance of tumor stage in the prediction of survival after radical cystectomy. © Wiley‐Liss, Inc.
Aberrations of tumor‐suppressor genes (p53, apc, mcc and Rb) in esophageal squamous‐cell carcinoma
Authors: Maesawa Chihaya , Tamura Gen , Suzuki Yasushi , Ogasawara Satoshi , Ishida Kaoru , Saito Kazuyoshi , Satodate Ryoichi
Published: February 2007

Loss of heterozygosity at 4 tumor‐suppressor gene loci (p53, apc, mcc and Rb) was investigated using polymerase chain reactions, in 49 esophageal squamous‐cell carcinoma specimens from patients who had undergone curative resection. Mutations in the p53 gene within exons 5 to 8 were also examined. LOH was detected in 9 (43%) of 21 p53 genes, 16 (55%) of 29 apc genes, 10 (48%) of 21 mcc genes, and 13 (52%) of 25 Rb genes for which heterozygosity could be determined. Mutations in the p53 gene were detected in 18 (36%) of 49 cases and were significantly more frequent in stage‐III tumors and in tumors exhibiting DNA aneuploidy. In 5 cases where heterozygosity could be determined for all the loci, all had 2 or more aberrations. Additionally, a heterozygous deletion of p53 gene was associated with a mutation of the remaining allele in 8 (89%) of 9 cases. Short‐term relapse within 3 to 12 months occurred significantly more frequently in patients having tumors with both p53 aberrations (p < 0.05). Thus, aberration of tumor‐suppressor genes was a frequent occurrence in esophageal squamous‐cell carcinoma and inactivation of the p53 gene may contribute to the progression of this tumor. © Wiley‐Liss, Inc.
Early‐life risk indicators of gastric cancer. A population‐based case‐control study in sweden
Authors: Hansson Lars‐Erik , Baron John , Nyrén Olof , Bergström Reinhold , Wolk Alicja , Lindgren Anders , Adami Hans‐Olov
Published: February 2007

Exposures early in life seem to play an important role in the development of gastric cancer, but their nature is not well understood. In a population‐based case‐control study, we examined weight, height and body‐mass index (BMI) at the age of 20 as well as indices of socioeconomic conditions. Face‐to‐face interviews were conducted with 338 of 456 eligible histologically confirmed gastric cancer patients and 679 of 880 eligible control subjects, sampled from population registers and frequency matched by age and gender. Gastric cancer risk was negatively associated with height. Risk was positively associated with weight at age 20 in both sexes. The highest BMI‐quartile was associated with an increased risk. This association between BMI and risk was confined to BMI at age 20, and disappeared for BMI 20 years prior to interview. High socioeconomic status (SES) as well as long education carried a decreased risk of gastric cancer. Number of siblings was positively associated with risk. Factors related to short stature and high adolescent body weight are associated with an increased risk of gastric cancer, as is a high number of siblings. These factors may reflect influences of dietary patterns early in life. © Wiley‐Liss, Inc.
Multiple sub‐sets of Cd4+ and Cd8+ cytotoxic T‐cell clones directed to autologous human melanoma identified by cytokine profiles
Authors: Maccalli Cristina , Mortarini Roberta , Parmiani Giorgio , Anichini Andrea
Published: February 2007

CD4+ and CD8+ cytotoxic T‐cell (CTL) clones, selected for T‐ceII‐receptor (TcR)‐dependent lysis of the autologous tumor and isolated from peripheral‐blood lymphocytes (PBL) or tumor‐infiltrating lymphocytes (TIL) of 3 melanoma patients, were characterized for the pattern of 13 different cytokines released by antibody‐ or tumor‐mediated triggering. Induction or enhancement of cytokine release by anti‐CD3 monoclonal antibody (MAb) led to the identification of 2 major sub‐sets of CD8+ CTL clones on the basis of production of IL‐4. Within the 2 groups of IL‐4‐producing or non‐producing clones, further sub‐sets could be identified on the basts of differential production of IL‐1 p, IL‐2, IL‐6, IL‐8, IL‐10, TNF‐α, TNF β and IFN‐γ. A similar analysis performed on a panel of CD4+ CTL clones indicated multiple patterns consistent with at least 4 major sub‐sets, but further complexity was evident in each sub‐set on the basis of differential production of IL‐1, IL2, IL‐6, IL‐10 and G‐CSF. The cytokine profile of CD4+ and CD8+ clones, as determined after anti‐CD3 stimulation, was different from the pattern seen after co‐culture with autologous tumor, since many clones released cytokines such as IL‐4, IL‐10, IFN‐α and‐β, TNF‐γ and GM‐CSF after activation with only 1 of the 2 stimuli. These results indicate that CD4+ and CD8+ CTL clones reacting to human melanoma belong to a highly complex repertoire of functional subsets characterized by distinct cytokine profiles. In addition, the cytokine pattern of each T‐cell sub‐set can be modulated by changing the activation signals delivered to the T cell. © Wiley‐Liss, Inc.
DNA base modifications in renal chromatin of wistar rats treated with a renal carcinogen, ferric nitrilotriacetate
Authors: Toyokuni Shinya , Mori Toshiaki , Dizdaroglu Miral
Published: February 2007

Ferric nitrilotriacetate (Fe‐NTA) causes renal proximal tubular necrosis, a consequence of iron ion‐mediated free‐radical‐associated damage, that finally leads to a high incidence of renal ad en oca re in dm a in male rats and mice. We have investigated the levels of typical hydroxyl radical‐induced DNA base modifications in renal chromatin of male Wistar rats treated with a single or repeated administrations of Fe‐NTA. Five pyrimidine‐derived and 5 purine‐derived modified DNA bases were identified and quantified by gas chromatography/mass spectrometry with selected‐ion monitoring. The modified bases were 5‐hydroxy‐5‐methylhydantoin, 5‐(hydroxymethyl)uracil, 5‐hydroxy‐cytosine, thymine glycol, 5,6‐dihydroxyuraril, 4,6‐diamino‐5‐form‐amidopyrimidine, 8‐hydroxyadenine, xanthine, 2‐hydroxyadenine and 8‐hydroxyguanine. The amounts of most of these compounds were significantly increased over control levels in renal chromatin of Fe‐NTA‐treated rats as measured 3 and 24 hr after treatment. Elevated levels of modified bases were accompanied by proximal tubular necrosis. On the 19th day, however, accumulation of modified DNA bases was not observed. Morphologically, scattered karyomegaiic cells were seen in the proximal tubules, but necrosis was rarely found. Some of the identified DNA base lesions are known to be promutagenic., although others have not been investigated. Presence of modified DNA bases concomitant with necrosis and regeneration of the renal proximal tubules may be a critical step in Fe‐NTA‐induced carcinogenesis. © Wiley‐Liss, Inc.
Reproductive history and cancer of the biliary tract in women
Authors: Moerman Clara J. , Berns Mary P. H. , de Messqita H. Bas Bueno , Runia Sytske
Published: February 2007

Although reproductive factors have been shown to be related to the composition of bile and functioning of the biliary system, their relationship with biliary tract cancer has not been studied in detail. Between 1984 and 1987 we conducted a case‐control study of 75 women with cancer of the biliary tract and 252 controls from the general population. An interviewer‐administered questionnaire was used to collect information on reproductive history. The information was obtained from the responders themselves (direct response) or from relatives (indirect response). Our results indicate that younger age at menarche, early age at first pregnancy, higher number of pregnancies and prolonged fertility may enhance the risk of cancer of the biliary tract. Overall, increased exposure to endogenous oestrogens and progesterone constitutes a higher risk. © 1994 Wiley‐Liss, Inc.
Time trends of lung and larynx cancers in Italy
Authors: Capocaccia Riccardo , Micheli Andrea , Berrino Franco , Gatta Gemma , Sant Milena , Ruzza Maria Rosa , Valente Fulvia , Verdecchia Arduino
Published: February 2007

During the period 1970‐1989, age‐adjusted mortality rates for lung cancer in Italy increased by more than 50%, while rates for larynx cancer in males decreased by approximately 13%. This study aims to interpret this difference, which seems to contradict the finding that cigarette smoking is a common major risk factor for both lung and larynx cancer. To this end, we jointly analyzed the time trends of incidence, survival and mortality. We first examined survival data taken from the population‐based Lombardy Cancer Registry (northern Italy). Based on data referring to 860 incident cases of larynx cancer, diagnosed during the period 1976‐1987, we estimated a 3% annual increase in relative survival. By contrast, no significant period effect was observed for survival rates of 2,259 incident cases of lung cancer.

National incidence rates were estimated using official mortality data and the above‐described survival data. Age‐adjusted estimated incidence rates increased, from 1970 to 1989, for both cancer sites: +55% for male lung, +56% for female lung, and +22% for male larynx. Moreover, the patterns of birth‐cohort effect, which are diverging for mortality, are nearly parallel with regard to incidence. This analysis suggests that a substantial improvement in survival of larynx cancer patients may largely explain the differences in mortality trends for cancer of lung and larynx. © 1994 Wiley‐Liss, Inc.
Multiple loci on human chromosome 11 control tumorigenicity of BK virus transformed cells
Authors: Sabbioni Silvia , Negrini Massimo , Possati Laura , Bonfatti Alessandra , Corallini Alfredo , Sensi Alberto , Stanbridge Eric J. , Barbanti‐Brodano Giuseppe
Published: February 2007

BK virus (BKV) is a human papovavirus that readily transforms rodent cells, but not human cells, to a neoplastic phenotype, suggesting that tumor‐suppressor functions expressed in human cells control BKV oncogenicity. Transfer of a normal human chromosome 11 to BKV‐transformed mouse cells suppresses the malignant phenotype. In this report we map the regions of chromosome involved in tumor suppression. Transfer of chromosome 11 to the BKV‐transformed hamster cell line HKBK produces monochromosomic hybrids retaining only portions of the transferred human chromosome. We have compared the tumorigenicity of the hybrids with the molecular mapping of chromosome 11 retained regions. This analysis indicated that 3 regions of human chromosome 11, 11p15.5, 11p13 and 11q13, cooperate in tumor suppression. However, 11q13 seems the most important, since all the HKBK/H11‐induced tumors analysed had lost this region, whereas 11p15.5 and 11p13 were sometimes retained. The chromosomal regions identified in this study are deleted in several types of human tumors, suggesting that the BKV transformation system specifically detects tumor‐suppressor genes on chromosome 11 that are involved in human oncogenesis. This model may be of use in isolating and cloning such genes. The results of this report raise the possibility that BKV may have a synergistic tumorigenic effect in human cells where tumor‐suppressor genes controlling its oncogenk potential are inactivated. © 1994 Wiley‐Liss, Inc.
Mechanism of inhibition of fadu hypopharyngeal carcinoma cell growth by tetraphenylphosphonium chloride
Authors: Rideout Darryl , Bustamante Andres , Patel Jasmin
Published: February 2007

Cationic phosphonium salts are interesting because they inhibit the proliferation of carcinoma cells more than untransformed epithelial cells in vitro. This differential anti‐proliferative effect has been used to identify phosphonium salts and other lipophilic cations that later demonstrated effects in animals. Using 6 carcinoma‐derived and 2 untransformed epithelial cell lines, tetraphenylphosphonium chloride (TPP) and other cat‐ionic aryl phosphonium salts (CAPS) demonstrated a growth inhibition pattern similar to that of cation rhodamine 123, suggesting that CAPS may inhibit mitochondrial function. We tested this hypothesis for the effect of phosphonium salt TPP on FaDu human hypopharyngeal carcinoma cells. TPP inhibited the proliferation of FaDu carcinoma cells at submicromolar concentrations. Uptake of 3H‐TPP by FaDu cells was partially inhibited in medium containing high K+ and fully inhibited by valinomycin in this medium, indicating that TPP accumulates preferentially in mitochondria, and to a lesser extent in the cytoplasm. FaDu cells exposed to TPP exhibited damage to mitochondrial inner membranes, reduced ATP/ADP ratios, decreased oxygen uptake rates and decreased mitochondrial membrane potentials. The treated cells secreted lactate more rapidly than untreated controls and exhibited hypersensitivity to 2‐deoxyglucose, an inhibitor of glycolysis. TPP's antimitochondrial effects apparently enhance cytoplasmic glycolysis. In conclusion, TPP inhibits FaDu carcinoma cell growth by inhibiting mitochondrial respiration and ATP synthesis. Cationic phosphonium salts that inhibit carcinoma cell growth through anti‐mitochondrial effects might be used to treat solid tumors without the risk of secondary tumors associated with agents affecting nuclear DNA. © 1994 Wiley‐Liss, Inc.
Interleukin‐6 serum levels in patients with gynecological tumors
Authors: Scambia Giovanni , Testa Ugo , Panici Pierluigi Bendetti , Martucci Robert , Foti Elvira , Petrini Marina , Amoroso Mariangela , Masciullo Valeria , Peschle Cesare , Mancuso Salvatore
Published: February 2007

Serum levels of IL‐6 were evaluated in a large group of patients with benign or malignant gynecological tumors. The results obtained were correlated with the patients' clinicopathological features and follow‐up data. Using a highly sensitive immunoenzymatic method for the evaluation of serum IL‐6 levels, we observed that > 5% of normal healthy women exhibited values within the range of 1.9‐6 pg/ml. Using a cut‐off of pg/ml, elevated levels of serum IL‐6 were found in 53% of 45 patients with primary epithelial ovarian cancer and less frequently in patients with endometrial and cervical cancer (37% and 10% respectively). Elevated levels of IL‐6 were occasionally seen in patients with benign disease. IL‐6 serum levels appeared to be less sensitive than CA 125 in ovarian cancer diagnosis. In cancer patients, increased IL‐6 serum levels were related to the presence of the tumor since all post‐operative patients exhibited a marked decrease. In patients with advanced ovarian cancer post‐operative levels of IL‐6 correlated with residual disease. Very high levels of IL‐6 were observed in the ascitic fluid of9 ovarian cancer patients, but IL‐6 mRNA was not detected in tumor cells. This suggests that the increased production of IL‐6 observed in ovarian cancer is reactive. Higher levels of IL‐6 were found in patients unresponsive to chemotherapy, as compared with responsive ones. Univariate analysis of survival data suggests that increased IL‐6 serum levels correlate with negative prognosis. © 1994 Wiley‐Liss, Inc.
p53 mutations in human tumors with chimeric EWS/FLI/1 genes
Authors: Hamelin Richard , Zucman Jessica , Melot Thomas , Delatre Olivier , Thomas Gilles
Published: February 2007

The Ewing family of tumors is recurrently characterized at the molecular level by the presence of a fusion transcript between the EWS gene on chromosome 22 and either the FL‐I or ERG genes, 2 closely related members of the Ets family of transcription factors. We have investigated 12 primary human tumors, II xenografts and II cell lines, which have been shown to express chimeric EWS transcripts in search of p53 mutations. Fragments of exons 5 to 8 and the corresponding consensus splice sequences were amplified by PCR and analyzed by denaturing gradient gel electrophoresis (DGGE). In 12 of 34 samples p53 mutations were detected (including 4 samples with multiple p53 mutations). The distribution of the mutations in the various samples was as follows: primary tumors 2/12; cell lines 5/11; xenografts 5/11. No correlation between the presence or absence of p53 mutations and the presence of a specific EWS chimeric transcript was observed. In addition, we observed that p53 mutations were almost always associated with a second hit (either deletion or second mutation) on the other p53 allele. © 1994 Wiley‐Liss, Inc.
Evaluation of the secretory component as a prognostic variable in colorectal carcinoma
Authors: Koretz Karin , Schlag Peter , Quentmeier Armin , Möller Peter
Published: February 2007

Expression of the secretory component (SC) of IgA was investigated in normal colonic mucosa, in adenomas and in 188 colon carcinomas. Of the carcinoma patients, 149 underwent potentially curative surgical treatment. In particular, it was of interest to determine whether pathohistological or clinical parameters showed any association with the mode of SC expression in carcinomas. Irrespective of anatomical site, normal colon mucosa was generally SC‐positive. Normal epithelium, however, displayed microheterogeneity in SC content, which was related to columnar and goblet‐cell type and micro‐topographical site, implying a subtle regulatory mechanism. In contrast to adenomas, which were evenly SC‐positive and showed focally weak SC expression in only 2 out of 20 cases, carcinomas were rather heterogeneous in their SC‐expression pattern. In all, 48 carcinomas were entirely positive, 48 were completely negative and the remaining 92 showed various patterns of heterogeneous SC expression. The mode of SC expression was correlated with tumor staging, i.e., complete absence of SC was more often found in Dukes' C and D groups. In addition, the presence of SC in carcinomas was statistically correlated with the mucinous type. The mode of SC expression was not correlated with tumor grading and tumor location. The rate of disease‐free survival and the risk of tumor‐related death revealed a significant correlation with the mode of SC expression when patients who had received potentially curative or non‐curative treatment were included in the log‐rank test. Absence or low levels of SC expression were more frequent in the group that suffered a tumor relapse than in the recurrence‐free cohort. Tumor‐related death was more frequent when primaries were characterized by absence or low levels of SC expression. We conclude that absence or low levels of SC expression are an unfavorable prognostic variable in colorectal carcinoma. © 1994 Wiley‐Liss, Inc.
Effects of urinary trypsin inhibitor on the invasion of reconstituted basement membranes by ovarian cancer cells
Authors: Kobayashi H. , Fujie M. , Shinohara H. , Ohi H. , Sugimura M. , Terao T.
Published: February 2007

Using the human ovarian cancer cell line HOC‐I, we investigated the effects of urinary trypsin inhibitor (UTI) purified from human urine and its related synthetic peptides on the invasive potential of cancer cells in an in vitro assay. Invasiveness of tumor cells was determined using a modified Boyden chamber and a reconstituted basement membrane Matrigel. Three peptides (peptide 1, peptide 2, and peptide 3), representing sequences within UTI, were synthesized. HOC‐I cells showed detectable and reproducible levels of expression of surface urokinase‐type plasminogen activator (uPA) and plasminogen/plasmin by cell ELISAs and enzyme assays. UTI was found to strongly inhibit plasmin and human leukocyte elastase (HLE). Peptide 2 and peptide 3 specifically inhibit HLE and plasmin activity respectively. Peptide 1 has essentially no inhibitory activity. Treatment with UTI and peptide 3 reduces the incidence of invasion, whereas peptide 1 and peptide 2 do not affect invasion. The inhibitory effect on cell invasion is dose‐dependent. The proteolytic enzyme plasmin may be involved in human ovarian cancer invasion in extracellular matrix degradation, and the use of UTI and peptide 3 that inhibits plasmin specifically reduces invasion by tumor cells. © 1994 Wiley‐Liss, Inc.
Regulation of cell survival in burkitt lymphoma: Implications from studies of apoptosis following cold‐shock treatment
Authors: Gregory Christopher D. , Milner Anne E.
Published: February 2007

Burkitt lymphoma (BL) tumour‐cell populations are known to display high rates both of proliferation and of apoptosis in vivo, but the mechanisms which determine whether a BL cell continues to cycle or engages its cell‐death programme are not understood. Group‐I BL‐derived cell lines, which retain in vitro the proliferateve and apoptotic capacities of the parental cells, selectively entered apoptosis when returned to 37°C after a brief period at low temperature (1°C). The induction of apoptosis by cold treatment, as determined by morphological characteristics and DNA fragmentation, was readily detectable within the first 1 to 2 hr of re‐incubation at 37°C, reaching a maximum at 4 to 6 hours. Commitment to enter apoptosis occurred after as little as 20 to 30 min at 1°C. Significant cell death at 1°C occurred only during prolonged incubation in the cold and displayed the characteristics of necrosis. Both bc1‐2‐dependent and ‐independent survival pathways were found to provide protection from cold‐induced apoptosis, but only if engaged before cold‐shock treatment. These results indicate that continued cycling of group‐1 BL cells is dependent upon their capacity to inhibit or circumvent their normally constitutively active apoptotic programme, and are consistent with the notion that the synthesis of one or more critical “survival” proteins of short half‐life is necessary to guarantee successful passage through the cell cycle. Notably, high levels of apoptosis were also inducible in group‐1 BL cells by inhibitors of RNA and protein synthesis. © 1994 Wiley‐Liss, Inc.
Developmental stages in experimental liver metastases: Relation to invasiveness
Authors: Dingemans Koert P. , van den Bergh Weerman Marius A. , Keep Robert F. , Das Pranab K.
Published: February 2007

We have previously reported that an invasive morphotype can be evoked in a rat colon carcinoma by transplanting it into pre‐induced subcutaneous granulation tissue. We have now studied the interaction of the same tumor with liver tissue, which is extremely poor in connective tissue in comparison with the subcutaneous site. Tumor cells were injected into the portal system and the resulting experimental liver metastases were examined by electron microscopy and immunohistochemistry. Early metastases consisted of well‐differentiated acini, fully surrounded by connective tissue that was derived from the periportal stroma. In a later stage, this connective tissue was overgrown by tumor cells and, almost immediately, acinar differentiation was lost. Most metastases eventually reached the liver capsule, which reacted by forming a layer of granulation tissue. Only in this layer, we observed invasion by thin tumor cell strands, which were often intimately associated with fibroblasts or with blood capillaries. The tumor cells remained smooth and rounded during this process. After fully penetrating the granulation tissue, the tumor cell strands reached the liver surface, where they formed poorly structured papillary masses that were nearly devoid of stroma. Our observations indicate that, even in a relatively homogeneous organ like the liver, the tumor‐host interaction is highly complex and dynamic. They also confirm the notion that granulation tissue stimulates tumor invasiveness. Finally, they show that tumor cells can actively invade host tissues without exhibiting a “fibroblastic” morphology. © 1994 Wiley‐Liss, Inc.
Correlation between p53 gene expression and tumor‐cell proliferation in oropharyngeal cancer
Authors: Bourhsis J. , Boso J. , Wilson G. D. , Bressac M. , Talbot M. , Leridant A. M. , Dendale R. , Janin N. , Armand J. P. , Luboinski B. , Malaise E. P. , Wibault P. , Eschwege F.
Published: February 2007

The aim of our study was to analyze the correlation between tumor‐cell kinetics measured in vivo and p53 gene expression in a series of 49 oropharyngeal cancers. The duration of the S phase (TS), the labelling index (LI) and the potential doubling time (Tpot) were obtained by flow‐cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromode‐oxyuridine into patients. An adjacent section of the same samples was studied by immunohistochemistry for the detection of p53 protein. Over‐expression of the p53 protein, as defined by strong p53 immunostaining of tumor nuclei, was found in 23/49 of the samples. Aneuploid tumors showed a higher LI, a shorter Tpot and a higher proportion of p53 gene over‐expression. A significant correlation was seen between p53 over‐expression and short Tpots. Indeed 87.5% of the tumors with a very short Tpot (⩽ 3 days) had p53 over‐expression, as compared with 27% of tumors with a longer Tpot (>3 days). Our data strongly suggest that over‐expression of the p53 gene is associated with rapid tumor‐cell proliferation in this type of cancer. © 1994 Wiley‐Liss, Inc.
Karyotypic characterization of bronchial large cell carcinomas
Authors: Johansson Maria , Dietrich Claudia , Mandahl Nils , Hambraeus Göran , Johansson Leif , Clausen Per Praetorius , Mitelman Felix , Heim Sverre
Published: February 2007

Cytogenetic analysis of short‐term cultures from 26 primary bronchial large cell carcinomas and 1 metastasis from a primary large cell carcinoma revealed clonal chromosome abnormalities in 20 tumors and a normal karyotype in 6. No outgrowth was obtained in 1 case. Simple aberrations were present in 3 tumors; in 1, the only change was a reciprocal translocation between chromosomes 1 and 6, in another the sole anomaly was a supernumerary marker ring chromosome and in a third loss of the Y chromosome was the only clonal change. The remaining 17 tumors had complex karyotypes. The chromosomes most frequently involved in structural rearrangements were chromosomes 1, 2, 3, 5, 6, 7, 6, 10, 11, 13, 14 and 17. The bands most frequently affected were 1q11‐12, 1p13. 7q11, and 17p11‐13. The rearrangements led to repeated losses of 1p, 1q, 3p, 6q, 7q and 17p and gains of 5q and 7p. The emerging karyotypic picture of large cell lung carcinomas indicates more similarities with adenocarcinomas than with other pathologic subgroups of lung cancer. © 1994 Wiley‐Liss, Inc.
Inhibition of growth of MKN45 human gastric‐carcinoma xenografts in nude mice by treatment with bombesin/gastrin‐releasing‐peptide antagonist (RC‐3095) and somatostatin analogue RC‐160
Authors: Pinski Jucek , Halmos Gabor , Yano Tetsu , Szepeshazi Karoly , Qin Yunfeng , Ertl Tibor , Schally Andrew V.
Published: February 2007

Nude mice bearing xenografts of the gastrin‐responsive human gastric carcinoma MKN45 cell line were treated for 4 to 5 weeks with bombesin/gastrin‐releasing‐peptide(GRP) antagonist (RC‐3095), somatostatin analogues RC‐160 and SMS 201‐995, or the combination of RC‐3095 and RC‐160. Tumor volumes and weights were reduced significantly to a similar extent by RC‐160 and SMS 201‐995, administered by daily s.c. injections at a dose of 100 μg/day. Bombesin/GRP antagonist RC‐3095, given s.c. at a dose of 20 μg/day, had the greatest inhibitory effect on tumor growth. The combination of RC‐3095 with RC‐160 did not further potentiate the suppression of tumor growth. Histologically, the number of mitotic cells decreased significantly in the groups treated with RC‐160 or the combination of RC‐3095 with RC‐160. Serum gastrin levels were significantly diminished in all treated groups. Therapy with RC‐160 or the combination also significantly decreased levels of serum growth hormone. Receptor assays on tumor membranes showed that bombesin was bound to 2 classes of receptor sites, one with high affinity and low capacity, the other with low affinity and high capacity. Binding sites for epidermal growth factor (EGF) were down‐regulated in tumor cells after treatment with RC‐3095, RC‐160 or the combination of RC‐3095 with RC‐160. In studies in vitro, both RC‐160 and RC‐3095 significantly inhibited the proliferation of MKN45 cells in culture as measured by cell number. These data demonstrate, for the first time, that the growth of human gastric cancer in nude mice can be inhibited not only by somatostatin analogues, but also by administration of modern bombesin/GRP antagonists, such as RC‐3095. © 1994 Wiley‐Liss, Inc.
Adoptive immunotherapy of established tumors. Acquisition of radioresistance by tumor‐specific T cells after passive transfer into tumor‐bearing recipients
Authors: Dunn Pamela L. , North Robert J.
Published: February 2007

The present study was undertaken to determine the sensitivity to ionizing irradiation of T cells from mice immunized against the Meth‐A fibrosarcoma and P815 mastocytoma after the transfer of these cells into tumor‐bearing recipients. It was found that T cells from memory‐immune donors were destroyed by exposing recipients to 500 rad of gamma irradiation up to 46 hr after transfer of the cells, but not thereafter. In contrast, activated immune cells were resistant to irradiation immediately after transfer. T cells were considered to be actively immune if they were harvested from donors in the process of rejecting their tumor, and were replicating, as evidenced by sensitivity to vinblastine. Memory‐immune cells, on the other hand, were T cells that were harvested long after rejection of the immunizing tumor and were vinblastine‐resistant. Additional results showed that CDB+ memory T cells were needed to cause regression of Meth‐A tumor in recipients, whereas CD4+ memory T cells were needed for P8IS tumor regression. These results support the idea that T cells that mediate tumor regression in this model of adoptive immunotherapy are radiosensitive while resting, and radioresistant after becoming activated. This knowledge needs to be taken into account when considering ionizing radiation as an immunomodulating agent for tumor immunotherapy. © 1994 Wiley‐Liss, Inc.
Flow‐cytometric and quantitative histologic parameters as prognostic indicators for occult retroperitoneal disease in clinical‐stage‐I non‐seminomatous testicular germ‐cell tumors
Authors: de Riese Werner T. W. , de Riese Cornelia , Ulbright Thomas M. , Walker Edwin B. , Messemer Jon , Jones Jeffrey A. , Reister Terry , Albers Peter , Allhoff Ernst P. , Foster Richard S. , Donohue John P.
Published: February 2007

Our study was performed to clarify whether the combination of DNA flow‐cytometric and quantitative histopathological parameters improves the prediction of occult metastatic disease in clinical stage‐I non‐seminomatous testicular germ‐cell tumors (NSGCT). We used archival paraffin primary‐tumor tissue of 67 clinical stage‐I NSGCT patients who had undergone retroperitoneal lymph‐node dissection (RPLND). According to the RPLND specimens, 24 patients were at pathological stage I and 43 at pathological stage II. Archival blocks were redissected for histological re‐evaluation. In addition, 50 μm sections were prepared according to the Hedley technique in order to obtain nuclear suspensions which were processed for flow cytometry (FC). In univariate analysis, the percentage of embryonal carcinoma, the percentage of immature teratoma and vascular invasion were the most accurate predictive histopathological parameters. The percentage of aneuploid cells in S‐phase was the best predictive FC parameter. In multivariate analysis, the percentage of embryonal carcinoma and the S‐phase fraction of aneuploid cells were the only independent markers for occult metastatic disease. According to this statistical approach, 91.0% of pathological stage‐I and stage‐II cases were correctly classified. Sensitivity was 95.3% and specificity was 83.3%. Using histopathological criteria alone, only 56.7% NSGCT patients were correctly classified.
Prognostic factors in renal‐cell carcinoma: Immunohistochemical detection of p53 protein versus clinico‐pathological parameters
Authors: But Fredrik J. , Godschalk Josian C. J. , Krishnadath Kausilia K. , Van Kwast Theo H. M. Der , Bosman Fred T.
Published: February 2007

Immunoreactivity forp53 protein was assessed in 100 cases of primary renal‐cell carcinoma (RCC). The results were correlated with clinical survival data (follow‐up 24 to 84 months: mean: 39 months) and with clinico‐pathological parameters, including nuclear grade, tumour stage, cell type, tumour architecture and tumour diameter. In all, 32% of the tumours were p53‐positive; there was no difference in survival between p53‐positive and ‐negative cases. Similarly, p53 expression did not correlate with any of the clinico‐pathological parameters mentioned. Nuclear grade (grade 1 + 2 vs. grade 3 + 4) had a striking impact on prognosis and so, to a lesser extent, did tumour stage and the occurrence of a spindle‐cell component. The immunohistochemical detection of p53 in RCC is not of prognostic value. The estimation of nuclear grade, however is a major predictor of prognosis.
Nutrients and gastric cancer risk. A population‐based case‐control study in Sweden
Authors: Hansson Lars‐Erik , Nykén Olof , Beagström Reinhold , Wolk Alicja , Lindgren Anders , Baron John , Adami Hans‐Olov
Published: February 2007

A population‐based case‐control study of gastric cancer was conducted in areas with contrasting incidence rates in Sweden. Face‐to‐face interviews were carried out with 338 (74.1 %) of all eligible cases and 679 (77.3%) of the selected controls. Consumption of selected nutrients during adolescence and 20 years prior to interview was estimated, together with life‐time intake of vitamin supplements. Ascorbic acid and β‐carotene had an unequivocal protective effect, but α‐tocopherol and nitrate were also negatively associated with gastric‐cancer risk. In a multivariate analysis including all of these factors, only ascorbic acid remained a significant protective factor. The only macronutrient positively associated with the risk of gastric cancer was fat: intake 20 years prior to interview, but not during adolescence, was found to have a significant impact. Supplementation with vitamins almost halved the risk after adjustment for dietary intake of the corresponding vitamins. While the protective effect of vitamin C and β‐carotene could conceivably be ascribed to other agents in the diet, the strong negative association between supplementation with vitamin C and risk of gastric cancer supports the hypothesis of a protective role of this anti‐oxidant.