bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic effect of retinoids and interferon α on tumor‐induced angiogenesis: Anti‐angiogenic effect on HPV‐harboring tumor‐cell lines
Authors: Majewski S. , Szmurlo A. , Marczak M. , Jablonska S. , Bollag W.
Published: February 2007

Various retinoids and interferons exert anti‐tumor effects both in experimental studies and in clinical trials. Recent reports indicate that they have a synergistic antineoplastic activity. Our study aimed to determine whether these synergistic anti‐tumor effects are related to inhibition of tumor‐cell‐induced angiogenesis. A further aim was to compare the anti‐angiogenic activity of various retinoids including 9‐cis retinoic acid, a ligand for nuclear retinoic acid receptor RXR, given alone and in combination with interferon α‐2a (IFNα‐2a). An in vivo experimental model of cutaneous angiogenesis in the mouse was used. Angiogenesis was induced by intradermal injection of HPVI6‐or HPVI8 DNA‐harboring tumor‐cell lines. All‐trom retinoic acid (all‐trans RA), 13‐cis retinoic acid (13‐cis RA) and 9‐cis retinoic acid (9‐cis RA) as well as 1FNα‐2a applied to mice intra‐peritoneally for S consecutive days before induction of angiogen‐esis resulted in significant inhibition of angiogenesis. Combination of retinoids with IFNα‐2a led to a synergistic inhibition of angiogenesis, as compared to the effects of the drugs given alone. Similar results were obtained when tumor cells were preincubated in vitro with the compounds, before injection into untreated mice. Our findings on synergistic anti‐angiogenic effects of retinoids and IFNα‐2a could explain, at least partially, the anti‐tumor efficacy of combined therapy with these agents, and provide support for the role of angiogenesis in tumor growth. © Wiley‐Liss, Inc.
Androgen responsiveness of the new human endometrial cancer cell line MFE‐296
Authors: Hackenberg Reinhard , Beck Simone , Filmer Angelika , Nia Abdolhamid Hushmand , Kunzmann Regina , Koch Manuela , Slater Emily P. , Schulz Klaus‐Dieter
Published: February 2007

MFE‐296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, arc derived from a moderately differentiated human endometrial adenoeardnoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near‐tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE‐296 cells was inhibited by the progestin RS020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole‐cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below S fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter‐gene construct, containing an androgen‐responsive element. In MFE‐296 cells the content of the androgen receptor was up‐regulated by its own ligand. © Wiley‐Liss, Inc.
Relaxin influences growth, differentiation and cell‐cell adhesion of human breast‐cancer cells in culture
Authors: Sacchi Tatiana Bani , Bani Daniele , Brandi Maria Luisa , Falchetti Alberto , Bigazzi Mario
Published: February 2007

The effects of different concentrations of relaxin (RLX) on growth and differentiation of a human breast‐cancer cell line (MCF‐7) have been studied after various times of exposure. The cells were cultured for 4 and 7 days in the absence (control) and the presence of highly purified porcine RLX at concentrations of 10−9 M and 10−6 M. (3H)‐Thymidine uptake assay was used to evaluate cell proliferation. Electron microscopy and immunocy‐tochemistry for the cell‐cell adhesion molecule E‐cadherin were carried out to evaluate cell differentiation. Analysis of DNA changes associated with apoptosis was performed to clarify whether RLX induces active cell death in the MCF‐7 cells. The findings obtained show that RLX, when applied at micromolar concentrations, or even at nanomolar concentrations for long exposure times, suppresses proliferation, stimulates differentiation, and enhances expression of the surface molecule E‐cadherin. Growth inhibition is not accompanied by apoptosis. The results of this study show that RLX can be recognized as a novel agent active in influencing growth and differentiation of MCF‐7 breast‐cancer cells. When applied at appropriate concentrations and exposure times, the peptide has a growth‐inhibitory action, thus reversing the growth‐stimulatory effect exerted at low concentrations for short exposure times, and promotes differentiation and cell‐cell adhesion. These last‐mentioned properties might result in a decrease in invasiveness of breast adenocarcinoma cells. © Wiley‐Liss, Inc.
Molecular analysis of chromosomh 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors
Authors: Bello M. Josefa , Vaquero Jesus , De Campos Jose M. , Kusak M. Elena , Sarasa Jose L. , Saez‐Castresana Javier , Pestana Angel , Rey Juan A.
Published: February 2007

Alterations of the short arm of chromosome I are recurrently found in cytogenetic analysis of malignant gliomas, and deletions of Ip36‐p32 region characterize at least the higher‐grade tumors, glioblsstoma multiforme. Molecular analysis of tumor‐derived and normal genomic DNA from 57 cases of gliomas, using a panel of chromosome I‐specific DNA probes showed LOH in 16 tumors. Allelic losses on I p were primarily restricted to glioblastoma multiforme (2/II) and to tumors with a major oligodendroglial component: grade II oligodendrogliomas (6/6), grade III anaplastic oligodendrogliomas (5/6) and grade II‐III mixed oligo‐astrocytomas (2/3). Losses for Iq markers were detected in only I tumor (glioblastoma multiforme). Our data suggest that anomalies of Ip primarily characterize oligodendrogliomas, whereas they are rare events in astrocytic tumors and indicate that a tumor‐suppressor gene on I p36‐p32 is involved in the development of brain tumors with oligodendroglial differentiation. © 1994 Wiley‐Liss, Inc.
Quercetin enhances transforming growth factor β1, secretion by human ovarian cancer cells
Authors: Scambia Giovanni , Panici Pierluigi Benedetti , Ranelletti F. O. , Ferrandina G. , de Vincenzo R. , Piantelli M. , Masciullo V. , Bonanno G. , Isola G. , Mancuso S.
Published: February 2007

Our study demonstrates that quercetin (Q)‐induced growth‐inhibitory activity in ovarian cancer cells may be mediated by modulation of transforming growth factor β1 (TGFβ1) production. We used the OVCA 433 cell line which is very sensitive to the anti‐proliferative effect of Q and expresses high‐affinity, low‐capacity TGFβ1 receptors. Conditioned medium (CM) from Q‐treated cells is able to displace 125I‐TGFβ1 from binding to its receptor; moreover Q (10 μM) increases TGFβ1 activity in CM in a time‐dependent fashion starting after 4 hr and reaching a maximum by 24 hr of Q treatment. Q‐induced growth inhibition is reversed by a neutralizing anti‐TGFβ1 MAb both in OVCA 433 and in a clonogenic assay of cells from a primary ovarian tumor. Q‐induced increase of TGFβ1 activity in CM is specific since other anti‐proliferative compounds, such as Dexamethasone, which is as active on the cell cycle as Q, had no effect on TGFβ1 secretion. Northorn‐blot analysis of TGFβ1 mRNA levels at various times of Q (10 μM) exposure revealed that there was no increase, suggesting that regulation of TGFβ1 occurs at post‐transcription at levels. © 1994 Wiley‐Liss, Inc.
Effects of testosterone, dihydrotestosterone and estrogen on 3,2′‐dimethyl‐4‐aminobiphenyl‐induced rat prostate carcinogenesis
Authors: Shirai Tomoyuki , Imaida Katsumi , Masui Tsuneo , Iwasaki Shogo , Mori Toshio , Kato Toshio , Ito Nobuyuki
Published: February 2007

Post‐initiation effects of testosterone propionate (TP), α‐dihydrotestosterone (DHT) and ethinyl estradiol (EE) on 3,2′‐dJmethyl‐4‐aminobiphenyl (DMAB)‐prostate carcinogenesis in F344 rats have been investigated by administration of each hormone individually or either androgen in combination with EE. DNAB plus TP resulted in induction of invasive adenocarcinomas in the lateral and anterior prostate and seminal vesicles, as shown in a previous study, whereas DHT did not exhibit any positive modulation potential. Administration of EE together with TP produced increased carcinoma incidence in the lateral and anterior prostate, from 17 and 28% to 70% and 80%, respectively. Dorsal prostate tumors, all of the non‐invasive in situ type, were also evident in 30% of animals receiving both TP and EE. Rats treated with DHT plus EE, however, did not develop tumors. Our experiment thus provides evidence that estrogen may play an important role in prostate carcinogenesis. © 1994 Wiley‐Liss, Inc.
Immunocytological detection of micrometastatic cells: Comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastric, colorectal and pancreatic cancer patients
Authors: Juhl Hartmul , Stritzel Matthias , Wroblewski Andreas , Henne‐Bruns Doris , Kremer Bernd , Schmiegel Wolff , Neumaier Michael , Wagener Christoph , Schreiber Hans‐Wilhelm , Kalthoff Holger
Published: February 2007

The prognosis of digestive cancers is poor mainly due to intraperitoneal relapse by cells which may have already been seeded at the time of surgery. Using immunocytology we investigated the peritoneal cavity and, as a comparison, the bone marrow of 147 patients with gastric, colorectal and pancreatic cancer for micrometastatic cells. Cytological samples from peritoneal cavity lavages and bone marrow aspirates were analyzed using monoclonal antibodies (MAbs) against tumor‐associated antigens (TAA) (CEA, CA‐19‐9, 17‐1‐A, C‐54‐0, Ra96) and compared to a MAb staining cytokeratins (KL‐I). Patients with benign diseases served as controls.

Intraperitoneal micrometastatic cells were detected in 27% of colorectal, 43% of gastric and 58% of pancreatic cancer patients. In the bone marrow, the corresponding data were 29% for colorectal, 25% for gastric and 58% for pancreatic cancer patients. Combined evaluation of both compartments increased the detection rate significantly (colorectal cancer: 40%, gastric cancer: 52%, pancreatic cancer: 72%). No unwarranted reactions were found in the control group. Combining 3 antibodies (CA‐19‐9, Ra96, C‐54‐0) enabled good detection for peritoneal cavity samples. In the bone marrow, the use of 2 antibodies (KL‐I and CA‐19‐9) detected 94% of all positive samples, whereas KL‐I and CA‐19‐9 stained approx. 70% of all positive samples in each case. The occurence of stained cells in the peritoneal cavity correlated with classical prognostic factors (TNM classification). © 1994 Wiley‐Liss, Inc.
Partial characterization of a cDNA for human stearoyl‐CoA desaturase and changes in its mRNA expression in some normal and malignant tissues
Authors: Li Juan , Ding Shi‐Fa , Habib Nagy A. , Fermor Beverley F. , Wood Chris B. , Gilmour R. Stewart
Published: February 2007

A segment of 712 bases coding for part of the human stearoyl‐CoA desaturase gene was made by polymerase chain reaction (PCR) using primers based on published rat cDNA sequences. The human PCR product was confirmed by DNA sequencing. It was next cloned into a vector from which anti‐sense, highly radioactive RNA transcripts were made in vitro using T7 polymerase. The transcripts were used to probe desaturase mRNA in a number of human tumour and control tissues, using a very sensitive solution hybridization/RNase protection assay. Increased desaturase mRNA levels were found in colonic and oesophageal carcinomas and in hepatocellular adenoma; however, no consistent trend was seen in hepatocellular carcinoma. It is suggested that certain classes of tumour may exhibit increased levels of desaturase mRNA. © 1994 Wiley‐Liss, Inc.
Association of H‐ras mutations with adenocarcinomas of the parotid gland
Authors: van Halteren Henk K. , Top Bert , Moor Wolter J. , Balm Alfons J. M. , Rodenhuis Sjoerd
Published: February 2007

We have examined 17 adenocarcinomas and 2 mixed tumors of the salivary glands for mutational activation of the oncogenes H‐ras, K‐ras and N‐ras. The presence of mutations was determined by in vitro amplification of gene fragments spanning codons 12, 13 and 61 and the use of mutation‐specific oligonucleotide hybridization. ras mutations were present in 3 of 13 adenocarcinomas (23%) of the parotid gland. The mutations were confirmed and characterized by means of cycle sequencing of polymerase chain reaction (PCR) fragments. In all 3 cases, the mutation was an A:T to G.C transition at the second position of codon 61 of the H‐ras gene. This rather unusual ras mutation could provide a clue to identify one or more carcinogens involved in the pathogenesis of parotid cancer. © 1994 Wiley‐Liss, Inc.
Modulation of associated ovarian carcinoma antigens by 5 cytokines used as single agents or in combination
Authors: Imbert‐Marcille B. M. , Thëdrez P. , Saï‐Maurel C. , Francois C. , Auget J. L. , Benard J. , Jacques Y. , Imai S. , Chatal J. F.
Published: February 2007

Optimization of intraperitoneal radioimmunotherapy of ovarian cancer depends on increasing the antigenic expression of tumor cells. For this purpose, we studied the effect of 5 cytokines (IFN‐α, IFN‐β, IFN‐γ, TNF‐α and TGF‐β), used as single agents or in combination, on 4 ovarian cancer cell lines which present different antigenic profiles with the monoclonal antibodies (MAbs) tested (OC125, OVTL‐3, MOv 18 and MOv 19). Analyses were performed by flow cytometry and the Scatchard technique in order to study antigenic modulation. The effect on proliferation was determined by cell counting. Expression of O3 antigen, recognized by the OVTL3 MAb, was increased up to 2.5 times after IFNs and TNF‐α (used as single agent) on the 2 lines presenting low basal expression (SHIN‐3 and IGROVI). The expression of CAI25 antigen and the antigens recognized by MOv 18 and MOv 19 MAbs was not increased by any of the cytokines tested. The combination IFN‐γ + TNF‐α was synergistic on cytotoxicity and enhanced O3 expression, providing 10 times as many sites per cell on the SHIN‐3 line. For 3 other associations (IFN‐α + IFN‐γ, IFN‐β + IFN‐γ and IFN‐α + TNF‐α), there was an additive effect on O3 expression and on cell cytotoxicity. © 1994 Wiley‐Liss, Inc.
Cytotoxic T lymphocytes recognize tumor antigens of a murine colonic carcinoma by using different T‐cell receptors
Authors: Rodolfo Monica , Castelli Chiara , Bassi Cinzia , Accornero Paola , Sensi Marialuisa , Parmiani Giorgio
Published: February 2007

To see whether different antigens expressed by the same tumor are recognized by distinct T ‐cell receptors (TCR), we used cytotoxic T‐lymphocyte (CTL) lines known to lyse in vitro the syngeneic BALB/c adenocarcinoma C‐26. Four of these CD3+ CD8+ lines showed 4 different patterns of lysis on a panel of MHC‐class‐I‐compatible targets. The activity was H‐2d‐restricted and could be blocked by anti‐CD3 and anti‐TCR‐α/β monoclonal antibodies (MAbs). The CTL lines were also effective, although to a different extent, in adoptive immunotherapy of mice bearing lung metastases. Phenotypic analysis revealed in all the lines a high frequency of cells positive for CD45, asialo GMI (ASGMI), lymphocyte‐function‐associated antigen‐I (LFA‐I), intercellular adhesion molecule‐I (ICAM‐I) and CD44, but negligible expression of L‐selectin (LAM‐I) and very late antigen‐4 (VLA‐4); 2 lines expressed the vitronectin‐receptor (VNR). Analysis of TCR Vβ‐chains used by the 4 lines showed selective presence of Vβ6, Vβ8.2, Vβ8.3 and of Vβ13 chains. MAbs directed to these Vβ chains blocked their lytic activity in vitro. Vα‐chain transcripts of the lines were identified by polymerase chain reaction (PCR) as VαITTII and Vα52 in 2 lines, while one could not be identified. Analysis of Vβs in mixed lymphocyte‐tumor‐cell cultres (MLTC) of T cells deriving from tumor‐infiltrating lymphocytes (TIL) or from spleen of C‐26 tumor‐bearing or immune animals indicated that the TCR of the CTL lines were representatives of the TCR repertoire recognizing C‐26 tumor, since their Vβ were shown to be selectively expanded in MLTC. © 1994 Wiley‐Liss, Inc.
Ki‐67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: Correlation with steroid receptors, epidermal‐growth‐factor receptor and cathepsin D
Authors: Henzen‐Logmans Sonja C. , Fieret Elly J. H. , Berns Els M. J. J. , van der Burg Maria E. L. , Klijn Jan G. M. , Foekens John A.
Published: February 2007

Ki‐67 immunoreactivity was studied in relation to immunohistochemically assessed expression of epidermal‐growth‐factor receptor (EGFR), estrogen receptor (ER) progesterone receptor (PgR) and cytosolic levels of cathepsin D in advanced human ovarian adenocarcinomas, borderline and benign cystadenomas and normal ovaries. A significantly higher number of Ki‐67‐positive cells were found in metastatic tumors vs. primary adenocarcinomas and in the total group of adenocarcinomas vs. benign/borderline cystadenomas. Cathepsin‐D levels were also significantly higher in metastatic tumors than in primary adenocarcinomas, which in turn presented higher levels than were found in normal ovaries. However, no significant difference was observed between cathepsin‐D levels in malignant adenocarcinomas and borderline/benign cystadenomas. Immunohistochemically assessed expression of ER and PgR was detected in variable percentages of epithelial tumor cells, and stromal cells were occasionally positive as well. In the group of primary adenocarcinomas, 46% were ER‐positive and 34% were PgR‐positive, although there was no significant difference between primary and metastatic lesions with respect to ER or PgR expression. Concordance between immunohistochemically assessed ER or PgR data and cytosolic ER and PgR levels measured with enzyme immunoassay was relatively low. EGFR, immunohistochemically assessed with MAb‐EGFRI, was positive in 76% of the primary and in 78% of the metastatic adenocarcinomas. A strong positive association was detected between ER and PgR, and EGFR was observed to present a weak positive correlation with Ki‐67 and ER. Cathepsin‐D levels were not found to be significantly correlated with the expression of ER, PgR, EGFR or Ki‐67. © 1994 Wiley‐Liss, Inc.
Distinct pattern of HSP72 and monomeric laminin receptor expression in human lung cancers infiltrated by γ/δ T lymphocytes
Authors: Ferrarini Marina , Pupa Serenella M. , Zocchi M. Ratfaella , Rugarli Claudio , Ménard Sylvie
Published: February 2007

We have previously demonstrated that γ/δ T lymphocytes may participate in the host immune response against lung adenocarcinomas. Here we show that, in about one‐fourth of human lung cancers, γ/δ T cells represented a significant proportion of freshly isolated tumor‐infiltrating lymphocytes. Moreover, these cells selectively expand in vitro upon culture in the presence of IL‐2, thus suggesting a prior activation in vivo. Finally, when we evaluated the expression of heat shock proteins and of a panel of tumor‐associated antigens in lung cancers infiltrated by γ.δ vs. α/β T cells, we found that the former displayed a distinct antigenic pattern, characterized by over‐expression of HSP72 and of the 67‐kDa high‐affinity laminin receptor, which might account for γ/δ T‐cell recognition. © 1994 Wiley‐Liss, Inc.
Alterations in serum levels of insulin‐like growth factors and insulin‐like growth‐factor‐binding proteins in patients with colorectal cancer
Authors: El Atiq Fatima , Garrouste Françoise , Remacle‐Bonnet Maryse , Sastre Bernard , Pommier Gilbert
Published: February 2007

It has been reported that insulin‐like growth factor (IGF) II is associated with human primary colorectal tumors and colon‐carcinoma cell lines. Here, we examine alterations in circulating levels of IGFs and IGF binding proteins (IGFBPs) in patients with colorectal carcinoma, and compare them to age‐ and nutrition‐adjusted references. We report (i) an increase in serum IGF‐11 concentrations (about 2‐fold), whereas IGF‐1 concentrations are regarded as normal when aging is taken into account; (ii) an apparent increase in serum IGFBP‐3 levels when compared to those of healthy elderly subjects, IGFBP‐3 only being detected in the 150‐kDa IGFBP ternary complex as in normal serum; (iii) abnormally elevated serum IGFBP 2 levels taking into account the apparent concentrations of IGFBP‐3. This simultaneous elevation of IGFBP‐3 and IGFBP‐2 in the serum of patients with colorectal tumors appears to be unique in that it reflects a break in the inverse relationship between the serum IGFBP‐3 and IGFBP‐2 levels that is observed in normal and in several physiopathotogical conditions. Moreover, it enables a distinction to be made between 76.5% (13/17) of patients with colorectal carcinoma and normal adults, age‐related healthy aged and malnourished patients. We propose that the disturbed serum IGFBP profile observed in the patients with colorectal cancer may be a consequence of oversecretion of IGF‐11 by the tumor cells. The usefulness of IGFs and IGFBPs as potential colorectal tumor‐associated metabolic markers should be further investigated. © 1994 Wiley‐Liss, Inc.
Successful immunotherapy of the highly metastatic murine ESb lymphoma with sensitized CD8+ T cells and IFN‐α/β
Authors: Kaido Thomas , Maury Chantal , Schirrmacher Volker , Gresser Ion
Published: February 2007

Daily IFN‐α/β therapy was totally ineffective in inhibiting the development of visceral metastases in DBA/2 mice injected i.v. with the ESb lymphoma regardless of the number of tumor cells injected. The finding that IFN‐α/β therapy increased the survival time of ESb‐tmmunized mice rechallenged with ESb cells suggested that cooperation between the immune system and IFN‐α/β was important. Adoptive transfer of ESb‐immune spleen cells (but not normal cells) together with IFN‐α/β treatment did inhibit the development of ESb metastases in immunocompetent DBA/2 mice. Either treatment alone was ineffective. The anti‐metastatic effect was specific for the ESb lymphoma as spleen cells from ESb‐immunized mice together with IFN‐α/β treatment did not inhibit the development of metastases in mice challenged with IFN‐α/β‐resistant 3C18 FLC. Depletion of CD8+ T cells (but not CD4+ T cells or B lymphocytes) prior to transfer eliminated the protective effect of ESb‐immune splenocytes in IFN‐α/β‐treated mice. As few as 1 × 106 ESb‐immune spleen cells highly enriched for CD8+ cells increased the survival time of IFN‐α/β‐treated ESb‐challenged DBA/2 mice. The combined therapy of ESb‐specific immune cells and IFN‐α/β resulted in long‐term immunity to this tumor. © 1994 Wiley‐Liss, Inc.
The lectin Griffonia simpucifolia I‐A4 (GS I‐A4) specifically recognizes terminal α‐linked N‐acetylgalactosaminyl groups and is cytotoxic to the human colon cancer cell lines LS174t and SW1116
Authors: Chen Yu‐Fang , Boland C. Richard , Kraus Eugene R. , Goldstein Irwin J.
Published: February 2007

The lectin GS I‐A4 binds to terminal α‐N‐acetylgalactosaminyl (GaINAc) groups (which include the Tn antigen), but not to the closely related tumor‐associated epitope, sialylated Tn antigen. The lectin also precipitates asialo OSM, but not its native sialylated form. Lectin histochemistry with human colonic tissues showed that GS I‐A4 specifically stained specimens of colon cancer and colonic tissues from individuals with FAP; however, normal colonic tissues from patients without colonic disease were rarely stained with this lectin. Glycoconjugates bound by GS I‐A4 were observed on the surface membranes of 2 human colon cancer cell lines, LS174t and SW1116, when fluorescein isothiocyanate (FITC)‐conjugated GS I‐A4 was used. GS I‐A4 was toxic to these 2 human colon cancer cell lines in monolayer culture, A dose‐response study conducted using 10‐160 μg/ml of GS I‐A4 demonstrated significant dose‐related toxicity against LS174t and SW1116 cells. At concentrations > 80 μg/ml, > 99% of LS174t and > 90% of SW1116 cells were killed. Four mM GaINAc specifically inhibited the cytotoxic effect of GS I‐A4 (p < 0.001), whereas 4mM N‐acetylglucosamine (GlcNAc) had no effect. Two other lectins that recognize terminal α‐GalNAc residues, DBA and LBL, were significantly less cytotoxic to the colon cancer cells than GS I‐A4. In the light of these findings, we speculate that GS I‐A4 may have potential use as a diagnostic agent against colorectal cancer. © 1994 Wiley‐Liss, Inc.
Anti‐tumor activity of mycophenolate mofetil against human and mouse tumors in vivo
Authors: Tressler Robert J. , Garvin Laura J. , Slate Doris L
Published: February 2007

Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti‐tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro‐drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 μM to 3.9 μM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T‐lymphoblast), Molt‐4 (T‐cell leukemia), CaPan‐2 (pancreatic adenocarcinoma), CaLu‐3 (non‐small‐cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B‐cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW 117‐H10 lymphoma cells in an experimental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK‐Hep‐1, a human hepatic endothe‐lioma, or Hep‐3B, a liver adenocarcinoma, at any of the doses tested. © 1994 Wiley‐Liss, Inc.
Harly endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high‐dose tumour necrosis factor alpha (rTNFα)
Authors: Renard N. , Liénard D. , Lespagnard L. , Eggermont A. , Heimann R. , Lejeune F.
Published: February 2007

Twenty‐seven patients treated with high‐dose rTNFα, IFNγ and melphalan by isolated limb perfusion were histologically documented. There were 20 cases of melanoma‐in‐transit metastases and 7 cases of high‐grade soft‐tissue sarcoma. Biopsies were taken before IFN7, after IFNγ, before TNFα and between 2 hr and 60 days after the TNFα perfusion. Immunohistochemistry was performed for adhesion molecules ICAM‐I, ELAM‐I (E selectin), VCAM‐I and PECAM. During the first hours after beginning perfusion, the endothelial cells of the tumour capillaries appeared swollen. Significant tumour necrosis was already observed 3 hours after the perfusion in melanoma cases. The overall predominant feature was coagulative necrosis associated or not with haemorrhagic necrosis. TNFα induced increased expression of ELAM‐I and VCAM‐I adhesion molecules on intratumoral endothelial cells. The activated tumour vessels were progressively destroyed. Significant intra‐vascular recruitment of polymorphonuclear cells (PMNs) was observed 3 hr after starting TNFα; it was followed by diapedesis and tumour colonization 3 days later. T lymphocytes and macrophages were detected during the first 7 days and B lymphocytes during the second week. Melanoma in transit metastases treated with alkylating agent alone did not show significant necrosis and did not express high levels of adhesion molecules (ELAM‐1, VCAM‐I) nor infiltration by PMN.
Expression of Ca2+‐binding proteins of the S100 family in malignant human breast‐cancer cell lines and biopsy samples
Authors: Pedrocchi Michele , Schäfer Beat W. , Mueller Heinz , Eppenberger Urs , Heizmann Claus W.
Published: February 2007

In order to examine whether the expression of calcium‐binding proteins of the SI00 family may correlate with the transformation grade of human mammary‐tumor cells, we studied the expression patterns of 4 members of this family (CACY, CAPL, S100L, S100α/β) in human breast‐cancer cell lines. Each S100 protein is shown to be individually regulated in the human breast‐cancer cell lines we studied, but it appears that the expression levels of S100 proteins do not strictly correlate with prognostic factors or the tumorigenicity of the cells. However, 2 aggressive cell lines, MDA‐MB‐231 and HS‐578T, show elevated expression of CAPL, We show that methylation may account for partial regulation of the SI00 genes, whereas neither genomic rearrangements in the S100 gene cluster region nor gene dosis effects seem to influence their expression pattern in MDA‐MB‐231 and MCF‐7 cells. On the basis of our genomic analyses, we can localize the gene for SIOOL within 5 kb upstream of S100E, thus extending the SIOO gene cluster by one gene. A series of primary breast tumors was collected and tested for expression of CAPL, CACY and S100α/β. The results show that all human breast‐cancer tissues tested express CACY, whereas the presence of CAPL is more restricted. There if a significant correlation between enhanced expression of CAPL and presence of the invasivity marker urokinase‐type plasminogen activator (uPA). This observation suggests that CAPL may play an important role in the acquisition of metastatic potential of human mammary epithelial cells.
Anti‐tumor effect of combined treatment with thymosin alpha 1 and interleukin‐2 after 5‐fluorouracil in liver metastases from colorectal cancer in rats
Authors: Rasi Guido , Silecchia Gianfranco , Sinibaldi‐Vallebona Paola , Spaziani Erasmo , Pierimarchi Pasquale , Sivilia Mariliana , Tremiterra Salvatore , Garaci Enrico
Published: February 2007

We studied the effect of combined chemo‐immunotherapy, 5‐FU followed by thymosin α1 (Tα1) and interleukin‐2 (IL‐2) at low doses, on liver metastases from colorectal cancer, induced by splenic injection of DHD/K12 cells (1,2‐dimethylhydraiine‐induced colon adenocarcinoma) in syngeneic BDIX rats. The presence of liver metastases was checked by laparotomy 14 days after tumor‐cell injection. Evaluable rats were assigned randomly to 5 experimental groups designated as control, 5‐FU, IL‐2, 5‐FU/IL‐2 and S‐FU/Tαl/IL‐2. S‐FU was administered i.v. as a continuous infusion for 7 days by an osmotic device implanted surgically. Tα1 and IL‐2 were administered for 4 days and repeated after 11 days. Combined chemo‐immunotherapy was shown both to significantly reduce the growth of liver metastases and to prevent extra‐hepatic spread. 5‐FU/Tαl/IL‐2 also improved survival rate. Combined immunotherapy after 5‐FU restored NK activity of the peripheral‐blood‐mononuclear‐cell (PBMC) in tumor and/or 5‐FU immunode‐pressed rats and enhanced PBMC cytotoxic activity against the OHD/K12autologous cell line. This model was devised to mimic the clinical situation of unresectable liver metastases.
HTLV‐I messenger RNA is expressed in vivo in adult T‐cell leukemia/lymphoma patients: An in situ hybridization study
Authors: Setoyama Mitsuru , Fujiyoshi Toshinobu , Mizoguchi Shimako , Katahira Yoshihiko , Yashiki Shinji , Tara Mitsutoshi , Kanzaki Tamotsu , Sonoda Shunro
Published: February 2007

Adult T‐cell leukemia/lymphoma (ATLL) is a malignancy involving peripheral blood, lymph nodes, skin and other organs. Human T‐cell leukemia virus type 1 (HTLV‐1) is etiologically associated with ATLL but cannot be detected by conventional methods in fresh samples of peripheral blood and skin taken from ATLL. The aim of this study was to investigate the feasibility of an in situ hybridization technique for detection of HTLV‐1 mRNA in atypical lymphoid cells of peripheral blood and skin lesions of patients with ATLL. We detected variable amounts of HTLV‐1 tax mRNA in the nuclei and cytoplasm of these cells in fresh peripheral blood samples and skin lesions from ATLL patients, and also in asymptomatic HTLV‐1 infected donors to a lesser extent. Out of 10 patients with ATLL, 7 showed strong positive in situ hybridization whereas the other 3 were only weakly positive. However, in the last 3 cases, the reaction became strongly positive after cells had been cultured for 24 hr. Furthermore, all 3 asymptomatic HTLV‐1‐infected donors exhibited a weakly positive response in their apparently mature lymphoid cells.
Trends in pancreatic cancer mortality in Europe, 1955–1989
Authors: Fernandez Esteve , la Vecchia Carlo , Porta Miquel , Negri Eva , Lucchini Franca , Levi Fabio
Published: February 2007

Trends in death certification rates from pancreatic cancer over the period 1955–1989 were analyzed for 25 European countries (excluding the former Soviet Union and a few smaller countries). In 1985–1989, rates for males ranged between 5.3/100,000 (age‐standardized world population) in Spain and 10.3/100,000 in Hungary and Czechoslovakia. Other high‐mortality areas were located in Northern Europe (Finland, Iceland, Ireland, Denmark) and Central Europe (Austria, Poland, Germany), whilst mortality was lower in Southern Europe (Portugal, Greece). Between 1955 and 1989, mortality rates increased in all the countries considered, the change ranging between 6% in Scotland and 279% in Spain; the rises were higher in the Mediterranean and Eastern European countries than in Northern Europe. Among females, Nordic countries such as Iceland, Sweden and Denmark had the highest mortality rates in 1985–1989 (over 6/100,000) and, as for males, Southern Europe (Spain, Portugal, Greece) appeared as a low‐mortality area (around 3/100,000). During the 1955–1989 period, upward trends were observed in all the countries studied, with the highest increase in Greece, Italy, Bulgaria, Poland and Spain. A negative correlation was observed between the percent change in mortality rates between 1955–1959 and 1985–1989 and the rate in 1955–1959 among both males (r = −0.95, p <0.001) and females (r = −0.81, p <0.001). Thus, a systematic levelling of rates was observed in most countries, with the exception of the UK and some Nordic countries, whose rates were already high in the late 1950s. Tobacco smoking and dietary factors could account for some of the generalized upward trends. Improved diagnostic and death certification of the disease might also partially explain the observed figures. © 1994 Wiley‐Liss, Inc.
Detection of immunoglobulin heavy‐chain gene rearrangement at the single‐cell level in malignant lymphomas: No rearrangement is found in hodgkin and reed‐sternberg cells
Authors: Roth Judith , Daus Heiner , Trümper Lorenz , Gause Angela , Salamon‐Looijen Monika , Pfreundschuh Michael
Published: February 2007

Hodgkin and Reed‐Sternberg (HRS) cells, the neoplastic cells of Hodgkin's disease (HD), represent only a minority of the cellular infiltrate in affected tissue. Therefore, rearrangements of the immunoglobulin heavy‐chain (IgH) gene detected in DNA extracted from an entire Hodgkin's lymph node cannot be attributed to the HRS cells and cannot be used as an argument for the B‐cell origin of HRS cells. We developed a new method for the amplification of rearranged DNA of the IgH gene from single cells. Using 6 “forward primers” which were constructed corresponding to consensus sequences of the 6 known families of the IgH variable (V) region (framework region I) and a mix of 2 “reverse primers” corresponding to consensus sequences of the different joining (J) segments, rearrangements of all 6 V‐families were detected in human peripheral blood lymphocytes. Rearranged IgH DNA could be amplified from single cells of B‐cell lymphoma‐cell lines and from 13 patients with B‐cell non‐Hodgkin's lymphomas. However, analysis of HRS cells isolated from lymph nodes of 13 patients with Hodgkin's disease did not show any rearrangement of the IgH gene locus. These findings, obtained by polymerase chain reaction (PCR) on isolated single HRS cells, contrast with previous studies that used Southern‐blot analysis of entire tissues affected by Hodgkin's disease. We conclude that the neoplastic HRS cells in Hodgkin's disease‐with the possible exception of the nodular paragranuloma subtype‐are probably not derived from B cells. © 1994 Wiley‐Liss, Inc.
Cellular immunodeficiency enhances the progression of human papillomavirus‐associated cervical lesions
Authors: Petry Karl Ulrich , Scheffel Danicla , Bode Ulrike , Gabrysiak Thomas , Köchel Heinrich , Kupsch Eckehardt , Glaubitz Michael , Niesert Stefan , Kühnle Henning , Schedel Ingolf
Published: February 2007

Most cases of low‐grade cervical intraepithelial neoplasia (CIN) associated with oncogenic human papillomavirus (HPV) types regress spontaneously within years. Unknown co‐factors seem to be necessary for a progression to malignancy. To determine the possible role of cellular immunodeficiency as such a co‐factor in the genesis of genital neoplasia, 48 HIV‐infected women and 52 allograft recipients were examined periodically during a 3‐year period. Colposcopy, cytology and HPV‐DNA typing (Vira Type) were performed at each visit. Each cervical lesion was matched prospectively with 2 lesions from immunocompetent controls. In all, 29/100 patients suffered from cervical neoplasms, including 2 advanced cervical cancers and 9 CIN3 lesions. Correlation between grade of lesion and HPV DNA 16/18 was significant. Low‐grade lesions among patients progressed more often than among controls and recurrent lesions after destructive treatment were seen more frequently among patients than among controls. All patients with CD4‐lymphocyte counts of <400/μl or immunosuppression for more than 3 years suffered from progressive lesions. We conclude that malfunction of the cellular immune response following either HIV‐induced depletion or iatrogenic inhibition of CD4‐lymphocyte activation, enhances the progression of HPV‐induced cervical lesions to malignancy. © 1994 Wiley‐Liss, Inc.
Meta‐[211AT]astatobenzylguanidine: Further evaluation of a potential therapeutic agent
Authors: Vaidyanathan Gunesan , Strickland Donald K. , Zalutsky Michael R.
Published: February 2007

Meta‐[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta‐iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake‐1 mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK‐N‐SH human neuroblastoma cells. This uptake was found to be energy‐dependent: In mice, pre‐treatment with DMI reduced uptake of[211At]MABG at 1 hr post‐injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 μM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK‐N‐SH cells. In SK‐N‐SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no‐carrieradded (n. c.a.) [121I]MIBG these values were similar, 60% and 48%. The ability of SK‐N‐SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n. c.a. MIBG. © 1994 Wiley‐Liss, Inc.
Potentiation of cytotoxic cancer therapies by TNP‐470 alone and with other anti‐angiogenic agents
Authors: Teicher Beverly A. , Holden Sylvia A. , Ara Gulshan , Sotomayor Enrique Alvarez , Huang Zhen Dong , Chen Ying‐Nan , Brem Harold
Published: February 2007

The ability of TNP‐470, a synthetic analog of fumagillin which has been described as an anti‐angiogenic agent, to potentiate cytotoxic cancer therapies was investigated in vivo in the murine FSaIIC fibrosarcoma and the Lewis lung carcinoma. TNP‐470 was more toxic toward FSaIIC tumor cells from tumors treated in vivo than toward bone‐marrow CFU‐GM from the same animals. TNP‐470 had a dose‐modifying effect on the toxicity of cyclophosphamide toward FSaIIC tumor cells which amounted to an 8‐fold increase in tumor‐cell killing at a cyclophosphamide dose of 500 mg/kg. Treatment with TNP‐470 and minocycline increased the permeability of the FSaII fibrosarcoma in vivo to the fluorescent dye Hoechst 33342 and increased the killing of both the bright and the dim tumor cells by cyclophosphamide. TNP‐470, especially in combination with minocycline, formed a highly effective modulator combination for treatment of the Lewis lung carcinoma with cytotoxic cancer therapies against primary and metastatic disease. The combination of TNP‐470/minocycline and cyclophosphamide led to 40 to 50% long‐term survivors in Lewis‐lung‐carcinoma‐bearing animals. Our results indicate that the use of anti‐angiogenic modulators in cancer therapy is a very promising area for further study. © 1994 Wiley‐Liss, Inc.
DNA repair capacity as a risk factor for non‐melanocytic skin cancer—a molecular epidemiological study
Authors: Hall Janet , English Dallas R. , Artuso Marina , Armstrong Bruce K. , Winter Michael
Published: February 2007

Capacity to repair UV‐induced DNA damage was studied by use of a host cell reactivation assay in T lymphocytes isolated from 86 cases and 87 controls (aged 44‐68 years) who were participants in a population‐based case‐control study of basal cell (BCC) or squamous cell (SCC) carcinoma of the skin in Geraldton, Western Australia. Lymphocytes were cultured and transfected with either control or UV‐irradiated plasmids (254 mm, 350 J/m2) containing a reporter gene [the chloramphenicol‐acetyltransferase (CAT) gene], and the repair capacity was determined by measuring CAT gene expression in protein extracts prepared from the transfected cells. DNA repair activity was 1.07 (95% confidence interval 0.94‐1.26) times greater in BCC cases than in controls for each 350 J/m2 increment in UV dose to the plasmids, and 1.04 (95% confidence interval 0.85‐1.26) times greater in SCC cases than in controls, though the differences were not statistically significant. DNA repair activity showed little association with age, sex and viability of the lymphocytes, though it was positively associated with their blastogenic rate (p=0.055).
Risk factors for esophageal cancer in Shanghai, China. II. Role of diet and nutrients
Authors: Gao Yu‐Tang , McLaughlin Joseph K. , Gridley Gloria , Blot William J. , Ji Bu‐Tian , Dai Qi , Fraumeni Joseph F.
Published: February 2007

A population‐based case‐control study of esophageal cancer (902 cases, 1,552 controls) in Shanghai, China, investigated the etiologic role of diet. After adjustment for cigarette smoking, alcohol consumption and other risk factors, increasing consumption of fruits, dark orange vegetables and beef or mutton was associated with statistically significant decreasing trends in risk for esophageal cancer. In general, risks were about 40% lower among those in the upper vs. lower quartiles of intake of these foods. Fivefold increases in risk were observed among those who consumed burning hot soup or porridge, with smaller excesses for preserved vegetables, salty and deep fried foods. Nutrient analysis revealed that increased dietary intake of protein, carotene, vitamins C and E and riboflavin was associated with reduced esophageal cancer risk. Our findings support the notion that the reported temporal increases in the per capita consumption of fruits, vegetables and animal products contribute to the substantial reduction in the incidence of esophageal cancer in Shanghai, particularly since cigarette and alcohol use has not decreased.
Human astrocytomas and glioblastomas express monocyte chemoattractant protein‐1 (MCP‐1) in vivo and in vitro
Authors: Desbaillets Isabelle , Tada Mitsuhiro , De Tribolet Nicolas , Diserens Annie‐Claire , Hamou Marie‐France , Van Meir Erwin G.
Published: February 2007

Expression of the monocyte chemoattractant protein‐I (MCP‐I) was examined in human central nervous system tumours (glioblastomas and astrocytomas) and normal human brain. Northern blot analysis demonstrated constitutive expression of MCP‐I mRNA in 6 of 12 glioblastoma cell lines. Expression could be stimulated by interleukin (IL)‐Iα and tumour necrosis factor (TNF)‐α in all cell lines tested. Immunoprecipitation demonstrated secretion of both isoforms, MCP‐Iα and ‐β, of the MCP‐I protein. Reverse‐transcription polymerase chain reaction and Northern blot analysis on tissues demonstrated MCP‐I mRNA expression in 17 of 17 glioblastomas, 3 of 6 anaplastic astrocytomas and 6 of 6 low‐grade astrocytomas, as well as in fetal brain but not in normal adult brain. In situ hybridization on 2 glioblastomas and I low‐grade astrocytoma indicates that neoplastic astrocytes and endothelial cells express MCP‐I mRNA in vivo. Moreover, tumour cyst fluids of glioblastomas and astrocytoms were able to induce monocyte chemoattraction in an in vitro assay. This chemotatic activity was specifically neutralized by anti‐MCP‐I antibodies in 9 of samples, further demonstrating the production of bioactive MCP‐I in vivo and supporting an important role for this factor in the infiltration of monocytes/macrophages into tumour tissue.
Lymphotoxin‐α/β heterodimer is expressed on leukemic hairy cells and activated human B lymphocytes
Authors: Mapara Markus Y. , Bargou Ralf C. , Beck Christian , Heilig Benhard , Dörken Bernd , Moldenhauer Gerhard
Published: February 2007

The expression of human lymphotoxin (LT) α/β cell‐surface complex was studied in human B‐cell lines as well as in normal and neoplastic human B lymphocytes. In the absence of TNF receptors, only the human hairy‐cell leukemia (HCL)‐derived cell line JOK‐I revealed constitutive cell‐surface expression of LT but not TNF‐a. Immunoprecipitation experiments with anti‐LT monoclonal antibody (MAb) 9B9 from cell‐surface radioiodinated JOK‐I cells revealed that a cell‐surface lymphotoxin molecule (25 kDa) is expressed in association with a 33‐kDa molecule. Enzymatic digestion with F/N‐glycosidase and O‐glyeosidase showed that both proteins contained N‐linked carbohydrate residues, whereas only the 25‐kDa molecule contained O‐linked sugar residues. Analysis of mRNA expression revealed specific transcripts of LT‐α and LT‐β in JOK‐I cells. Resting tonsillar B cells did not express cell‐surface LT. However, LT‐β mRNA was observable in unstimulated tonsillar B cells, whereas LT‐α mRNA, cell‐surface LT and LT secretion could only be detected upon in vitro activation. Thus LT‐β and α appear to be sequentially expressed in human B cells. Neoplastic B cells from chronic lymphocytic leukemia (BCLL), being devoid of constitutive cell‐surface LT expression, could be induced to express surface LT by in vitro stimulation with Staphylococcux aureus Cowan I (SAC). Constitutive LT‐β transcripts, however, could also be detected in 4 out of 5 cases of BCLL. In contrast, human HCL cells displayed constitutive cell expression of lymphotoxin‐α and β. These findings demonstrate that cell‐surface LT‐α is expressed in association with LT‐β on activated normal B cells and neoplastic B cells representing an activated state.