bluuebunny/crossref_metadata_2025 huggingface dataset:
Risks of second primary malignancy in patients with cutaneous and ocular melanoma in denmark, 1943–1989
Authors: Swerdlow A. J. , Storm H. H. , Sasieni P. D.
Published: February 2007

Risks of 2nd primary cancer were assessed in all patients with cutaneous melanoma (12,460) and all patients with ocular melanoma (2,018) incident in Denmark from 1943 to 1989 and followed for totals of 88,667 person‐years and 16,045 person‐years, respectively. After cutaneous melanoma, 972 2nd cancers occurred. The risk of non‐melanoma skin cancer was significantly raised in each sex. Risk of all non‐skin cancers was not raised for all ages but was significantly increased for patients with the primary melanoma incident at ages under 50 years (standardised incidence ratio [SIR], i.e., ratio of observed to expected cancer incidence, multiplied by 100 = 117; 95% confidence interval [CI] 101 – 134). There were significantly increased risks of chronic lymphocytic leukaemia in males and both sexes combined, brain and nervous system cancers in females and both sexes combined and oropharyngeal cancer in both sexes combined. Risk of pancreatic cancer was not raised, suggesting that cutaneous melanoma patients generally do not share the diathesis for this malignancy which has been observed in certain families with atypical naevi and melanoma. There was no relation of 2nd primary cancer risks to duration since the first primary and no indication of any appreciable treatment‐related risk. After ocular melanoma, 216 2nd cancers occurred. There was a significantly increased risk of 2nd cancer overall in males but not females and a significantly increased risk of liver cancer in each sex. Risk of non‐melanoma skin cancer (NMSC) was not raised, which suggests that the aetiology of ocular melanoma is not mainly dependent on UV exposure, at least of the type causing NMSC. © 1995 Wiley‐Liss, Inc.
Reduction of EGP‐2‐positive pulmonary metastases by bispecific‐antibody‐redirected T cells in an immunocompetent rat model
Authors: Kroesen B. J. , Helfrich W. , Bakker A. , Wubbena A. S. , Bakker H. , Kal H. B. , The T. H. , De Leu L.
Published: February 2007

Effectiveness of bispecific‐monoclonal‐antibody (BsMAb)‐mediated cellular anti‐tumour activity was evaluated in vitro and in vivo in relation to the additional need for T‐cell activation in a new immunocompetent rat tumour model. L37 tumour cells, derived from a squamous‐cell carcinoma of the lung of Wag/Rij rats, were transfected with the cDNA coding for the human 38‐kDa transmembrane pan‐carcinoma‐associated antigen EGP‐2. Intravenous inoculation of EGP‐2‐positive L37 cells resulted in a rapid outgrowth of EGP‐2‐positive tumour nodules in the lungs. A BsMAb BIS‐19, recognizing EGP‐2 on the transfected tumour cells and the T‐cell receptor of the rat, was made and allowed specific lysis of EGP‐2‐transfected L37 tumour cells by activated rat T lymphocytes in vitro. In vivo T‐cell activation, assessed by up‐regulation of IL‐2‐receptor expression, could be induced by daily injection of rat rIL‐2. Intravenous treatment of tumour‐bearing EGP‐2‐positive L37 tumour with BIS‐19 together with rat rIL‐2 resulted in almost complete disappearance of established tumour. In contrast, animals treated with BIS‐19 alone, IL‐2 alone or a combination of anti‐EGP‐2, anti‐TcR and IL‐2 showed much less or no tumour reduction. These results show effectiveness of systemic treatment with BsMAbs to induce anti‐tumour activity in established tumours. Immune activation prior to or during treatment with BsMAbs, as achieved with IL‐2, appears to be a prerequisite for successful treatment. © 1995 Wiley‐Liss, Inc.
Chemoprevention by galanin against colon carcinogenesis induced by azoxymethane in wistar rats
Authors: Iishi Hiroyasu , Tatsuta Masaharu , Baba Miyako , Uehara Hiroyuki , Yano Hiroyuki , Nakaizumi Akihiko
Published: February 2007

The effects of the neuropeptide galanin on the development of colon tumors induced by azoxymethane (AOM) and on the labeling index of colon epithelial cells were investigated in Wistar rats. Treatment with galanin significantly decreased the incidence of colon tumors at week 45. Galanin did not influence the histological appearance of the colon tumors, but it slightly increased the frequency of sub‐mucosal adenocarcinomas. Furthermore, it significantly decreased the labeling index of colon mucosa during and after AOM treatment. These findings indicate that galanin inhibited the development of colon tumors and that this effect may be related to its suppression of colon‐epithelial‐cell proliferation. © 1995 Wiley‐Liss, Inc.
Menstrual and reproductive factors and pancreatic cancer risk in women
Authors: Fernandez Esteve , La Vecchia Carlo , D'Avanzo Barbara , Negri Eva
Published: February 2007

To investigate possible correlates of the systematically higher pancreatic cancer rates in males than in females, the role of menstrual, reproductive and hormonal factors in females have been assessed using data from a case‐control study conducted in Northern Italy. Cases were 133 women with histologically confirmed incident cancer of the pancreas, and controls were 377 women in hospital for acute, non‐neoplastic, non‐digestive‐tract disorders. After allowance for age, education, area of residence and smoking habit, an increased risk of pancreatic cancer was observed in women with early menarche (⩽ 13 years) (OR = 1.9; 95% Cl; 1.0–3.6), but no significant association was observed with age at menopause or length of fertile life. Parous women were at reduced risk as compared to nulliparous women (OR = 0.7), although the trend in risk with number of births was not significant. No association with spontaneous or induced abortions was observed. Pancreatic cancer risk was inversely related to early age at first birth (first birth < 25 versus nulliparae: OR = 0.5; 95% C1: 0.3–0.9; p‐value for trend < 0.01) and to age at last birth (last birth < 25 versus nulliparae: OR = 0.3; 95% C1: 0.1–0.8; p‐value for trend < 0.05). Ever‐users of estrogen replacement therapy showed a non‐significantly increased risk (OR = 2.2). Although no clear pattern of association is evident, the present results are in agreement with previous epidemiological observations and experimental research indicating that hormonal (menstrual and reproductive) factors could explain part of the male‐to‐female differential in incidence and mortality from pancreatic cancer. © 1995 Wiley‐Liss Inc.
Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas
Authors: Kitahara Kenji , Yasui Wataru , Kuniyasu Hiroki , Yokozaki Hiroshi , Akama Yoshihiko , Yunotani Seiji , Hisatsugu Takeharu , Tahara Eiichi
Published: February 2007

The genetic changes of cyclin A, Dl, E and CDK2 were examined in human colorectal carcinomas by Southern‐blot analysis. Gene amplification of cyclin E was detected in 5 of 53 (9.4%) primary colorectal carcinoma tissues. Interestingly, in 3 of 5 tumors showing cyclin E gene amplification, the CDK2 gene was amplified simultaneously with rearrangements. No obvious correlation was detected between gene amplification and clinico‐pathological features of colorectal carcinomas. Out of 7 colon carcinoma cell lines, 2 showed gene amplification of cyclin E without gene amplification of CDK2. No amplification of cyclin A or Dl gene was found in any of the colorectal carcinoma tissues or colon carcinoma cell lines. Our results suggest that the concurrent amplification of cyclin E and CDK2 genes may play a role in colorectal carcinogenesis. © 1995 Wiley‐Liss Inc.
Apical release of base‐labile fatty acyl groups commensurate with stimulation of glycoprotein sialosyl Lewisa secretion in colorectal carcinoma cells
Authors: Liepkalns V. A. , Eboue D. , Kuksis A. , Beringer T. , Icard‐Liepkalns C.
Published: February 2007

The rate of polarized secretion of a putative adhesion ligand, sialosyl Lewisa (19–9), by SW1116 colorectal carcinoma cells is stimulated at least 20‐fold after pre‐incubation with, and the incorporation of, retinoic acid (RA). In order to investigate the possible involvement of fatty acylation in the export of the epitope, purified ligandsfrom carcinoma‐cell membranes, membrane subfractions and media were analyzed during RA‐induced secretion. Incorporation of radioactivity from (3H)palmitate into membrane subfractions and purified sialosyl Lewisa antigenic molecular species of Mr > 150,000 (SiaLeams) was stimulated by RA treatment. Most of the intracellular lipid radioactivity which bound to solid‐phase 19–9 antibody behaved chromato‐graphically, either like ganglioside or like NH2 OH‐labile acyl groups, but most of the (3H) bound to SiaLeams of post‐incubation media behaved like base‐labile fatty acyl groups, or free fatty acid. Release of base‐labile lipid radioactivity after 3 hr (associated with antigen) was almost exclusively into the apical media of membrane inserts. Gas‐liquid chromatography/mass spec, analyses of purified Sialeams revealed the presence of palmitate (16:0), as well as stearate (18:0) and oleate (18:1) fatty acyl groups. Our results suggest that fatty acylation of SiaLeams may be co‐ordinated with alterations in glycosylation and participate in directing these molecules to the apical surface. Lipid analyses were consistent with ganglioside chaperonage of SiaLeams to the apical surface, where N‐fatty‐acylated gangliosides remain for the most part integrated into the bilayer, but some oxyester or thioester bonds may be cleaved to permit release of SiaLeams to the apical medium. © 1995 Wiley‐Liss Inc.
Inhibition of cis‐diamminedichloroplatinum (II)‐induced DNA interstrand cross‐link removal by 7‐ethyl‐10‐hydroxy‐camptothecin in HST‐1 human squamous‐carcinoma cells
Authors: Masumoto Naoko , Nakano Shuji , Esaki Taito , Fujishima Hiromitsu , Tatsumoto Takashi , Niho Yoshiyuki
Published: February 2007

The combination of cis‐diamminedichloroplatinum(II) (CDDP) and 7‐ethyl‐10‐[4‐(I ‐piperidino)‐I ‐piperidino]carbonyloxycamptothecin (CPT‐I I), a topoisomerase‐l inhibitor, has been shown to be synergistic in vitro and clinically active against several human cancers refractory to chemotherapy. To elucidate the mechanism of the synergistic cytotoxicity of CDDP and 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), an active metabolite of CPT‐11, we studied the interaction of these agents using an HST‐I human squamous‐carcinoma cell line. Cells were exposed to the IC50 concentration of SN‐38 (5.0 ng/ml) for I hr and various concentrations of CDDP for 1 hr in several different treatment schedules. SN‐38 augmented the anti‐tumor activity of CDDP in all schedules, with maximal synergy observed with simultaneous administration. Evaluation of the kinetics of the removal of DNA interstrand cross‐links, measured by alkaline elution, showed significant reduction of this removal in the cells exposed to SN‐38 and CDDP, as compared with the cells exposed to CDDP alone. No differences, however, were found in the initially attained level of DNA interstrand cross‐links induced by CDDP between these cells. Moreover, the intracellular accumulation of platinum measured by atomic‐absorption spectrophotometry, was virtually identical between these cells. These results indicate that SN‐38 can modulate the removal of platinum‐DNA adducts, thereby potentiating the cytotoxicity of CDDP, suggesting a critical role for topoisomerase I in the repair of DNA interstrand cross‐links. © 1995 Wiley‐Liss Inc.
The effect of active oxygen generated by xanthine/xanthine oxidase on genes and signal transduction in mouse epidermal JB6 cells
Authors: Singh Neeta , Aggarwal Sudeepta
Published: February 2007

To gain insight into the gene regulation and signal transduction effects of active oxygen in tumour promotion and progression, we studied the effect of active oxygen generated extracellulariy by xanthine/xanthine oxidase (X/XO) in promotion‐insensitive (P−), promotion‐sensitive (P+) and transformed (Tx) mouse epidermal JB6 cells. Active oxygen inhibited growth, particularly of P− cells and increased poly ADPR transferase activity and PKC activity more significantly in P− cells. No phenotypic differences in the distribution pattern of PKC isotypes α, β and γ were seen in JB6 cells. PKCα was expressed abundantly, whereas β and γ were not detected. Basal levels of the antioxidant enzymes catalase and CuZn. Superoxide dismutase were higher in P+ and Tx cells. X/XO resulted in an initial decrease in the activity of these enzymes, followed by recovery or transient induction in Tx and P+ cells. X/XO induced c‐myc and c‐fos expression in JB6 cells, with c‐fos induction being more pronounced in P− cells, whereas a biphasic increase in c‐jun was seen in P+ cells. These early genes may play a role in proliferation whereas post‐translational poly ADP‐ribosylation and, perhaps, phosphorylation suggest a genetic‐epigenetic mechanism in oxidant tumour promotion and progression. © 1995 Wiley‐Liss Inc.
Establishment and characterization of an uveal‐melanoma cell line
Authors: De Waard‐Siebinga Itte , Blom Derk‐Jan R. , Griffioen Marieke , Schrier Peter I. , Hoogendoorn Ed , Beverstock Geoff , Danen Erik H. J. , Jager Marline J.
Published: February 2007

A human uveal melanoma cell line (92–1) was established from a primary uveal melanoma, and has now been maintained in culture for over 2½ years. Light microscopy of the cultured cells demonstrated extremely pleiomorphic cells with large prominent nucleoli. Cell proliferation was determined with a non‐radioactive propidium‐iodide assay and indicated an in vitro doubling time of approximately 58 hr. Furthermore, the cell line was characterized by cytogenetic analysis, electron microscopy, immunocytochemistry and Northern blotting for HLA and c‐myc‐mRNA analysis. Cytogenetic analysis revealed numerical abnormalities of chromosome 8 and structural abnormalities of chromosome 6. By electron microscopy, different stages of melanosome development were observed. Immunocytochemical analysis demonstrated expression of the melanoma‐associated antigen gp100. Expression analysis of HLA antigens revealed a very low level of, in particular, the HLA‐B locus products, which could be induced by interferon‐α or ‐γ treatment. Likewise, Northern‐blot experiments revealed decreased levels of HLA‐B mRNA as compared with HLA‐A. In addition, high levels of c‐myc expression were observed. The phenotypic characteristics of the cultured cells indicate that we have established an uveal melanoma cell line. This now well‐characterized uveal melanoma cell line can be used in future studies. © 1995 Wiley‐Liss, Inc.
Evidence that a low‐fat diet reduces the occurrence of non‐melanoma skin cancer
Authors: Black Homer S. , Thornby John I. , Wolf John E. , Goldberg Leonard H. , Herd J. Alan , Rosen Theodore , Bruce Suzanne , Tschen Jaime A. , Scott Lynne W. , Jaax Suzanne , Foreyt John P. , Reusser Brenda
Published: February 2007

The effect of a low‐fat diet on occurrence of non‐melanoma skin cancer was examined in a 2‐year dietary intervention trial. A total of 101 skin‐cancer patients were randomized either to a control group that consumed, on average, 38% of caloric intake as fat, and in which no changes in dietary habits were introduced, or to a low‐fat dietary‐intervention group, in which patients were instructed to limit their calories from fat to 20% of total caloric intake. Patients were examined at 4‐month intervals by dermatologists blinded to their dietary assignments. Nutrient analyses, conducted at each of the 4‐month follow‐up visits, indicated that the % calories of fat consumed in the intervention group had been reduced to 21% at 4 months and remained below this level throughout the 2‐year period. There were no significant differences in total calories consumed, or in mean body weights, between the control and the intervention groups. Nor were there significant group differences in PJS ratios until month 24. Numbers of new skin cancers treated at each examination were analyzed in 8‐month periods of the 2‐year study. Comparisons of skin‐cancer occurrences revealed no significant changes in the control group from baseline values. However, cancer occurrence in the low‐fat intervention group declined after the first 8‐month period and reached statistical significance by the last 8‐month period. Patients in this group had significantly fewer cancers in the last 8‐month period than did patients in the control group. In addition, there was a significant reduction in the number of patients developing skin cancer in the last 8‐month period, as compared with the first 8‐month period, within the low‐fat intervention group. There were no significant changes in the control group. These data indicate that a low‐fat diet can significantly reduce occurrence of a highly prevalent form of cancer. © 1995 Wiley‐Liss, Inc.
Apoptosis of a fibrosarcoma induced by protein‐free culture involves DNA cleavage to large fragments but not internucleosomal fragmentation
Authors: Watanabe Hideomi , Kanbe Katsuaki , Shinozaki Tetsuya , Hoshino Hiroo , Chigira Masaki
Published: February 2007

A murine fibrosarcoma clone, Gc‐4 SD, grows depending on fetal calf serum. In MTT assay, protein‐free cultivation resulted in a reduction of the viable cell number time‐dependently. Electron‐microscopic and flow‐cytometric analyses revealed that the reduction in growth was accompanied by the appearance of apoptotic cells. However, no internucleosomal fragmentation was observed even after SI‐nuclease treatment. On the other hand, pulse field gel electrophoresis revealed that cleavage of DNA into high‐molecular‐weight fragments estimated as SO to 150 kilobase pairs (kbp), with a peak of 100 kbp, was found in the serum‐deprived cells. Large fragments disappeared from the DNA extracts when the smaller cells with high blue fluorescence with Hoechst 33342 were removed by flow cytometry, suggesting direct correlation between the large DNA fragmentation and apoptosis. The addition of aurintricarboxylic acid neither abolished the large DNA fragmentation nor inhibited the reduction in the number of viable cells. Both cycloheximide and actinomycin D enhanced the reduction in the number of viable cells as well as the large DNA fragmentation. These results suggest that apoptosis of a fibrosarcoma induced by protein‐free culture involves a specific endogenous endonuclease, which may be distinct from and independent of the ATA‐sensitive endonuclease producing internucleosomal DNA fragmentation. © 1995 Wiley‐Liss, Inc.
Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis
Authors: Simile M. , Pascale R. M. , De Miglio M. R. , Nufris A. , Daino L. , Seddaiu M. A. , Muroni M. R. , Rao K. N. , Feo F.
Published: February 2007

Dehydroepiandrosterone (DHEA) inhibits the development of early pre‐neoplastic lesions and prevents tumor development in various tissues when given to animals during the initiation/ promotion stages of carcinogenesis. Our purpose was to evaluate whether DHEA can also arrest the growth and progression of late lesions, such as persistent nodules (PNs) of rat liver. Male F344 rats were subjected to initiation by diethylnitrosamine followed by selection according to the “resistant hepatocyte” (RH) protocol. Fifteen weeks after initiation, when PNs were present in the liver, the rats were fed a diet withJwithout 0.6% DHEA for a maximum of 15 weeks. Glucose‐6‐phosphate dehydrogenase (G6PD) activity was 17‐ to 20‐fold higher in PNs than in normal liver 15–30 weeks after initiation. It significantly decreased, in both liver and PNs, 16 hr after starting DHEA feeding. Further DHEA feeding for 3–15 weeks decreased G6PD activity by 55–58% in both tissues. Eight weeks after starting DHEA, a fall in the proportion of labeled cells, after continuous contact with 3H thymidine for 7 days, was found in nodules. Treatment for 15 weeks with DHEA caused a marked decrease in the number of nodules per liver, as well as in the incidence of PNs with diameters of 3–6 and > 6 mm, respectively, while it did not affect PNs with diameters < 3 mm. Nodules showing patterns of malignant transformation were present in 40% of rats not treated with DHEA, but not in DHEA‐treated rats. All of 8 surviving rats not treated with DHEA had carcinomas at the 56th week, while only I out of 4 surviving rats treated with DHEA had carcinoma. These data indicate that DHEA inhibits G6PD activity in rat liver and in PNs In vivo. This is associated with growth restraint of PNs and results in inhibition of their progression to malignancy. © 1995 Wiley‐Liss, Inc.
Mitochondria‐bound hexokinase as target for therapy of malignant gliomas
Authors: Oudard Stéphane , Poirson Florence , Miccoli Laurent , Bourgeois Yveline , Vassault Anne , Poisson Michel , Magdelénat Henri , Dutrillaux Bernard , Poupon Marie‐France
Published: February 2007

Hexokinase plays an important role in glucose‐utilizing tissues like normal brain and cancers. In these tissues, hexokinase (HK) is mainly bound to mitochondria (mHK). Our objectives were to evaluate total HK (tHK) activity and mHK fraction in gliomas and to determine whether mHK binding could be targeted for therapy. Tumors were obtained from 26 patients and 13 were xenografted. HK, lactate and ATP were measured in cytosol and mitochondria extracts. The tHK expressed in mU/mg protein were 147 ± 19 and 78 ± 12, in fresh gliomas and xenografts, respectively, and of 489 in the normal brain. The mHK fraction was 76% in normal brain, 74 ± 4% in fresh tumors and 53 ± 6% in xenografts. Lactate/mHK ratios were higher in gliomas than in normal brain. The ATP was 10,52 ± 31 and 19 ± 8 nmol/mg protein in normal brain, xenografts and fresh gliomas respectively. Loss of one copy of chromosome 10 which carries the HKI gene, was evidenced in 11 of the 13 xenografted gliomas. The anti‐tumor effect of lonidamine (LND), which affects glycolysis in interfering with mHK activity, was tested in nude mice bearing 4 gliomas. LND (125 mg/kg, given i.p., twice daily for 5 days) led to a growth inhibition of TG‐7‐RO of 72%, with 2‐fold growth retardation, and had no effect for TG‐8‐OZ. Intermediate LND‐sensitivities for TG‐II‐DU and TG‐IO‐PY were noted. The LND‐sensitivity was correlated with the mHK activity (R2 = 0.73) and mHK fraction (R2 = 0.88). HK binding to mitochondria is a key of glycolysis in malignant gliomas, and targetting this binding with appropriate agents could be an effective therapeutic approach. © 1995 Wiley‐Liss, Inc.
Insulin‐like growth‐factor‐binding protein 3 is decreased in early‐stage operable pre‐menopausal breast cancer
Authors: Bruning Peter F. , Van Doorn Jaap , Bonfrèr Johannes M. G. , Van Noord Paul A. M. , Korse Catharina M. , Linders Theodora C. , Hart Augustinus A. M.
Published: February 2007

Insulin‐like growth factor 1 (IGF‐1) is a potent mitogen for human breast‐cancer cells in vitro. In circulation, most of IGF‐1 is bound to IGF‐binding protein 3 (IGFBP‐3). This high‐affinity binding is thought to have an important limiting effect on the availability of IGF‐1 for biological activity. To assess the availability of IGF‐1 for receptor binding, we determined serum levels of IGF‐1 and IGFBP‐3 and IGF‐1/IGFBP‐3 ratios. In a case‐control study, 150 women aged 38 to 75 years presenting with stage‐l or‐II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population‐based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF‐1 serum concentrations, decreased IGFBP‐3 levels and increased IGF‐1/IGFBP‐3 ratios. The IGF‐1/IGFBP‐3 ratio was a significant breast‐cancer risk factor, also after adjustment for age, family history, height, body‐mass index, body‐fat distribution, and serum levels of C‐peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF‐1/IGFBP‐3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF‐1 in the circulation of pre‐menopausal women may contribute to the development of breast cancer. © 1995 Wiley‐Liss Inc.
Expression and release of intercellular adhesion molecule‐1 in renal‐cancer patients
Authors: Santarosa Manuela , Favaro Daniela , Quaia Michele , Spada Antonella , Sacco Cosimo , Talamini Renato , Galligioni Enzo
Published: February 2007

We examined ICAM‐1 expression in 37 freshly dissociated renal‐cancer cell populations. Immunoperoxidase analysis revealed that 31 of the 37 renal tumors expressed ICAM‐I to various degrees; ICAM‐1 expression was significantly lower in tumor cells obtained from patients remaining tumor‐free after a median follow‐up of 60 months (mean value 24.4% ± 21) than in tumor cells obtained from the relapsed patients (mean value 40.8% ± 22), and the low expression of this molecule on the cell surface seemed to correlate with favorable clinical behavior. In 41 patients, the mean level of sICAM‐1 was 551 ± 260 ng/ml, significantly higher than normal. However, sICAM‐1 levels were significantly lower in the 20 tumor‐free (mean 467 ± 158 ng/ml) than in the 21 metastatic patients (mean 631 ± 318 ng/ml). Eleven renal‐cancer cell populations were cultured in order to examine the expression and release of ICAM‐1. All of these cells were positive for ICAM‐1 expression, which was elevated in 6 cases (> 50%) and low in the remaining 5 cases (18–35%). However, only the 5 cell populations expressing low levels of ICAM‐1 released this molecule, showing an inverse correlation with cellular expression. Five of the cell populations were treated for 48 hr with rIFN‐γ; in these cells, both ICAM‐1 expression and sICAM‐1 levels increased, although sICAM‐1 levels in the supernatants of the cell populations with constitutive high ICAM‐1 expression remained very low. © 1995 Wiley‐Liss Inc.
Characterization of cell lines established from human hepatocellular carcinoma
Authors: Park Jae‐Gahb , Lee Jae‐Ho , Kang Myung‐Soo , Park Kyu‐Joo , Jeon You‐Me , Lee Hyun‐Ju , Kwon Hae‐Sung , Park Hyun‐Sook , Yeo Kyong‐Sook , Lee Kuhn‐Uk , Kim Soo‐Tae , Chung June‐Key , Hwang You‐Jin , Lee Hyo‐Suk , Kim Chung Yong , Lee Young Ik , Chen Tchaw‐Ren , Hay Robert J. , Song Sang‐Yong , Kim Woo‐Ho , Kim Chul‐Woo , Kim Yong‐Il
Published: February 2007

We characterized 8 human hepatocellular‐carcinoma cell lines established from the primary tumors of Korean patients. All lines showed substrate adherence and one line from anaplastic tumor also grew as floating aggregates. Most cultured cells maintained many morphological characteristics of the original tumors from which they were derived. Doubling times varied from 34 to 72 hr. All lines showed relatively high viability and were not contaminated with Mycoplasma or bacteria. All lines showed aneuploidy and were proven to be unique by DNA fingerprinting analysis. Hepatitis‐B‐virus (HBV) DNA was integrated in the genomes of all lines. Two of the cell lines (SNU‐354, SNU‐368) showed expression of HBV and HBVx (HBx) transcripts. SNU‐354 strongly expressed albumin, and SNU‐368 expressed transferrin and insulin‐like growth factor II. No lines produced alpha‐fetoprotein at the RNA and protein level. These cell lines represent useful tools for in vitro studies related to hepatocellular carcinoma. © 1995 Wiley‐Liss Inc.
An in vivo model of intratumoural aromatase using aromatase‐transfected MCF7 human breast cancer cells
Authors: Lee Kathryn , Macaulay Valentine M. , Nicholls Joanne E. , Detre Simone , Ashworth Alan , Dowsett Mitchell
Published: February 2007

About two‐thirds of human breast carcinomas contain detectable levels of aromatase, the enzyme which converts androgens to oestrogens. Assessment of the importance of this enzyme to breast cancer growth has been hampered by the absence of an adequate model system. We have previously reported that MCF7 human hormone‐dependent breast cancer cells transfected with human aromatase cDNA (Aram I cells) showed a growth response in vitro to exogenous androgens and this effect was blocked by aromatase inhibitors. We report here our use of these cells to develop a xenograft model in athymic nude mice. Neither MCF7 cells nor Aram 1 cells formed tumours in oophorectomised (ovx) nude mice unless provided with oestradiol (E2) support. Once established, Aram 1, but not MCF7, tumours could be grown in ovx females supplemented with androstenedione (Δ4A). The mean plasma level of Δ4A was 14 nmol/L in supplemented animals and < 0.5 nmol/L in unsupplemented animals. Similarly, unsupplemented male nude mice were able to support the growth of Aram 1 tumours but not MCF7 tumours. The potent and highly specific aromatase inhibitor CGS20267 (letrozole) significantly decreased tumour growth at 2 mg/kg/day and completely inhibited growth at 20 mg/kg/day in Δ4A‐supplemented but not E2‐supplemented animals. Our results indicate that Δ4A‐dependent growth of Arom 1 tumours in vivo is mediated through the action of intratumoural aromatase. This model should allow an assessment of the critical levels of aromatase required for tumour growth support. © 1995 Wiley‐Liss Inc.
Increased experimental pulmonary metastasis in pregnant mice
Authors: Tanaka Hajime , Tanigaki Yumiko , Saeki Yoshiko , Ishibashi Hiroko , Matsuhisa Tadao , Mori Yoichi , Ogawa Mutsuko , Akedo Hitoshi
Published: February 2007

The effect of pregnancy on experimental pulmonary metastasis was studied. Compared to the incidence of pulmonary metastasis induced by G6 cells in non‐pregnant mice, the incidence of such metastasis was found to be greatly enhanced when the cells were injected i.v. in the latter half of pregnancy. The maximum enhancement was seen on the 15th day of pregnancy. The incidence of pulmonary metastasis returned to the level observed in non‐pregnant mice when the cells were injected 4 days after parturition. Pregnancy also significantly increased the incidence of pulmonary metastasis of 2 other cell lines (3LL and Colon 26). Injection of G6 cells after hysterectomy performed on the 15th day of pregnancy resulted in decreased lung colonization, similar to that seen after parturition. Quantificative analysis of the arrest of G6 cells labeled with [1251]‐5‐iodo‐2′‐deoxyuridine in the lungs showed that the tumor‐cell clearance from the lungs during the 24–72 hr after tumor‐cell injection was much slower in pregnant than in non‐pregnant mice. The continuous administration of β‐estradiol and/or progesterone, which maintained serum levels of the hormones equivalent to those prevailing on the 15th day of pregnancy, did not affect the lung colonization of G6 cells. Tumor‐cell‐platelet aggregation was more extensive with platelets obtained from mice at the 15th day of pregnancy than with those from non‐pregnant mice. When platelets isolated from pregnant mice were injected into normal mice 5 min before G6 injection, lung metastasis was also enhanced. These findings suggest that a pregnant host is handicapped with regard to pulmonary metastasis, this being partly due to increased platelet‐aggregating activity in response to tumor cells. © 1995 Wiley‐Liss Inc.
Inflammatory carcinomas of the breast: A clinical, pathological, or a clinical and pathological definition?
Authors: Bonnier Pascal , Charpin Colette , Lejeune Christiane , Romain Sylvie , Tubiana Nicole , Beedassy Bassodeo , Martin Pierre Marie , Serment Henri , Piana Lucien
Published: February 2007

Some controversy remains about the clinical or pathological definition of the different types of inflammatory breast cancer (IBC) and especially the diagnostic and prognostic value of dermal lymphatic involvement. Our purpose was to classify the different types of IBC for which diagnosis was confirmed intraoperatively and ascertain features allowing reliable diagnosis. We studied clinical findings, biological data, and treatment outcome in a series of 144 successive patients. Our results suggest that there are 2 biologically different entities i.e., true IBC and pseudo‐IBC. True IBC, whose course is currently fatal in all cases, can be divided into 2 sub‐categories i.e., common true IBC (75.7% of cases), in which inflammatory signs occur primarily or secondarily, and occult true IBC (13.2% of cases). Dermal emboli have been observed in 61% of common true IBC, but their absence did not alter the rapidly unfavourable outcome. Extensive lymph‐node involvement, other biological features and survival were the same in the 2 sub‐categories. Pseudo‐IBC (11.1% of cases) can easily be confused with common true IBC. The biological characteristics of pseudo‐IBC differ from those of true IBC: no dermal lymphatic involvement and little or no lymph‐node involvement. Despite large tumour size, outcome was particularly favourable. It is of great importance to differentiate true and pseudo‐IBC, for which the treatments are different. Confirmation of true IBC requires pathological demonstration of dermal lymphatic emboli or extensive lymph‐node involvement. Occult IBC must be identified for patients presenting rapidly growing tumours. © 1995 Wiley‐Liss, Inc.
Overall and site‐specific risk of malignant melanoma associated with nevus counts at different body sites: A multicenter case‐control study of the german central malignant‐melanoma registry
Authors: Rieger Edgar , Soyer H. Peter , Garbe Claus , Büttner Petra , Kofler Regina , Weiss Jürgen , Stocker Ulrich , Krüger Sabine , Roser Marianne , Weckbecker Jörg , Panizzon Renato , Bahmer Friedrich , Tilgen Wolfgang , Kerl Helmut , Orfanos Constantin E.
Published: February 2007

A large number of benign melanocytic nevi is the major risk factor for malignant melanoma (MM). In a multicenter case‐control study, the number of common (CN) and clinically atypical (AN) nevi were counted separately at individual sites in 278 melanoma patients and 278 age‐and gender‐matched non‐melanoma controls. Relative risk (RR) adjusted for age and sex was calculated. In men as well as women, the number of CN on the legs was the best predictor of overall melanoma risk. In men, RR for developing MM when ≥1 AN were present on the trunk was 4‐fold (vs. none). In women, presence of AN on the arms increased RR 9.5‐fold. For men and women combined, after adjusting for age and gender, the RR for developing MM on the trunk and on the legs was best predicted by counts of CN at the respective body region. However, high counts of CN on the arms were associated with high melanoma risk on the legs (somewhat lower on the trunk). For AN, no site‐specificity of melanoma risk was found. Our data suggest that nevus counts of the legs are the best predictor of overall melanoma risk if total body nevus counts are not feasible. Although high counts of CN on the trunk and legs are associated with a higher risk of developing MM at the respective site than at another site, our data do not unequivocally support a direct site‐specific melanoma risk. © 1995 Wiley‐Liss, Inc.
Insulin resistance, insulin‐like growth factor I and breast cancer: A hypothesis
Authors: Kazer Ralph R.
Published: February 2007

Consideration of existing data regarding clinical and biochemical risk factors for the development of breast cancer leads to the hypothesis that enhanced insulin‐like growth factor 1 (IGF‐1) activity plays a significant role in the development of this disease. Abnormal IGF‐1 activity may be related to events occurring prenatally, during puberty, or during adult life. Insulin resistance, a common feature in populations characterized by high caloric intake, may result in the amplification of IGF‐1 action at the tissue level by altering serum concentrations of IGF‐1 binding proteins. Several approaches toward testing the hypothesis are proposed, and potential opportunities for clinical application are described. © 1995 Wiley‐Liss, Inc.
Expression and in‐situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer
Authors: Gress T. M. , Müller‐Pillasch F. , Lerch M. M. , Friess H. , Büchler M. , Adler G.
Published: February 2007

Pancreatic cancer shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissue (collagens type I and III, fibronectin). In this study we have analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix‐degrading metalloproteinases (MMP‐1,‐2,‐3 and‐9) and tissue inhibitors of metalloproteinases (TIMP‐1 and‐2) in pancreatic cancer and control pancreatic tissue by Northern‐blot analysis and mRNA in situ hybridization. Transcripts for MMP‐1 (interstitial collagenase) and MMP‐3 (stromelysin‐1) were not detectable in pancreatic cancer and control tissues. Steady‐state levels of transcripts encoding extracellular matrix proteins, MMP‐2 (72‐kDa collagenase IV), MMP‐9 (92‐kDa collagenase type IV), TIMP‐1 and TIMP‐2 were elevated in the majority of pancreatic‐cancer tissue samples as compared to control pancreatic tissue. A good correlation was seen between overexpression of these MMPs and TIMPs and the steady‐state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of the desmoplastic reaction. In situ hybridization studies localized transcripts coding for collagens type I and III to spindle‐shaped stromal cells, whereas transcripts for MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 were found in both stromal and tumor cells. However, MMP‐2 transcripts appeared to be more abundant in stromal cells, TIMP‐1 and TIMP‐2 transcripts were evenly distributed over tumor and stromal cells and relatively more MMP‐9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 may be involved in processes leading to the strong desmoplastic reaction observed in these tumors. Both stromal and tumor cells appear to be the source of MMPs and TIMPs in human pancreatic cancer. © 1995 Wiley‐Liss, Inc.
Apoptosis in human lymphoblastoid cells induced by acivicin, a specific γ glutamyltransferase inhibitor
Authors: Graber Riccardo , Losa Gabriele A.
Published: February 2007

We examined the effects of acivicin, a specific inhibitor of the ectoenzyme γ‐glutamyltransferase (γ‐GT), on γGT activity and apoptosis in 2 human T‐lymphoblastoid CEM cell lines, CCRF and VBL‐100. In both cell lines, acivicin was found to cause morphological and biochemical changes of apoptosis in a dose‐ dependent manner. There was a close correlation between inhibition of γ‐GT activity and the emergence of apoptotic cells. However, VBL‐100 cells had a 50% higher γ‐GT basal activity than CCRF‐CEM cells, their enzyme activity was more inhibited, and, they had a greater apoptotic response to acivicin. The γ‐GT‐specific activity in apoptotic/dead cells was also almost totally inhibited, while that of cells that remained alive after 5 days of acivicin treatment was not. These findings confirm that γ‐GT is implicated in the process of apoptosis of CEM cells. © 1995 Wiley‐Liss, Inc.
Patterns of splice variant CD44 expression by normal human urothelium in situ and in vitro and by bladder‐carcinoma cell lines
Authors: Southgate Jennifer , Trejdosiewicz Ludwik K. , Smith Barbara , Selby Peter J.
Published: February 2007

CD44 core and splice variant exon expression was investigated in the stratified transitional epithelium of the urinary tract and in normal and malignant bladder epithelial cell lines in vitro. Antibodies against core CD44 epitopes and splice exon variants v3, v4/5, v5 and v6 showed an intense reaction in the basal and lower intermediate urothelial cell layers, which was consistently lost from the upper intermediate and superficial cell layers. Seven independent cell lines established from normal human urothelium expressed complex multiple‐spliced CD44 mRNA transcripts when tested by RT‐PCR and were positive with antibodies against CD44 core epitopes and splice variants v3, v4/5, v5 and v6. Of the 13 bladder‐carcinoma cell lines, all were positive for CO44 core. The more differentiated cell lines had retained some splice‐variant antibody reactivity and showed multiple but less complex CD44 mRNA transcript patterns, compared with normal cells. Anaplastic cell lines did not react with variant antibodies and did not contain multiple‐spliced CD44 transcripts. These data suggest that loss of alternatively‐spliced CD44 may reflect a selection pressure in the evolution of anaplastic bladder cancers. © 1995 Wiley‐Liss, Inc.
Tumor‐reactive superantigens suppress tumor growth in humanized scid mice
Authors: Lando Peter A. , Dohlsten Mikael , Ohlsson Lennart , Kalland Terje
Published: February 2007

Superantigens are extremely potent activators of T lymphocytes. To develop a tumor‐reactive superantigen for cancer therapy, we made a recombinant fusion protein of the superantigen staphylococcal enterotoxin A (SEA) and the Fab region of the C242 monoclonal antibody (C242Fab‐SEA), which recognize human colon carcinoma cells. The therapeutic effect of C242Fab‐SEA on colon‐cancer growth was examined in lymphocyte‐engrafted humanized SCID mice bearing intraperitoneally growing Colo205 colon carcinomas. I.V. injections of C242Fab‐SEA significantly inhibited tumor growth. The anti‐tumor effect required the presence of human T cells in the SCID mice. Optimal therapeutic effects were seen with C242Fab‐SEA, but not with C242Fab fragment or SEA alone, demonstrating that both entities of the fusion protein were required. C242Fab‐SEA‐treated tumors showed a massive infiltration of T cells in the tumor parenchyme, and was accompanied by enhanced expression of ICAM‐I and HLA‐DR on the tumor cells. The results demonstrate that Fab‐SEA fusion proteins convey superantigenicity on tumor cells which evoke T‐cell‐dependent suppression of tumor growth. © 1995 Wiley‐Liss, Inc.
The pure antiestrogen ICI 182,780 binds to a high‐affinity site distinct from the estrogen receptor
Authors: Parisot John P. , Hu Xiu F. , Sutherland Robert L. , Wakeling Alan , Zalcberg John R. , Deluise Mario
Published: February 2007

Both estrogen receptor‐positive (ER+), tamoxifen‐sensitive (5–21) and tamoxifen‐resistant (5–23) subclones of the parental MCF‐7 breast cancer cell line were used in competitive ligand binding studies involving either [3H]ICI 182,780 or 4‐OH‐[3H]tamoxifen (4OHT) displacement by unlabelled estradiol (E2) or the antiestrogens (AE) 4OHT and ICI 182,780. Neither radioligand was displaced significantly by E2 over a range of concentrations; binding was predominantly inhibited by the corresponding radio‐inert ligand. Scatchard analysis of the data revealed that the binding capacities of both cell lines for ICI 182,780 were approximately 7‐fold greater than the previously determined number of ER sites per cell, with the affinity being an order of magnitude less than that of E2 for ER. No difference was found between the TAM‐sensitive and ‐resistant cells in their binding of either AE. When cells were preincubated with either E2, TAM or 4OHT at a high, fixed concentration to block the ER or AE binding sites (AEBS), respectively, displaceable binding of [3H]ICI 182,780 was still observed, indicating binding at a site other than the classical ER or previously described AEBS. Our results suggest that there is a specific, saturable and relatively high‐affinity binding site for ICI 182,780 in MCF 5–21 and MCF 5–23 breast cancer cells. However, the physiological relevance of this binding site requires further clarification because in cell growth assays, E2 (at the dose of ICI 182,780) overcame the inhibitory effect of the antiestrogen in both of the cell lines. © 1995 Wiley‐Liss, Inc.
Pro‐transforming growth factor‐alpha processing in human colon carcinoma cells: Role of protein kinase C
Authors: Ramesh Gadiraju , Levine Alan E.
Published: February 2007

The human colon cancer cell lines HCT 116 (poorly differentiated) and CEO (well differentiated) express the mitogenic peptide transforming growth factor alpha (TGF‐α). The secretion of TGF‐α was enhanced by phorbol 12‐myristate 13‐acetate (PMA), indicating the possible role of protein kinase C (PKC) in the formation of mature TGF‐α. Cells were metabolically labeled with 3SS‐cysteine and the formation of the mature 6 kDa TGF‐α polypeptide from the 17 kDa pro‐TGF‐α precursor was determined. The conversion of pro‐TGF‐α was complete in 2–4 hr with the HCT 116 cells showing faster kinetics of TGF‐α formation than GEO cells. HCT 116 cells secreted more TGF‐α than GEO cells and the rate and extent of formation of TGF‐α was enhanced by PMA in both cell lines. The expression of several PKC isozymes by HCT 116 and GEO cells was examined by immunoblotting. The expression of all isozymes examined was higher in HCT 116 cells compared with GEO cells. Calphostin C, an inhibitor of PKC, reduced the enzyme activity and significantly inhibited the PMA‐induced secretion of TGF‐α by both cell lines. Two agonists of PKC that act on specific PKC isozymes, thymeleatoxin and 12‐deoxyphorbol 13‐phenylac‐etate 20‐acetate (dPPA), stimulated the release of TGF‐α into the medium to the same extent as PMA. Since dPPA has been reported to stimulate PKC‐4bT1 specifically, our results suggest a potential role for PKC‐β in the processing of pro‐TGF‐α by these 2 human colon carcinoma cell lines. © 1995 Wiley‐Liss, Inc.
Low‐dose IL‐2 treatment: Activation of discrete T‐ and NK‐cell sub‐populations in vivo
Authors: Farace Franchise , Angevin Eric , Dietrich Pierre‐Yves , Leboullaire Christophe , Vanderplancke Josy , Escudier Bernard , Triebel Frédéric
Published: February 2007

The activation of T‐ and NK‐cell sub‐populations in vivo was evaluated in a phase‐l study (18 patients) with a 3‐month course of low‐dose s.c. IL‐2, 1,3 and 6±10* IU/day once daily, 6 days a week. At the higher doses, we observed early on (day 15) an increase in CD3+ CD56−, CD3− CD56+ and CD56+ DR+ cell counts, as well as an increase in circulating slL‐2R and non‐MHC‐restricted cytotoxicity against K562 and Daudi cells. In contrast, at the lowest dose, T‐ and NK‐cell counts were not appreciably altered, while a substantial increase in NK cytotoxic activity was still observed. In addition, thyroid dysfunction resembling that described in auto‐immune thyroiditis, was documented in 6 out of the 14 patients studied. Using a high‐resolution method analyzing CDR3 sizes of TCRp transcripts, we observed the appearance of dominant T‐cell clonotypes in I patient out of 2 analyzed, corresponding to the clonal expansion of T cells primed in vivo. Overall, these results show that long courses of low‐dose s.c. IL‐2 treatment lead to the activation of discrete T‐and NK‐cell sub‐populations. © 1995 Wiley‐Liss, Inc.
Plasma endothelin‐1 As a marker for doxorubicin cardiotoxicity
Authors: Yamashita Jun‐Ichi , Ogawa Michio , Shirakusa Takayuki
Published: February 2007

The use of doxorubicin is often limited by cardiotoxicity that can lead to congestive heart failure (CHF). Although various techniques have been used to predict its cardiotoxicity, none has proven useful. We reported 2 patients in whom the level of plasma endothelin (ET)‐ I rose progressively during doxorubicin treatment of breast cancer, and who subsequently developed CHF. Accordingly, we conducted a prospective study of 30 consecutive patients, 23 with breast cancer and 7 with small‐cell lung cancer, who were treated with doxorubicin. Serial changes in plasma ET‐I during doxorubicin treatment were measured by a specific radioimmunoassay, and plasma levels of atrial natriuretic peptide (ANP) were determined by a sensitive immunoradiometric assay. M‐mode echocardiography was performed serially to monitor the fractional shortening (FS) and the left ventricular ejection fraction (LVEF). The plasma concentrations of ET‐I rose progressively in 5 of the 30 patients during doxorubicin treatment. Two of the 5 patients developed clinically overt CHF after developing cumulative doses of doxorubicin of 500 and 480 mg/m2. Serial measurement of plasma levels of ANP, FS and LVEF showed no abnormalities until the development of CHF. Another 25 patients who had received doxorubicin (cumulative doses ranging from 400 to 660 mg/m2) and had not developed CHF showed no appreciable change in plasma ET‐I or other, markers. This prospective study suggests that plasma ET‐I may be useful for predicting the risk of doxorubicin‐induced cardiotoxicity. © 1995 Wiley‐Liss, Inc.