bluuebunny/crossref_metadata_2025 huggingface dataset:
Second malignant tumors after elective end of therapy for a first cancer in childhood: A multicenter study in Italy
Authors: Rosso Paolo , Terracini Benedetto , Fears Thomas R. , Jankovic Momcilo , Bellani Franca Fossati , Arrighini Alberto , Carli Modesto , Di Montezemolo Luca Cordero , Garrè Maria L. , Guazzelli Carlo , Izzi Giancarlo , Loiacono Giuseppe , Mancini Antonia , Tamaro Paolo , Testi Anna M. , Masera Giuseppe , Haupt Riccardo
Published: February 2007

To evaluate the incidence of second malignant tumors in a cohort of subjects previously treated for childhood cancer, we analyzed data from the Off‐Therapy Registry (OTR) of the Italian Association of Pediatric Hematology/Oncology, which collects information on children treated for Hodgkin's disease, non‐Hodgkin's lymphoma, Wilms' tumor, acute lymphoblastic leukemia (ALL) and acute non‐lymphatic leukemia and who had been removed from treatment in the absence of clinical signs of disease,i.e.the off‐therapy stage. Second malignant tumors (SMT), diagnosed before December 31, 1988, were identified through a special enquiry to the 36 institutions cooperating in the registry. Observed cases were compared to expected numbers estimated from age‐ and sex‐specific incidence rates derived from the Cancer Registry of the Province of Varese. In a total of 3,310 study subjects, 27 SMTs have been registered. The Cumulative Risk (CR) of SMT was 2.9% 15 years after the end of treatment and the Standard Incidence Ratio (SIR) was 10.8. The ALL sub‐cohort had the highest risk of SMT (SIR 13.6) and 9 cases of CNS tumor occurred in this group (SIR 58.9). All 9 had received prophylactic cranial radiotherapy (CRT) and 5 had been treated on one protocol, characterized by low‐dose intrathecal methotrexate (IT MTX) given monthly for 2 years after CRT. The Off‐Therapy Registry has unique criteria for inclusion; direct comparisons with similar studies are therefore somewhat problematic. However, our data suggest that the risk of SMT in childhood ALL cancer survivors may be greater than previously reported, and that CNS tumors are the most common SMT in this group. The administration schedule of IT MTX may be an important risk factor. © 1994 Wiley‐Liss, Inc.
Micronuclei, a biomarker for chemoprevention trials: Results of a randomized study in oral pre‐malignancy
Authors: Benner Steven E. , Lippman Scott M. , Wargovich Michael J. , Lee J. Jack , Velasco Marco , Martin Jack W. , Toth Bela B. , Hong Waun K.
Published: February 2007

Biomarkers are being sought that could serve as surrogate end points for chemoprevention trials. Micronuclei, cytoplasmic fragments of DNA, have been proposed as a biomarker and studied in oral pre‐malignancy. This study evaluated micronuclei frequency in a randomized chemoprevention trial of oral pre‐malignancy. A recent clinical trial evaluated the responses of pre‐malignant oral lesions to 3 months of therapy with isotretinoin followed by 9 months of either low‐dose isotretinoin or beta‐carotene. For 57 study participants, micronuclei were counted in mucosal scrapings of the lesion and in normalappearing mucosa at baseline and following 3 months and 12 months of therapy. Micronuclei counts were higher in scrapings from the lesion than in the normal‐appearing mucosa. Following 3 months of isotretinoin, the micronuclei counts in scrapings of the lesion were significantly reduced. With treatment, the mean micronuclei count declined at 3 months. In a randomized comparison, both isotretinoin and beta‐carotene maintained the suppression of micronuclei. The change in micronuclei count was not associated with the clinical or histological response to treatment. Chemoprevention treatment with isotretinoin led to a reduction in frequency of micronuclei, a marker of recent DNA injury, which was then maintained by both isotretinoin and beta‐carotene. © 1994 Wiley‐Liss, Inc.
Adult T‐Cell leukemia/lymphoma: A working point‐score classification for epidemiological studies
Authors: Levine Paul H. , Cleghorn Farley , Manns Angela , Jaffe Elaine S. , Navarro‐Roman Lydia , Blattner William A. , Hanchard Barrie , De Oliveira M. S. , Matutes Estella , Catovsky Daniel , Shimoyama M. , Tajima Kazuo , Sonoda Shunro , Yamaguchi Kazunari , Takatsuki Kiyoshi
Published: February 2007

Adult T‐cell leukemia/lymphoma (ATL) is a malignancy that occurs most frequently in south‐western Japan and the Caribbean basin. The primary etiologic agent for this disease, human T‐lymphotropic virus type I (HTLV‐I), is endemic in these areas. Only a small percentage of individuals infected with HTLV‐I develop ATL. The factors that determine the development of malignant disease as an outcome of HTLV‐I infection in an individual are unknown. ATL is histopathologically heterogeneous and firm diagnosis is made on the contribution of clinical, laboratory and histopathologic features. The wide variety of laboratory assays available to geographically diverse populations has led to a need to standardize the criteria for determining the diagnosis of this disease for epidemiologic studies. This report summarizes current information regarding ATL and proposes a classification facilitating comparison of case series in geographically and ethnically different populations. © 1994 Wiley‐Liss, Inc.
Cross‐sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high‐risk area in northeast thailand
Authors: Haswell‐Elkins Melissa R. , Mairiang Eimorn , Mairiang Pisaln , Chaiyakum Jittaroen , Chamadol Nittaya , Loapaiboon Vallop , Sithithaworn Paiboon , Elkins David B.
Published: February 2007

We describe an innovative strategy to quantify risk of cancer associated with varying levels of exposure to chronic parasitic infection through the identification of asymptomatic cases of cholangiocarcinoma within a population‐based survey of Opisthorchis viverrini infection. Stool samples from 12,311 adults over age 24 years from 85 villages in northeast Thailand were examined for intensity of liver fluke infection. People from varying egg count categories were selected for ultrasound examination to identify hepatobiliary disease. Fifteen preclinical cases of cholangiocarcinoma were diagnosed from a total of 1,807 people based on ultrasonographic evidence with confirmation by endoscopy where possible. The prevalence odds of the diagnosis of cholangiocarcinoma increased gradually within the light and moderate intensity groups. In contrast, sharply elevated prevalence odds [age‐, sex‐ and licality‐adjusted prevalence odds ratio (POR) 14.1, p < 0.05] were observed within the most heavily liver fluke‐infected group compared with the uninfected group. Males were more frequently affected than females (crude POR 4.5), but after controlling for intensity of infection, age and locality, the magnitude and significance of this measurement was reduced. Our data clearly demonstrate a significant relationship between intensity of liver fluke infection and cholangiocarcinoma and a strikingly high prevalence of the disease among heavily infected males. © 1994 Wiley‐Liss, Inc.
HLA‐DQB1*0301 association with increased cutaneous melanoma risk
Authors: Lee Jeffrey E. , Reveille John D. , Ross Merrick I. , Platsoucas Chris D.
Published: February 2007

Susceptibility to a variety of malignancies has been linked to human leukocyte antigen (HLA) genes, including the HLA class II allele DQBI*0301. To determine whether melanoma risk is associated with HLA class II alleles, molecular oligotyping of HLA class II‐DRBI, ‐DQAI and ‐DQAI genes was performed for 45 patients with melanoma. The DQBI *0301 allele was present in 56% of melanoma patients vs. 27% of 200 local Caucasian controls. This difference was highly significant (Bonferroni'scorrected chi‐square p = 0.003, OR = 3.4). No other class II allele tested was present at significantly increased or decreased frequency in melanoma patients. Furthermore, presence of DQBI*0301 in melanoma patients was associated with advanced disease. Melanoma patients carrying the DQBI*0301 allele presented on average with thicker primary tumors (mean 3.7 mm vs. 1.8 mm, 2‐tailed p = 0.02) and were more likely to present with regional or distant metastatic disease (stages III‐IV, 44% vs. 5%, chi‐square p = 0.003), compared to melanoma patients without DQBI*0301. Risk of melanoma incidence or progression may be influenced by DQBI*0301 or a closely linked gene. © 1994 Wiley‐Liss, Inc.
Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric‐cardia carcinogenesis
Authors: Wang Li Dong , Shi Stephanie Tao , Zhou Qi , Goldstein Susan , Hong Jun‐Yan , Shao Peter , Qiu Song‐Liang , Yang Chung S.
Published: February 2007

The objective of this study was to quantify the changes in p53 and cyclin DI protein levels in different stages of human esophageal and gastric cardia carcinogenesis in a high‐risk population in Henan, China. Immunoreactivity of p53, cyclin DI and proliferating‐cell nuclear antigen (PCNA) was observed in the cell nuclei of esophageal and gastric cardia biopsies. The number of p53‐immunostaining‐positive cells was low in normal epithelia, slightly increased in basal‐cell hyperplasia (BCH), markedly increased in dysplasia (DYS) (10‐fold), and further increased in squamous‐cell carcinoma (SCC) (40‐fold). This pattern of change was similar to that of cell proliferation as indicated by PCNA immunostaining. On the other hand, the number of cyclin DI‐immunostaining‐positive cells did not increase from BCH to DYS, although a slight increase from DYS to SCC was noted. In the gastric cardia, again, the pattern of change of p53‐positive cells in different stages of lesions paralleled the pattern of cell proliferation. The number of p53‐positive cells was very low, much lower than that of PCNA‐positive cells, in normal, chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG); therefore, the increase of p53‐positive cells from CAG to DYS was more dramatic (100‐fold). From DYS to adenocarcinoma (AC), the p53‐positive and the PCNA‐positive cells increased 4‐fold. On the other hand, the number of cyclin DI‐positive cells did not increase in pre‐cancerous lesions, but increased slightly in AC. This study demonstrates that p53 protein accumulation increased with the progression of pre‐cancerous lesions, especially in the genesis of dysplasia, both in the esophagus and in the gastric cardia. Our approach of quantitative immunohistochemistry sheds light on the mechanisms of genesis of esophageal and gastric‐cardia cancers, which frequently occur together in many highincidence areas. © 1994 Wiley‐Liss, Inc.
Circadian changes in mitoxantrone toxicity in mice: Relationship with plasma pharmacokinetics
Authors: Lévi Francis , Tampellini Marco , Metzger Gérard , Bizi Ernest , Lemaigre Guy , Hallek Michael
Published: February 2007

Circadian time‐dependent differences in clinical toxicity of several anti‐cancer agents were predicted from murine studies. Mitoxantrone is an anthracenedion (an anthracycline‐related class of compounds) of increased clinical use, which may benefit from selective circadian timing. In 3 consecutive studies, a total of 428 male B6D2F1 mice aged from 8 to 10 weeks were synchronized by an alternation of 12 hr of light and 12 hr of darkness (LD 12:12). They received a single i.v. injection of mitoxantrone at one of 6 or 4 circadian stages differing by 4 or 6 hr. A dose‐response relationship characterized body‐weight loss and survival rate. Dose‐toxicity relationship further closely depended upon circadian dosing time. Thus, a dose of 16 mg/kg killed 100% of the mice injected at 3 hr after light onset (HALO), and none of them at 11 or at 15 HALO (p from x2 < 0.001). Body‐weight loss varied from 41% at 3 HALO to 32% at 15 HALO (p from ANOVA < 0.0001). Least hematologic toxicity and fastest recovery of a normal circulating leukocyte count corresponded to mitoxantrone injection near the middle of the dark‐activity span, at 16 HALO. Similar findings characterized colonic and splenic lesions. Moreover, mitoxantrone was both distributed and eliminated faster after injection at 16 HALO. If such data apply to cancer patients, as was the case for other drugs investigated with this methodology, an afternoon infusion should enable high‐dose mitoxantrone to be well tolerated. © 1994 Wiley‐Liss, Inc.
Interclonal heterogeneity in a human epithelioid‐sarcoma cell line (Gru‐1)
Authors: Engers Rainer , Gerharz Claus D. , Moll Roland , Pohl Anke , Sarbia Mario , Gabbert Helmut E.
Published: February 2007

Three clonal sub‐populations, GRU‐IA, GRU‐IB, and GRU‐IC, isolated from the human epithelioid sarcoma cell line GRU‐I, were characterized morphologically, cytogenetically and with regard to proliferation kinetics. Immunocytochemically, major differences became evident in the expression of cytokeratin 18 and neurofilament proteins, which are indicative for epithelial and neural differentiation respectively. Vimentin, a mesenchymal differentiation marker, however, could be detected in all tumor cells of each sub‐population. Laminin, a major compound of basement membranes, formed abundant intercellular network‐like patterns in GRU‐IB and GRU‐IC, whereas GRU‐IA was characterized by a diffuse intracellular reaction, suggesting a disorder in laminin secretion. Cytogenetically, all sub‐populations proved to be DNA‐aneuploid, the DNA index ranging from 1.4 to 1.5. Proliferation analysis revealed doubling times ranging from 13 (GRU‐IC) to 19 hr (GRU‐IA). These strictly defined clonal sub‐populations provide a valuable tool for further investigations of the biological behavior of human epithelioid sarcoma with special regard to tumor heterogeneity. © 1994 Wiley‐Liss, Inc.
Preserved foods and nasopharyngeal carcinoma: A case‐control study among singapore chinese
Authors: Lee Hin Peng , Gourley Lynn , Duffy Stephen W. , Esteve Jacques , Lee James , Day Nicholas E.
Published: February 2007

The association between the consumption of preserved foods in infancy, childhood and adulthood and the risk of nasopharyngeal carcinoma was investigated in a case‐control study among Singapore Chinese: 200 cases (73% male) were compared with 406 hospital controls (71% male). Significantly increased risks were observed in association with frequent adult consumption of salted soy beans (OR 7.3 for consumption 4 or more times per week, compared with never), canned pickled vegetables (p = 0.01; OR 4.5 for 4 or more times per week), “sze chuan chye”, a salted Chinese tuber, (OR 2.4 for 4 or more times per month) and “kiam chye”, salted mustard greens (OR 2.7 for 4 or more times per week). A protective effect of high vitamin‐E intake in adulthood was observed (OR 0.5 for the highest third of the control range, as compared with the lowest).
Identification of a novel neutralization epitope on envelope GP46 antigen of human t‐cell‐leukemia virus‐type‐II (HTLV‐II)
Authors: Tanaka Yuetsu , Tanaka Reiko , Hoshino Hiroo
Published: February 2007

Having observed that multiple neutralization epitopes of human T‐cell‐leukemia‐virus‐type‐l (HTLV‐I) envelope gp46 clustered in a region between amino acids 187 and 199, we speculated that a region of HTLV‐II gp46 corresponding to the HTLV‐I‐neutralization region may contain HTLV‐II‐specific neutralization epitopes. To test this, we immunized a NZW rabbit and BALB/c mice with a synthetic peptide containing the HTLV‐II gp46 amino acids 182 to 199 (pep 182–199) conjugated to OVA. The serum from the rabbit reacted to the HTLV‐II gp46 and neutralized HTLV‐II‐mediated syncytium formation. One monoclonal antibody (MAb), M2E186NI, generated from the BALB/c mice, stained specifically the surface of HTLV‐II‐positive cells and reacted with HTLV‐II gp46 by Western blot. This MAb was of the IgA isotype and inhibited HTLV‐II‐ but not HTLV‐I‐mediated syncytium formation at a final antibody concentration of 200 μ/ml; it also neutralized an HTLV‐II‐VSV pseudotype virus specifically. Epitope mapping by ELISA using overlapping synthetic peptides indicated that the neutralization epitope recognized by the M2E186NI MAb was located between HTLV‐II gp46 amino acids 186 and 192, corresponding to the sequence Leu‐Gln‐His‐Val‐IIe‐Leu‐Gln‐Pro. These new observations will be helpful in developing vaccines against HTLV‐II infection.
Epithelial‐to‐mesenchymal transition in hpv‐33‐transfected cervical keratinocytes is associated with increased invasiveness and expression of gelatinase a
Authors: Gilles Christine , Polette Myriam , Piette Jacques , Birembaut Philippe , Foidart Jean‐Michel
Published: February 2007

The invasive potential of a set of HPV‐33‐ and HPV‐33+ras‐transfected cervical keratinocytes was investigated. These cell lines were previously separated into 2 groups according to their behavior on collagen rafts. Cell lines from the first group reconstituted CINIII‐like lesions, whereas cell lines from the second group reconstituted epithelia comparable to microinvasive carcinomas. They were thus postulated to represent distinct stages of cervical carcinogenesis. The present results have shown that lines from group I, which have conserved an epithelial morphology in monolayer, (i) could not invade matrigel when tested in a modified Boyden chamber assay, (ii) produced solely gelatinase B and (iii) were unable to activate exogenous gelatinase A. On the other hand, lines from group II associated epithelial‐to‐mesenchymal transition (acquisition of elongated morphology, vimentin positivity) with high in vitro invasive potential and with the ability both to produce and to activate gelatinase A. These results strongly support the hypothesis that the epithelial‐to‐mesenchymal transition and the associated events might be implicated in the progression to the metastatic phenotype.
Expression and functional activity of fibroblast growth factors and their receptors in human pancreatic cancer
Authors: Leung Hing Y. , Gullick William J. , Lemoine Nicholas R.
Published: February 2007

We have analysed expression of the first 7 members of the family of heparin‐binding fibroblast growth factor (FGFs) and their 4 high‐affinity receptors (FGFRs) in human pancreatic carcinoma cell lines, both at the mRNA and protein levels. In cell lines expressing FGFRs, 2 typical patterns were observed: (i) expression of FGFR‐1, −3 or −4 along with the expression of at least one FGF; (ii) co‐expression of FGFR‐3 and FGFR‐4 in the absence of FGF expression. Using RT‐PCR, transcripts representing multiple isoforms of both extracellular and intracellular domains of FGFR‐1 were detected in the cell line PT45. A novel extracellular domain variant of FGFR‐1 was predicted to encode the first immunoglobulin loop in a potentially secreted form. Protein expression of the splice variants of FGFR‐1 was confirmed by immunoprecipitation with specific antibodies in radiolabelled ligand cross‐linking experiments. The type I carboxyl end and the α subtype extracellular domain were detected in the PANC‐1 cell line, while the type I carboxyl terminus and the γ subtype extracellular domain were expressed in the PT45 cell line. Expression of FGF‐2 in PT45 was also detected by immunoprecipitation using 3 different anti‐FGF‐2 antibodies. Apart from the 18‐kDa product, higher molecular weight isoforms, namely 22‐ and 23‐kDa isoforms, were expressed. In an assay of anchorage‐independent growth, exogenous FGF‐2 stimulated a maximum 15‐fold and 10‐fold increase in colony formation by the cell lines MIA PACA‐2 and PANC‐1 respectively. Treatment of monolayer cultures of the same cell lines did not promote growth. However, a specific neutralising antibody against FGF‐2 reduced cell proliferation of MIA PACA‐2 cells by 50%.
AN association between high Ly‐6A/E expression on tumor cells and a highly malignant phenotype
Authors: Katz Ben‐Zion , Eshel Rinat , Sagi‐assif Orit , Witz Isaac P.
Published: February 2007

Murine Ly‐6 is a molecule expressed by various cells, including several types of hematopoietic cells such as pluripotent stem cells, and activated T cells. Ly‐6 is also expressed on tumor cells originating from a variety of tissues. Preliminary observations suggested that the expression of Ly‐6A/E is up‐regulated on highly tumorigenic variants of polyoma‐virus(PyV)‐transformed BALB/c 3T3 cells as compared with weakly tumorigenic variants. On the basis of these observations, we sorted PyV‐transformed A3C cells or DA3 mammary adenocarcinoma cells into stable sub‐populations expressing high or low levels of membrane or mRNA Ly‐6A/E. In vivo studies indicated that the high‐Ly‐6A/E‐expressing cells in both tumor systems expressed a considerably more malignant phenotype (higher efficiency in local tumor production as well as in lung colonization) than low‐Ly‐6A/E expressors. Since the high‐Ly‐6A/E expressors did not exhibit any growth advantage in vitro over low Ly‐6A/E expressors, we concluded that interactions of the former cells with micro‐environmental factors operating in vivo (e.g., Ly‐6A/E ligands) conferred upon these cells a highly malignant phenotype. Apart from the difference in Ly‐6A/E expression, no other phenotypic characteristics distinguished highly from weakly malignant tumor cells. Similarly to T cells, where antibodies to Ly‐6 transduce (or co‐transduce) a proliferative signal, antibodies to Ly‐6A/E were found to transduce a mitogenic signal to high‐Ly‐6A/E‐expressing tumor cells but not to low‐Ly‐6A/E expressors. Taken together, these results show that Ly‐6A/E expression is directly or indirectly associated in vivo with a highly malignant phenotype of 2 types of non‐lymphoid murine tumors.
Globo‐series carbohydrate antigens are expressed in different forms on human and murine teratocarcinoma‐derived cells
Authors: Krupnick Jason G. , Damjanov Ivan , Damjanov Andrea , Zhu Zheng M. , Fenderson Bruce A.
Published: February 2007

The glycolipids of human teratocarcinoma‐derived cell line NCCIT were compared with those of 5 murine teratocarcinoma‐derived cell lines. Glycolipid antigens were identified by cell surface immunofluorescence and high‐performance thin‐layer chromatography (HPTLC) immunostaining with a panel of monoclonal anti‐carbohydrate antibodies. Human NCCIT embryonal carcinoma (EC) cells contained extended globo‐series glycolipids Gb5 (galactosyl globoside) and GL7 (sialyl galactosyl globoside) recognized by antibodies to stage‐specific embryonic antigens 3 and 4 (SSEA‐3 and −4). SSEA‐4 was not detected by immunofluorescence on the surface of any of the 5 murine teratocarcinoma‐derived cell lines examined; however, SSEA‐3 was detected on the surface of murine cell lines resembling primitive endoderm (JC44, NF‐PE) and trophectoderm (E6496D). HPTLC analysis revealed a large amount of globoside (Gb4) in these differentiated cells, which may account for their labeling with anti‐SSEA‐3 antibody. Globo‐series glycolipids were also detected in murine EC cells; however, differences were noted between the 2 cell lines examined. F9 cells contained primarily Gb4 and Forssman glycolipid, whereas NF‐I cells contained only minor amounts of Gb4 and lacked Forssman glycolipid entirely. Our results, coupled with the known distribution of Forssman antigen in the egg cylinder‐stage mouse embryo, suggest that F9 and NF‐I murine EC cells are replicas of cells at different stages of development of the embryonic ectoderm. Glycolipids of normal mouse embryos were examined for comparison. Gb4 and Forssman glycolipid were present in both embryonic and extra‐embryonic tissues, whereas Gb5 and GL7 were restricted to visceral yolk sac and placenta. Our results demonstrate that human and murine teratocarcinoma‐derived cells both synthesize extended globo‐series glycolipids; however, oligosaccharide chain elongation takes different pathways in the 2 species. These differences reflect species‐related and cell type‐specific patterns of glycosylation.
Tumor cells suppress cytokine‐induced nitric‐oxide (no) production in cerebral endothelial cells
Authors: Murata Jun‐Ichi , Corradin Sally Betz , Janzer Robert Charles , Juillerat‐Jeanneret Lucienne
Published: February 2007

Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events involved in brain metastasis, the modulation of NO production in rat‐brain‐derived EC was investigated. NO release was increased by tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), interleukin‐1β, lipopolysaccharide or forskolin in EC2I9 cells, a rat‐brain‐microvessel‐derived EC line. Dexamethasone decreased NO release by cytokine‐activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat coloncarcinoma cell line) were highly adherent to EC2I9 cells, and adhesion was not modified by TNF‐α plus IFN‐γ, or by dexamethasone. Addition of tumor cells or tumor‐cell‐conditioned medium significantly inhibited NO release induced by any of the stimuli examined, but only if added during the initial phase of endothelial‐cell activation. Tumor‐derived suppression of NO release was also observed in primary cultures of cerebral EC. NO synthase (NOS) activity in cytosol extracts of the cerebral EC line was Ca2+‐independent and required both NADPH and tetrahydrobiopterin. NOS activity was increased by TNF‐α and IFN‐γ, and significantly reduced by tumor‐cell‐conditioned medium. These results suggest that rat colon‐carcinoma cells may have developed a protective mechanism involving the release of (a) soluble factor(s) which inhibit(s) NO production by cerebral EC.
Increased risk of colorectal cancer among smokers: Results of a 26‐year follow‐up of us veterans and a review
Authors: Heineman Ellen F. , Zahm Shelia Hoar , McLaughlin Joseph K. , Vaught Jimmie B.
Published: February 2007

To clarify the relationship between tobacco use and risk of colorectal cancer, we evaluated a cohort of 248,046 American veterans followed prospectively for 26 years. In comparison with veterans who had never used tobacco, the risk of death was significantly increased for colon cancer and rectal cancer among current and former cigarette smokers and among pipe or cigar smokers, controlling for social class and occupational physical activity. Rectal‐cancer risk was also significantly elevated among users of chewing tobacco or snuff. For both sites, risk increased significantly with pack‐years, earlier age at first use, and number of cigarettes. These results reinforce 2 recent reports of the association of cigarette smoking and colorectal cancer in men and women. Inconsistencies in the findings of earlier epidemiologic studies appear to be due in large part to differences in length of follow‐up or in choice of controls. Studies with at least 20 years of follow‐up or population‐based controls have tended to find elevated risk with tobacco smoking, while those with shorter follow‐up or hospital controls have not. This, plus the strength and consistency of the association of smoking and colon polyps, suggest that smoking may primarily affect an early stage in the development of colon cancer. If this association is causal, tobacco use may be responsible for 16% of colon‐cancer and 22% of rectal‐cancer deaths among these veterans.
Identification and characterization of autocrine‐motility‐factor‐like activity in oral squamous‐cell‐carcinoma cells
Authors: Ishisaki Akira , Oida Shinichiro , Momose Fumio , Amagasa Teruo , Rikimaru Koichi , Ichijo Hidenori , Sasaki Satoshi
Published: February 2007

A human oral squamous‐cell‐carcinoma cell line, HOC313, was found to produce a factor which stimulates cell motility in an autocrine manner. The motility factor of HOC313 cells also promoted the locomotory activity of B16 murine melanoma cells reported to be sensitive to autocrine motility factor (AMF). HOC313 cells were found to express a large amount of AMF receptor mRNA. In addition, the cell motility activity of HOC313 cells was completely blocked by pertussis toxin, a known inhibitor of AMF activity, suggesting that the motility factor of HOC313 cells may be AMF or a closely related factor. Immunocytochemical analysis has revealed that the AMF‐like factor of HOC313 cells diminishes the cell‐surface expression of adhesive molecule E‐cadherin. These results suggest that down‐regulation of E‐cadherin may be involved in the cell‐motility activity induced by the AMF‐like factor of HOC313 cells.
Bcl‐2 expression is associated with lymph node metastasis in human ductal breast carcinoma
Authors: Sierra Angels , Lloveras Belen , Castellsagué Xavier , Moreno Loli , García‐Ramirez Marta , Fabra Angels
Published: February 2007

The Bcl‐2 proto‐oncogene product blocks apoptosis. We retrospectively studied Bcl‐2 expression in 124 primary tumors from patients diagnosed with T1 (2 cm or less) breast carcinoma with (T1N1) or without (T1N0) lymph‐node metastasis. Bcl‐2 protein was detected by immunohistochemistry on paraffinembedded tissue sections. Multivariate logistic regression modeling was used to estimate prevalence odds ratios for lymphnode metastasis. Bcl‐2 was widely expressed among T1 tumors showing a strong positive relationship with estrogen (F.R)‐ and progesterone (PR)‐receptor‐positive tumors. However, a significant inverse correlation was seen between Bcl‐2 expression and histological grade, Bcl‐2 being absent in the majority of Tl undifferentiated tumors (grade‐Ill carcinomas). Furthermore, Bcl‐2 was more frequently expressed in T1N1 cases (72.2%) than in T1N0 specimens (45.7%). The odds for lymph‐node metastasis in the Bcl‐2‐positive group was 3.6 times larger than that in the Bcl‐2‐negative group. The co‐expression of PR significantly modified the effect of Bcl‐2 on the odds for lymph‐node metastasis, suggesting the existence of a synergistic interaction between the 2 parameters. We studied the percentage of dead cells in primary tumors by in situ DNA fragmentation (FDNA), and found an inverse correlation between Bcl‐2 expression and FDNA. This supported the hypothesis that Bcl‐2 extends cell survival. In conclusion, our study provides evidence that Bcl‐2 expression is involved in breast‐cancer progression, at least in a subset of well‐differentiated and PR‐positive tumors. © 1995 Wiley‐Liss, Inc.
EGF receptor and p185erbB‐2‐specific single‐chain antibody toxins differ in their cell‐killing activity on tumor cells expressing both receptor proteins
Authors: Wels Winfried , Beerli Roger , Hellmann Peter , Schmidt Mathias , Marte Barbara M. , Kornilova Elena S. , Hekele Armin , Mendelsohn John , Groner Bernd , Hynes Nancy E.
Published: February 2007

Many human tumors over‐express erbB‐2 and EGF receptors. The membrane localization of these receptor tyrosine kinases make them appropriate targets for directed tumor therapy. We have used recombinant DNA technology to produce single‐chain antibody exotoxin A (scFv‐ETA) fusion proteins which specifically bind the erbB‐2 and EGF receptors. The scFv portion is composed of the heavy‐ and light‐chain variable domains of monoclonal antibodies which recognize the extracellular portion of each receptor. We have previously described the anti‐tumor activity of the bacterially produced scFv(FRP5)‐ETA directed to the erbB‐2 receptor. In this paper we describe the characteristics of scFv(225)‐ETA, a protein which binds the EGF receptor. The bacterially produced recombinant protein binds to the receptor with high affinity and inhibits the in vitro growth of the EGF receptor over‐expressing tumor cell lines A431 and MDA‐MB468. Combination treatment with scFv‐(FRPS)‐ETA and scFv(225)‐ETA led to an additive inhibitory effect on the in vitro growth of A431 cells. SKBR3 cells expressing low levels of EGF receptor but high levels of p 185erbB‐2 were not affected by scFv(225)‐ETA treatment but were sensitive to scFv(FRP5)‐ETA. Stimulation of SKBR3 cells and HCII RI#11 mouse mammary epithelial cells expressing the human erbB‐2 with EGF led to an increase in scFv(FRP5)‐ETA activity, showing that the EGF‐induced activation of erbB‐2 can potentiate the action of the erbB‐2‐directed toxin. Treatment of athymic nude mice with scFv(FRP5)‐ETA and the combination of both scFv‐ETA proteins led to the transient arrest of growth of established A431 tumors. scFv(22S)‐ETA treatment alone was the most effective, leading to tumor shrinkage during the course of treatment, whereas treatment with the parental monoclonal antibody 225 led to retarded tumor growth. © 1995 Wiley‐Liss, Inc.
Cervical cancer and herpes simplex virus type 2: Case‐control studies in Spain and Colombia, with special reference to immunoglobulin‐G sub‐classes
Authors: Muñoz Nubia , Kato Ikuko , Bosch F. Xavier , De Sanjosé Silvia , Sundquist Vivi‐Anne , Izarzugaza Isabel , Gonzalez Luis Carlos , Tafur Luis , Gili Miguel , Viladiu Pablo , Navarro Carmen , Moreo Pilar , Guerrero Eloisa , Shah Keerti V. , Wahren Britta
Published: February 2007

Two casecontrol studies, including 449 histologically confirmed cases of cervical intraepithelial neoplasia (CIN) III and 425 controls, and 2 studies on invasive cervical cancer, involving 316 histologically confirmed cases and 330 population controls, were conducted in Colombia and Spain to assess the role of herpes simplex virus type 2 (HSV‐2) in cervical neoplasia. Antibodies to this virus were also measured in the sera of 931 husbands of cases and controls. A serological assay using typespecific antigens, glycoprotein C for type I (gC‐1) and glycoprotein G for type 2 (gG‐2) was employed. Immunoglobulin‐G (IgG) subclasses, IgG1 and lgG3r were measured in women positive for HSV‐2 antibodies. No increase in risk of CIN III or invasive cancer was found in women whose sera or whose husbands' sera were positive to HSV‐2. However, compared with women negative to HSV‐2, the risk of CIN III progressively increased with increasing levels of IgG1. The trend was statistically significant in Colombia. There was also a statistically significant increasing trend in risk of invasive cancer with levels of IgG1 in Spain. The levels of lgG3 and its ratio to lgG1, which may indicate recurrent infections, were not associated with the risk of either type of cancer. When the association with lgG1 was analyzed by human papillomavirus (HPV) DNA status, as determined by polymerase chain reaction, the trend was clearer in women whose HPV status was not determined or in those with negative HPV DNA. These results suggest that the role of HSV‐2 is merely marginal and do not support the hypothesis that recurrent HSV‐2 infections are of importance for cervical neoplasia.
Comparison of immunohistochemistry and RT‐PCR for detection of CD44v‐expression, a new prognostic factor in human breast cancer
Authors: Dall Peter , Heider Karl‐Heinz , Sinn Hans‐Peter , Skroch‐Angel Petra , Adolf GÜNther , Kaufmann Manfred , Herrlich Peter , Ponta Helmut
Published: February 2007

In different human tumors, splice variants of the surface glycoprotein CD44 (CD44v) are correlated with advanced stages of tumor growth and metastatic potential. In breast cancer and colon cancer, expression of epitopes encoded by exon v6 on primary tumors is an independent prognostic factor for poor patient survival. Two different screening methods for the detection of CD44 variants in tumors have been applied: immunohistochemistry (IHC) and semi‐quantitative reverse transcription PCR (RT‐PCR). In this study, we have compared the predictive capacity and the applicability of both approaches, using 31 human breast‐tissue specimens (normal and neoplastic). IHC reveals lack of expression of CD44v on normal ductal epithelial cells but strong expression on myoepithelial cells. The majority of tumors express CD44 epitopes encoded by several variant exons. RT‐PCR detects splice variants in normal epithelium, probably derived from RNA expressed in the myoepithelium. In tumors, RT‐PCR reveals expression of a wide range of splice variants, including new ones that are not detected in normal breast tissue, e.g. ones that contain all variant exons. The conclusion of this comparison is that IHC is the better method for breast‐tumor sample screening but that the increased sensitivity of RT‐PCR can help to distinguish CD44v‐positive from CD44v‐negative tumors in cases where only a few tumor cells express variants or where epitopes are masked.
Co‐expression of urokinase, urokinase receptor and PAI‐1 is necessary for optimum invasiveness of cultured lung cancer cells
Authors: Liu Guohui , Shuman Marc A. , Cohen Robert L.
Published: February 2007

We investigated the importance of the urokinase (uPA)‐plasmin system in fostering invasion of human lung cancer cells through artificial basement membranes composed of Matrigel. Eight cell lines (including 1 small cell and 7 non‐small cell fines) were examined. One cell line did not express any components of the urokinase system. Four cell lines had substantial levels of endogenous uPA detectable on their surfaces. Three of these cell lines co‐expressed the plasminogen activator inhibitor PAI‐1 in addition to uPA. Assays for invasiveness revealed 4 cell lines capable of traversing a Matrigel barrier, including the 3 which co‐expressed uPA, PAI‐1 and uPA receptor. Surprisingly, the cell line expressing only uPA and uPA receptor displayed no invasive capacity despite levels of secreted uPA more than 20‐fold higher than the other cell lines studied. Based on these observations, we hypothesized that both uPA and PAI‐1 might be important for invasion by lung tumor cells, at least in vitro. We therefore tested polyclonal antibodies which inhibit uPA and PAI‐1 activity for their effects on the highly invasive H292 cell line. After 3 days, invasive capacity was inhibited by antibodies to both uPA and PAI‐1 in a dose‐dependent manner. The plasmin inhibitor aprotinin reduced H292 cell invasion by 70%. Taken together, our data demonstrate that in cultured human lung cancer cells the uPA‐plasmin system is important in promoting invasion into basement membranes and suggest that a critical balance between uPA and PAI‐1 is necessary for optimal invasiveness. Our data are consistent with results from recent clinical studies showing that PAI‐1 expression in tumor tissue is an adverse prognostic feature.
Suppression of Burkitt's lymphoma tumorigenicity in nude mice by co‐inoculation of EBV‐immortalized lymphoblastoid cells
Authors: Wolf JÜRgen , Draube Andreas , Bohlen Heribert , Jox Andrea , Mücke Susanne , Pawlita Michael , Möller Peter , Diehl Volker
Published: February 2007

EBV‐immortalized B‐lymphoblastoid cell lines (LCL) inoculated s.c. into T‐cell‐deficient nude mice regress completely after a short initial growth period. We tested whether the putative host response underlying this phenomenon might also be directed against progressively growing Burkitt's lymphoma (BL) tumors in nude mice. Outgrowth of BL tumors was suppressed when cells of the highly tumorigenic BL cell line BL 60 were mixed with cells of the autologous LCL IARC 277 before s.c. inoculation into nude mice. Even when the cells were inoculated separately and simultaneously into contralateral flanks of the mice, regression of initially growing BL tumors could be observed, albeit with reduced frequency and dependent on the dose of LCL cells. Tumor growth of BL 60 cells could also be suppressed by co‐inoculation with the non‐autologous LCL IARC 174 and IARC 277 cells could suppress growth of the non‐autologous BL cell line Eli. Pronounced infiltration with murine (m)CD‐11b‐positive mouse macrophages and mCD‐8a‐positive mouse lymphoid cells, most probably natural killer cells, was seen in histological tissue sections of regressing BL 60 tumors when LCL cells were inoculated contralaterally. In regressing BL tumors, these mouse cells were present not only in necrotic areas but also in vital BL tissue, indicating that infiltration of mouse cells had taken place before the development of necrosis. Since tumor‐infiltrating mouse cells can be activated at least by some human cytokines, we measured cytokine production of BL 60 and IARC 277. High amounts of IL 6 and IL 10 were produced by the LCL cells, whereas IL‐6 and IL‐10 production by the BL 60 cells was beyond or close to the detection threshold. In addition, IL 8 was secreted up to 5‐fold more by the LCL than by the BL cells. The results presented here thus suggest a host response of the nude mouse, which is triggered by cytokines released from the LCL but, once induced, is directed also against BL cells.
Antiproliferative activity of taxol on human tumor and normal breast cells vs. effects on cardiac cells
Authors: Brouty‐Boye DaniéLe , Kolonias Dcspina , Lampidis Theodore J.
Published: February 2007

The antiproliferative activity of the chemotherapeutic agent taxol was evaluated on 2 normal and 2 carcinoma human breast‐cell lines and compared with its effects on newborn rat cardiac cells growing in vitro. Relatively little difference in ID50 response (ranging from 0.6 to 2.0 ng/ml) to taxol was found between normal and tumorous breast epithelial cells. Arrhythmias and slowing of beat frequencies of cardiac cells were induced by taxol but at doses approximately 10 times higher than those necessary to inhibit proliferation in dividing cells. Microtubules assayed by immunostaining appeared to be similarly retracted around the nucleus in both breast and heart cells. Overall, our results suggest that taxol does not selectively inhibit the growth of tumor vs. normal human breast cells. They also support the hypothesis that effects on microtubule integrity are associated with effects on cardiac function and that the clinical cardiac activity of taxol already reported may be due, at least in part, to a direct effect of taxol on cardiac cells as demonstrated in these in vitro studies. Thus, caution is needed, in view of possible cardiac effects, when using taxol in future clinical protocols, especially when combined with other cardioactive agents such as Adriamycin.
Production of soluble HLA‐class‐I molecules by IFN‐γ‐induced colon‐adenocarcinoma cells
Authors: Le Junming , Hua Jia‐Cheng
Published: February 2007

High levels of soluble HLA‐class‐l molecules (sHLA) were found to be produced in a time‐ and dose‐dependent manner by colon‐adenocarcinoma Colo20S cells in response to IFN‐γ stimulation. Among other cytokines tested, only IL‐6, TNF, IFN‐α and IFN‐β showed weak inducibility. IFN‐γ‐induced production of sHLA was synergistically enhanced by IL‐lα, IL‐6 or TNF, and combined treatment with TNF and IL‐6 exhibited an additive to synergistic induction. Expression of sHLA is unlikely to result from IFN‐γ‐induced enhancement of overall HLA‐class‐l expression, as at low concentrations IFN‐α, IFN‐β and IFN‐γ stimulated increased expression of cell membrane HLA‐class‐l molecules in Colo205 cells with almost equal efficiency, whereas only IFN‐γ induced high level production of sHLA. Immunoblot‐ting with a monoclonal antibody recognizing, β2‐microglobulin‐free HLA‐class‐l heavy chain revealed 3 major forms of sHLA heavy chain, i.e., 45/43‐, 37‐ and 33‐kDa molecules, in the culture supernatants of IFN‐γ‐induced Colo20S cells. The 45/43‐kDa proteins can be partitioned into Triton X‐114, representing intact HLA‐class‐l heavy chains shed from the cell membrane. The hydrophilic 37‐ and 33‐kDa heavy chain, which remained almost exclusively in the aqueous phase after extraction with Triton X‐l 14, could well be due to alternative RNA splicing, with deletion of exon 5 encoding the hydrophobic transmembrane region of membrane‐anchored HLA‐class‐l heavy chain.
Reduction of the systemic toxicity of cisplatin by intra‐arterial hepatic route administration for liver malignancies
Authors: Vexler Akiva M. , Mou Xiaode , Gabizon Alberto A. , Gorodetsky Raphael
Published: February 2007

Cisplatin (CDDP) administration by the intra‐arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti‐tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed‐up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25–80 mg/m/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose‐independent bi‐exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro‐ or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV‐1063, was used. A cytotoxic effect was recorded only within 2 hr following high‐dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side‐effects following i.a.h. CDDP treatment.
The role of hyaluronan in tumour neovascularization (review)
Authors: Rooney P. , Kumar S. , Ponting J. , Wang M.
Published: February 2007

Tumour growth and metastasis are totally dependant upon neovascularization. The target cell for tumour neovascularization is the blood‐vessel endothelial cell, and specific angiogenic molecules produced or induced by the tumour are believed to initiate the process. In this report, we review one of these angiogenic molecules, the glycosaminoglycan hyaluronan (HA), which appears to have differing roles in neovascularization depending on its molecular mass. High‐molecular‐mass HA is anti‐angiogenic whereas oligosaccharides of HA, of specific size, actively stimulate endothelial‐cell proliferation and migration, 2 of the key events associated with neovascularization, and induce angiogenesis in vivo. We provide details of the action of HA oligosaccharides on endothelial cells, from binding to cell‐surface receptors, through activation of signal transduction pathways and gene expression to protein synthesis, cell proliferation and cell migration. We also suggest a model to account for HA of differing molecular mass being present, at different locations, within a single tumour and how this HA aids both general tumour growth and tumour metastasis.
Mechanisms of MRP over‐expression in four human lung‐cancer cell lines and analysis of the MRP amplicon
Authors: Eijdems Elisabeth W. H. M. , de Haas Marcel , Coco‐Martin José M. , Ottenheim Cecile P. E. , Zaman Guido J. R. , Dauwerse Hans G. , Breuning Martijn H. , Twentyman Peter R. , Borst Piet , Baas Frank
Published: February 2007

Some multidrug resistant cell lines over‐express the gene encoding the multidrug‐resistance‐associated protein (MRP). In all cell lines reported thus far, over‐expression is associated with gene amplification. We have studied the predominant mechanisms of MRP over‐expression in 4 human lung‐cancer cell lines that cover a range of drug‐resistance levels, and we have analyzed the MRP amplicon. In the SW‐1573‐derived, weakly resistant cell line 30.3M, MRP mRNA is elevated 3‐fold in the absence of gene amplification. Run‐on analysis shows that the increased MRP gene expression in this cell line is due to transcriptional activation. In the highly resistant GLC4/ADR and COR‐L23/R cells, MRP gene amplification predominates, whereas in the moderately resistant MOR/R cells, gene amplification is combined with a mechanism resulting in an additional increase in the level of MRP mRNA. Fluorescence in situ hybridization shows that, in the GLC4/ADR cells, amplified MRP sequences are present both in double minute chromosomes (DM) and in homogeneously staining regions (HSR). By pulsed‐field gel electrophoresis we show that the MRP‐containing DM are 1 Mb in length. Chromosome‐16‐specific repetitive sequences adjacent to the MRP gene are also present in the DM and HSR, compatible with the involvement of these sequences in recombination events underlying MRP gene amplification. Our results show that low levels of drug resistance may arise by transcriptional activation of the MRP gene, whereas at high levels of drug resistance amplification of the MRP gene predominates, possibly facilitated by the presence of recombination‐prone sequences.