bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of MAGE genes in primary and metastatic cutaneous melanoma
Authors: Brasseur Francis , Rimoldi Donata , Liénard Danielle , Lethé Bernard , Carrel Stefan , Arienti Flavio , Suter Ludwig , Vanwijck Romain , Bourlond André , Humblet Yves , Vacca Angelo , Conese Marina , Lahaye Thierry , Degiovanni Gérard , Deraemaecker Rika , Beauduin Marc , Sastre Xavier , Salamon Emile , Dréno Brigitte , Jäger Elke , Knuth Alex , Chevreau Christine , Suciu Stefan , Lachapelle Jean‐Marie , Pouillart Pierre , Parmiani Giorgio , Lejeune Ferdy , Cerottini Jean‐Charles , Boon Thierry , Marchand Marie
Published: February 2007

Human genes MAGE‐1 and MAGE‐3 code for antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These antigens may constitute useful targets for specific anti‐tumor immunization of cancer patients, since genes MAGE‐1 and MAGE‐3 are expressed in a number of tumors of different histological types, but are not expressed in normal adult tissues other than testis. This also applies to genes MAGE‐2 and MAGE‐4, which are closely related to MAGE‐1 and MAGE‐2. We have analyzed the expression of these 4 MAGE genes in cutaneous melanoma. Sixteen of 100 primary tumors vs. 69 (48%) of 145 metastases from individual patients expressed MAGE‐1. Similar differences in the frequency of gene expression between primary and metastatic tumor samples were observed for MAGE‐2, MAGE‐2, and MAGE‐4.MAGE expression in primary tumors was correlated with tumor thickness: there was a significantly increased frequency in the expression of MAGE‐1, ‐2 and ‐3 in tumors of greater thickness. Benign and dysplastic nevi, as well as in situ melanomas, did not express any of the 4 MAGE genes.
Radioimmunotherapy of prostatic adenocarcinomas: Effects of 131I‐labelled E4 antibodies on cells at different depth in DU 145 spheroids
Authors: Essand Magnus , Grönvik Christina , Hartman Torbjörn , Carlsson Jörgen
Published: February 2007

Spheroids of the human prostatic adenocarcinoma cell line DU 145 were used to study experimental radioimmunotherapy. Spheroids were incubated with the 131l‐labelled monoclonal E4 antibody until the radionuclide immunoconjugate had bound the 5 to 6 outermost cell layers of the spheroids. A set of 50 spheroids were exposed, either immediately or 48 hr after antibody incubation and washings, to a dilute trypsin solution with the aim of stripping off cells from the spheroid surface. Stripped cells were collected in fractions corresponding to defined spherical shells. Cells were subsequently plated for clonogenic growth. The technique of automated sequential trypsinization of spheroids followed by a clonogenic survival assay permits studies on therapeutic efficacy for radionuclide immunoconjugates on cells from different layers of spheroids. In addition, the absorbed doses throughout a spheroid were calculated. The binding and retention kinetics of the radionuclide immunoconjugate and the excess of 131l‐E4 in the culture medium during incubation are factors that were all accounted for in the calculations. If the calculated absorbed doses were inserted into the linear‐quadratic survival model and the low dose rate was taken into account, survival values were well in accordance with the experimentally obtained values. The results demonstrate that the 131I‐labelled E4 antibody is capable of sterilizing cultured tumour cells that have bound the radionuclide immunoconjugate and, by means of radiation “cross‐fire”, those cells located in close proximity.
c‐jun expression and growth stimulation in human ovarian carcinoma cell lines following exposure to cytokines
Authors: Spinner Daniel M. , Brandstetter Thomas , Kiechle‐Schwarz Marion , Du Bois Andreas , Angel Peter , Bauknecht Thomas
Published: February 2007

We evaluated the effects of recombinant human G‐CSF, rhGM‐CSF, rhM‐CSF and rhIL‐1α on proliferation and regulation of c‐jun gene expression in 4 human ovarian‐carcinoma (HOC) cell lines, NIH:OVCAR‐3, SK‐OV‐3, HEY and BG‐I, and in one primary ovarian tumor in vitro. The cytokines were administered in concentrations of 0.1 U/ml to 1000 U/ml. Cell growth was measured by crystal‐violet‐ and thiazolyl‐blue(MTT)‐based cell counts, c‐jun transcripts were measured by the solution hybridization/RNAse protection assay. RhM‐CSF and rhGM‐CSF showed no growth stimulation of any of the 5 cell lines tested. Results from exposure to rhG‐CSF were different. The cell lines NIH:OVCAR‐3, SK‐OV‐3, BG‐I and the primary ovarian tumor showed no proliferative response. A 2‐ to 3‐fold increase in proliferation was observed in the HEY HOC cell line. rhIL‐lα led to growth stimulation in the BG‐I cell line, but showed an inhibitory effect in the NIH:OVCAR‐3 cells. No effects of rhIL‐1α were observed in the remaining 2 cell lines nor in the primary ovarian tumor. Growth stimulation was accompanied by an increase in c‐jun expression in the HEY cell line, and the BG‐I cell line. No alterations in c‐jun expression were observed in the remaining 3 cell lines. Our results indicate that rhG‐CSF or rhIL‐1α influence cell proliferation in 2 out of 5 human ovarian‐tumor cell lines, accompanied by an increase in c‐jun expression.
Effects of organic and inorganic selenium compounds on rat mammary tumor cells
Authors: Ronai Ze'Ev , Tillotson Joanne K. , Traganos Frank , Darzynkiewicz Z. , Conaway C. Clifford , Upadhyaya Parmod , El‐Bayoumy Karam
Published: February 2007

To explore cellular effects of potent organoselenium chemo‐preventive agents we have used a rat mammary tumor cell line. We demonstrate that 1,4‐phenylenebis(methylene) selenocyanate (p‐XSC) at a dose of 5 μM is a more potent inhibitor of DNA, RNA and protein synthesis as well as of mitochondrial transmembrane potential than its chemopreventive counterparts benzyl selenocyanate (BSC) and sodium selenite. These differences were also reflected in reduced growth rate by 24 and 48 hr. Cell‐cycle and cell‐morphology analysis revealed that higher doses of p‐XSC (10 μM) caused DNA fragmentation which was accompanied with partial loss of nuclear stainability, whereas BSC caused a noticeable change in cell‐cycle distribution and extensive micronucleation. Overall, our results point to cellular targets of selenium compounds which may mediate their chemopreventive activities in mammary tissues.
Multiple APC messenger RNA isoforms encoding exon 15 short open reading frames are expressed in the context of a novel exon 10A‐derived sequence
Authors: Sulekova Zora , Reina‐Sanchez Julio , Ballhausen Wolfgang G.
Published: February 2007

Intragenic splice mechanisms affecting the coding exons 8 to 15 of the human adenomatous polyposis coli (APC) gene have been analyzed. Three mechanisms within this gene area were found to contribute to mRNA heterogeneity: (i) facultative expression of exon 9‐encoded sequences; (ii) in‐frame insertion of a 54‐nucleotide sequence encoded by a novel exon located 1.6 kb down‐stream from exon 10, provisionally designated APC exon 10A; (iii) skipping of exon 14, resulting in a novel exon 13/15 connection. Interestingly the latter event provided the mRNA with a novel open reading frame, which was terminated after 19 codons of exon 15‐derived sequences. Combinatorial joining of these segments yielded 7 different transcripts in addition to an mRNA species resulting from an exon 10/15 connection, as determined by cloning and sequence analysis. RT‐PCR expression analyses were carried out to demonstrate that this complexity of splice variants is indeed synthesized in cell lines derived from various tissues. Furthermore, in accordance with our findings at the transcript level, we provide Western blot analyses demonstrating that moderate steady‐state levels of genuine APC‐specific low m.w. polypeptide chains exist. These APC “light chains”, however, are not identical with polypeptide chains, which have been reported to accompany apoptosis and necrosis, since the molecules described here are definitively co‐expressed with p300apc at the transcript and protein levels.
Toombak dipping and cancer of the oral cavity in the Sudan: A case‐control study
Authors: Idris A. M. , Ahmed H. M. , Malik M. O. A.
Published: February 2007

To investigate the possible causal association between squamous‐cell carcinomas of the oral cavity and use of toombak, we retrospectively compared the history of use of this substance in 375 patients with squamous‐cell carcinomas of the lip, buccal cavity and floor of mouth, and 271 patients with squamous carcinomas of the tongue, palate and maxillary sinus, with 204 patients exhibiting non‐squamous oral and non‐oral malignant neoplasms and 2,820 individuals who had no malignancy, selected from the general population. The study revealed that the high prevalence of oral cancer in the Sudan is largely due to chronic use of toombak. The adjusted ORs associated with toombak dipping for the first case group, cancer of the lip, buccal cavity and floor of mouth in comparison with the hospital and population control groups, were 7.3 and 3.9 (95% confidence limits, 4.3–12.4 and 2.9–5.3) respectively and among long‐term users the adjusted ORs were 11.0 and 4.3 (95% confidence limits, 4.8–25.1 and 2.9–6.3) respectively. The elevated risk found when investigating intra‐oral cancers of sites in direct contact with toombak quid compared to those with little or no contact, confirms the hypothesis that direct contact with tissues is an important factor in tobacco carcinogenesis in the mouth. The increased risk associated with the use of toombak is of particular concern in view of its wide consumption in the Sudan.
Dietary fiber and risk of benign proliferative epithelial disorders of the breast
Authors: Baghurst Peter A. , Rohan Thomas E.
Published: February 2007

Following a recent finding, from a case‐control study in Adelaide, South Australia, of a reduced risk of breast cancer among women consuming diets rich in fiber, the fiber densities in the diets of 354 women with incident benign proliferative epithelial disorders of the breast (BPED) were compared with the fiber densities of the diets of 354 matched community controls and with those of 189 unmatched controls having breast conditions for which there was no evidence of BPED at biopsy. Fiber intakes were estimated by means of a self‐administered quantitative food‐frequency questionnaire, and the risk of BPED was estimated for each quintile of fiber density (grams of fiber/megajoule of total energy intake) relative to an arbitrarily assigned risk of one for the lowest quintile. For women with the highest dietary fiber densities the estimated risk was 0.64 (95% Cl 0.34, 1.19) when cases were compared with community controls, and 0.45 (95% Cl 0.24, 0.82) when cases were compared with biopsy‐negative controls. Similar trends in risk were observed for the intakes of other major fiber components, the association being stronger when the comparison was made with biopsy‐negative as opposed to community controls. If these findings can be substantiated, they may open the way to dietary intervention strategies for reducing the incidence of breast cancer.
Human T‐cell‐leukemia virus type I in post‐transfusional spastic paraparesis: Complete proviral sequence from uncultured blood cells
Authors: Bazarbachi Ali , Huang Menger , Gessain Antoine , Saal Fortuna , Saib Ali , Peries Jorge , De The Hugues , Galibert Francis
Published: February 2007

Hhdman‐T‐cell‐leukemia virus type I (HTLV‐I) is the causative agent of adult T‐cell leukemia/lymphomhd (ATL) and tropical spastic paraparesis/HTLV‐I‐associated myelopathy (TSP/HAM). The different disease outcome may be attributable to subtle mutations leading to modification of viral tropism or infectivity. Initial attempts found a very high level of sequence conservation among all HTLV‐I strains. However, only one complete proviral DNA sequence is reported from a TSP/HAM patient, with a provirus derived from immortalized lymphocytes, which might be expected to be a leukemogenic variant rather than a neutrotropic one. We cloned and sequenced a complete HTLV‐I provirus (HTLV‐Iboi) derived from the uncultured lymphocytes of a sub‐acute post‐transfusional TSP/HAM patient with clonal integration of HTLV‐I. HTLV‐Iboi proviral genome is 9033 bp long, and its overall genetic organization is similar to that of the prototype HTLV‐I(ATK), without major deletions or insertions. No premature termination codon was found in the 4 open reading frames of the pX region. Divergence at the nucleotide level of HTLV‐lBoi from the reported full‐length HTLV‐I varies from 1 to 9.4%, and indicates that it corresponds to a cosmopolitan genotype. This study did not identify specific sequences associated with neurotropic strains.
Trisomy 20 is a primary chromosome aberration in desmoid tumors
Authors: Mertens Fredrik , Willén Helena , Rydholm Anders , Brosjö Otte , Carlén Birgitta , Mitelman Felix , Mandahl Nils
Published: February 2007

Chdtogenetic analysis revealed trisomy 20 in 4 desmoid tumors: in 2 cases as the sole aberration, in hd together with +X, ‐Y and −13 and in I with +8 and a supernumerary marker chromosome. Our findings indicate that gain of chromosome 20 is an early event in the development of a large subset of desmoid tumors and that it is as frequent as +8, the only consistent chromosomal change previously reported in this tumor type. The non‐random occurrence of trisomies 8 and 20 in desmoid tumors indicates shared pathogenetic mechanisms with infantile fibrosarcoma, a fibrous tissue tumor characterized by various combinations of trisomies for chromosomes 8, 11, 17 and 20.
Implication of the αvβ3 integrin in the adhesion of the ovarian‐adenocarcinoma cell line IGROV1
Authors: Carreiras Franck , Lehmann Maxime , Sichel François , Marvaldi Jacques , Gauduchon Pascal , Le Talaer Jean‐Yves
Published: February 2007

Accumulating evidence suggests that integrins, which participate in many complex cellular processes, are important for tumor progression and metastasis. In order to understand the role of these cell‐surface receptors and of their ligands in the biological behavior of ovarian tumor cells, we have examined the expression of integrins in the human ovarian‐adenocarcinoma cell line IGROVI. These cells expressed the αv sub‐unit and used it to attach on vitronectin (Vn). A monoclonal antibody (MAb) (69‐6‐5) specific to αv blocked the attachment of IGROVI cells on Vn and fibrinogen (Fg), but not on fibronectin (FN) and other adhesive ligands. Immunoprecipitation of surface biotinylated cells followed by Western blotting showed that the αv sub‐unit was associated with β3, but not with β1, β5 or β6. When cells were cultivated on glass coverslips or on Vn sub‐stratum in serum‐free medium, immunofluorescence staining with MAb 69‐6‐5 revealed the presence of αv at cell‐cell contacts and at focal contacts, supporting its active participation in adhesion as part of a functional heterodimer. Furthermore, immunofluorescence data showed the presence of Vn as a fibrillar network in IGROVI cells cultivated on FN‐coated slides. These results suggest that αvβ3 and its Vn ligand may play a important role in the behavior of ovarian epithelial tumors.
Bidirectional interactions between the estrogen receptor and the c‐erbB‐2 signaling pathways: Heregulin inhibits estrogenic effects in breast cancer cells
Authors: Grunt Thomas W. , Saceda Miguel , Martin Mary Beth , Lupu Ruth , Dittrich Evelyn , Krupitza Georg , Harant Hanna , Huber Heinz , Dittrich Christian
Published: February 2007

Thde responsiveness of estrogen receptor (ER)‐positive breast cancer to endocrine therapy is frequently reduced ihd cells over‐expressing c‐erbB‐2. Stimulation of ER suppresses c‐erbB‐2, indicating that estrogen controls the activity of c‐erbB‐2. Heregulin (HRG) has been described to bind to c‐erbB‐3/c‐erbB‐4 and to stimulate c‐erbB‐2. Here we describe the effects of HRG on cell growth and on ER and c‐erbB‐2 expression in breast cancer cell lines containing distinct levels of c‐erbB‐2 and ER (BT‐474: c‐erbB‐2 + + +, ER +; MDA‐MB‐361: c‐erbB‐2 + +, ER ++; MCF‐7: c‐erbB‐2 +, ER + + +). Proliferation of estrogen‐stimulated, c‐erbB‐2 and ER‐positive cells is inhibited by HRG in a dose‐dependent manner. In addition, HRG dose‐dependently inhibits ER expression. Estrogen, however, inhibits c‐erbB‐2. Estrogen‐mediated down‐regulation of c‐erbB‐2 is most pronounced in MCF‐7 but weaker in BT‐474. In the latter cells HRG efficiently blocks the estrogenic effect on c‐erbB‐2. In MCF‐7 cells, however, the inhibition of c‐erbB‐2 cannot be completely reverted by HRG. This modulation occurs in all 3 cell lines at protein, RNA and transcriptional levels, suggesting that the activity of the c‐erbB‐2 promoter, which contains an estrogen‐responsive region, is affected by HRG. The intensity of the mutual inhibition between the HRG/c‐erbB‐2 and the estrogen/ER system depends on the relative levels of ER and c‐erbB‐2 expression in the respective cell lines.
Dominant‐negative p53 can restore tumorigenicity of L‐929 cells in immunocompetent mice
Authors: Appleman Leonard J. , Frey Alan B.
Published: February 2007

Thd study the effect of a transforming allele of the tumor suppressor p53 upon the anti‐tumor immunhd response, anti‐genic L‐929 cells were transfected with the dominant‐negative valine135 mutant of murine p53. Several p53val135‐expressing transfectants formed non‐regressing tumors in immunocompetent hosts. The growth rates of tumorigenic and non‐tumorigenic clones were equivalent in vitro in sublethally irradiated C3H/HeN mice and in nude mice. Tumorigenic and non‐tumorigenic p53val 135‐expressing L‐929 clones expressed equivalent levels of cell surface class I major histocompatibility complex (MHC) glycoproteins. Immunization with a tumorigenic Lp53val135 clone protected mice from subsequent challenge and primed MHC class I‐restricted cytotoxic T‐lymphocytic precursors. Secretion of an immunosuppressive cytokine, transforming growth factor β‐1 and sensitivity to tumor necrosis factor‐α were equivalent from tumorigenic and non‐tumorigenic cell lines. These data suggest that expression of a transforming allele of p53 can allow L‐929 cells to escape the host immune system.
Expression of the cyclin‐dependent kinase inhibitors p16INK4, p15INK4B and p21Waf1/cip1 in human breast cancer
Authors: Musgrove Elizabeth A. , Liuschkis Richard , Cornish Ann L. , Lee Christine S. L. , Setlur Vittal , Seshadri Ram , Sutherland Robert L.
Published: February 2007

Ahderrant cyclin expression has been implicated in oncogenesis in a number of human cancers. Since alterehd function of regulators of cyclin‐dependent kinase (CDK) activity other than cyclins, in particular CDK inhibitors, might play a similar role in oncogenesis, we examined the expression and regulation of the CDK inhibitors p16INk4 p15INK4B and p21WAF1/CIP1 in human breast cancer cell lines. Both the INK4 and INK4B genes were homozygously deleted in 3 cell lines, while INK4 alone was deleted in 2 cell lines. A further 2 cell lines displayed loss of an allele at this locus, and in 1 of these the remaining allele contained a mis‐sense mutation within the coding region of the p16INK4 protein. The majority of cell lines examined, including 2 normal mammary epithelial cell strains, expressed low levels of INK4 mRNA and low or undetectable levels of INK4B mRNA. However, INK4 mRNA was expressed at high levels in 5 cell lines, and this was associated with deletion or inactivation of the retinoblastoma susceptibility gene product pRB but not with mutation of TP53. No deletions of the WAF1/CIP1 gene were observed, but WAF1/CIP1 mRNA levels were reduced in cell lines with TP53 mutation. Transfection of a p16INK4 expression vector into MDA‐MB‐231 cells lacking the INK4 gene failed to produce any p16INK4‐expressing cell lines, suggesting that such cells were selected against in continuous culture. Despite the frequent deletion of INK4 in breast cancer cell lines, no evidence was obtained for INK4 deletions in DNA from 45 primary breast carcinomas. Thus, homozygous deletion of the INK4 gene appears to be a rare event in primary breast cancer.
Influence of hepatic artery occlusion and desferrioxamine on liver‐tumour growth
Authors: Lindnér Per , Naredi Peter , Peterson Anders , Hafström Larsolof
Published: February 2007

Thde mechanisms behind tumour regression during ischaemic therapy of liver malignancy are not thoroughlhd elucidated. Ischaemia‐reperfusion injury and release of free radicals is one mechanism suggested. The aim of the present study was to explore whether inhibition of hydroxyl radicals, by complex binding Fe+++ with desferrioxamine (DFO), counteracted the retardation in tumour growth rate after HAL and whether DFO in itself had an effect on tumour growth in 2 experimental rat liver tumours. Rats with a hepatoma or an adenocarcinoma were subjected to HAL or to a sham procedure with or without additional injections of DFO daily for 2 or 7 days. HAL had an inhibitory effect on tumour growth rate. The effect of HAL was not counteracted by DFO, while DFO alone caused a decrease in tumour volume. There was an additive effect of DFO and HAL on tumour growth rate in both tumour systems. In vitro there was a growth inhibitory effect of DFO in both tumours, more pronounced in the hepatoma than in the adenocarcinoma. Our findings indicate that the effect of HAL is not mediated by release of oxygen free radicals. In the adenocarcinoma system, an additive effect of DFO and HAL was seen. As a rate‐limiting enzyme for DNA synthesis is dependent on iron, depletion of iron can decrease mitotic activity, a mechanism that could explain the effect of DFO on tumour growth.
c‐erbB‐2 anti‐sense phosphorothioate oligodeoxynucleotides inhibit growth and serum‐induced cell spreading of p185c‐erbB‐2‐overexpressing ovarian carcinoma cells
Authors: Wiechen Kai , Dietel Manfred
Published: February 2007

Overexpression of the c‐erbB‐2 proto‐oncogene product (p185c‐erbB‐2) occurs frequently ihd different types of human cancer and is correlated with a significantly decreased survival in ovarian cancer patients. The effect of c‐erbB‐2 anti‐sense phosphorothioate oligodeoxynucleotides (S‐ODNs) was examined on the ovarian cancer cell line SK‐OV‐3. p185c‐erbB‐2 levels were specifically reduced by a single‐dose application of 5 μM c‐erbB‐2 anti‐sense S‐ODNs. This was accompanied by a 60% inhibition of anchorage‐dependent cell growth. More strikingly, c‐erbB‐2 anti‐sense S‐ODNs almost completely abrogated serum‐induced cell spreading. A control of complementary sense oligodeoxynucleotides did not show significant inhibitory effects on cell growth or on cell spreading. The inhibition of cell spreading was imitated by a monoclonal antibody (9G6) targeting the extracellular domain of p185c‐erbB‐2 and by the tyrosine kinase inhibitor erbstatin. The inhibitory activity of these 2 compounds was lost after a few hours, while the inhibition of serum‐induced cell spreading by anti‐sense S‐ODNs was still present after 24 hr. Our results show that c‐erbB‐2 anti‐sense S‐ODNs effectively inhibit the mitogenic and spreading activity of p 185c‐erbB‐2 in ovarian cancer cells. Thus, anti‐sense strategies have the potential of providing new strategies for the therapy of ovarian cancer.
Expression of p21WAF1/CIP1 is heterogeneous and unrelated to proliferation index in human ovarian carcinoma
Authors: Barboule N. , Mazars P. , Baldin V. , Vidal S. , Jozan S. , Martel P. , Valette A.
Published: February 2007

The growth‐inhibitory protein p21WAF1/CIP1 is a potent inhibitor of various cyclin‐dependent kinases, the expression of which is regulated at the transcriptional level by p53‐dependent and ‐independent mechanisms. We examined p21WAF1/CIP1 mRNA and protein expression in 5 human ovarian‐adenocarcinoma cell lines, I primary culture of normal surface epithelium and 17 human ovarian‐tumor specimens. In culture cells, the p21 WAF1/CIP1 protein was expressed in normal ovarian epithelial cells and at a high level in the adenocarcinoma 2008 and IGROV‐I cell lines. p21WAF1/CIP1 expression was undetectable at the mRNA and protein levels in the NIH‐OVCAR‐3 and SKOV‐3 ovarian‐adenocarcinoma cell lines which are respectively mutated and deleted in the p53 gene. Heterogeneous expression of p21 WAF1/CIP1 observed in ovarian‐cancer cell lines in culture was also found in vivo on tumor specimens. p21WAF1/CIP1 expression is undetectable in 25% of the ovarian biopsies examined. Since it has been found that the p53 gene is mutated in 79% of ovarian cancer, the absence of p21WAF1/CIP1 expression in 25% of these ovarian cancer could not be correlated with p53 mutation. The proliferation index of the 17 tumors showed great variation from one tumor to another. However, no significant correlation was found between p21 WAF1/CIP1 expression and the proliferation rate of the tumors. © 1995 Wiley‐Liss, Inc.
Loss of heterozygosity at 9p21 loci and mutations of the MTS1 and MTS2 genes in human lung cancers
Authors: Shimizu Tatsunori , Sekiya Takao
Published: February 2007

To elucidate the involvement of abnormalities of the MTS1/p16 and MTS2/p15 genes located at chromosomal region 9p21 in human lung cancers, we analyzed DNA from 30 primary lung cancers and detected loss of heterozygosity at the 9p21‐p23 region in 15 tumors. Single‐strand‐conformation‐polymorphism analysis of polymerase‐chain‐reaction products from the MTS1 and MTS2 genes and determination of the nucleotide sequences revealed the presence of a mutated MTS1 gene in 2 of 15 tumors with a loss of corresponding loci. No mutations of the MTS2 gene were found. These results suggested that mutations of the MTS1 gene are associated with at least some human lung cancers. © 1995 Wiley‐Liss, Inc.
Cell kinetics of CD34‐positive hematopoietic cells following chemotherapy plus colony‐stimulating factors in advanced breast cancer
Authors: Danova Marco , Rosti Vittorio , Mazzini Giuliano , De Renzis Maria R. , Locatelli Franco , Cazzola Mario , Riccardi Alberto , Ascari Edoardo
Published: February 2007

Bone‐marrow (BM) hematopoietic precursors are recruited into proliferative activity when colony‐stimulating factors (CSF) are sequenced with chemotherapy (CT). Previous studies suggested that further CT can be safely administered only when the increased proliferative activity of these cells has subsided, because most cytostatic drugs selectively damage cycling cells. The safest interval between CSF discontinuation and the start of the next CT course needs to be ascertained in vivo. Thirty patients with advanced breast cancer were treated with an intensified FEC regimen, planned at 21‐day intervals, sequenced with granulocyte‐macrophage (GM)‐CSF (15 patients) or granulocyte (G)‐CSF (15 patients). Using flow cytometry (FCM) we evaluated the proliferation kinetics of CD34+ BM hematopoietic progenitors before CT + CSF and at different times after CSF administration was stopped. FEC + GM‐ and FEC + G‐CSF sequences both induced a rapid and sustained increase in the percentage of BM myeloid precursors (BMMP%) and in the cycling status of CD34+ BM cells. However, while the BMMP% remained elevated in both cases after CSF were stopped, the enhanced proliferative activity of CD34+ cells decreased more rapidly after GM‐ than after G‐CSF. Using FCM, CD34+ BM‐derived hematopoietic presursor cell kinetics is readily evaluated in the clinical setting. The administration of CSF following CT increases both the proliferative activity of CD34+ BM cells and the BMMP%. After CSF were discontinued a kinetic refractoriness of hematopoietic progenitors was more evident after GM‐CSF than after G‐CSF. These data may be of value in designing clinical trials to avoid cytostatic damage to the BM hematopoietic stem‐cell compartment. © 1995 Wiley‐Liss, Inc.
Over‐expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma
Authors: Kawamata Hitoshi , Kawai Koji , Kameyama Shuji , Johnson Mark D. , Stetler‐Stevenson William G. , Oyasu Ryoichi
Published: February 2007

The balance between matrix metalloproteinases and their inhibitors is a critical factor which affects tumor invasion and metastasis. We have established a rat bladder carcinoma cell line, LMC19, which is tumorigenic, invasive and metastatic to the retroperitoneal lymph nodes and to the lungs in nude mice. LMC19 cells secrete pro‐gelatinases A and B as well as tissue inhibitors of matrix metalloproteinase (TIMP1 and TIMP2). We conducted the present study to determine whether or not over‐expression of TIMP1 and TIMP2 can affect the metastatic potential of LMC19 cells. We transfected the cells with an expression vector containing TIMP1 or TIMP2 cDNA, isolated several clones over‐expressing TIMP1 or TIMP2 and assessed their invasive and metastatic potential by inoculation at an orthotopic site (urinary bladder) in nude mice. Our results show that the transfectants over‐expressing TIMP1 and TIMP2 marginally affect primary tumor growth, local invasion or metastasis to the retroperitoneal lymph nodes but significantly inhibit extravascular growth of pulmonary tumor emboli. Our results suggest that the net activity of matrix metalloproteinases of tumor cells may be a critical factor that controls extravasation at this distant metastatic site. © 1995 Wiley‐Liss, Inc.
A novel human B‐cell line (U‐2904) bearing t(8;14) and t(14;18) translocations
Authors: Sambade Clara , Sállström Jan , Wiklund Helena J. , Enblad Gunilla , Kivi Syrje , Gartner Fátima , Zech Lore , Glimelius Bengt , Sundström Christer
Published: February 2007

Sequential activation of bcl‐2 and c‐myc appears to be involved in the pathogenesis of rare de novo acute lymphoid leukemias bearing both t(8; 14) and t(14;18). Acquisition of t(8;14) by follicular‐lymphoma cells with t(14;18) has also been related to the clinical transformation into an overt acute lymphoid leukemia in rare cases reported, and a role for c‐myc involvement in the progression of some follicular lymphomas with t(14;18) has been suggested by the detection of c‐myc rearrangements in association with histologic transformation. However, c‐myc abnormalities different from those observed in Burkitt's lymphoma have been reported in diffuse large‐cell lymphomas with breakpoints in 8q24, and a t(8;14) molecularly different from the classical one has been found in follicular lymphomas without t(14;18). We report the preliminary characterization of the EBV‐negative cell line U 2904 established from a transformed follicular lymphoma that carries both t(8;14) (q24;q32) and t(14;18) (q32;q21) translocations. U 2904 cells have a mature B‐cell phenotype, grow in agarose and are tumorigenic in nude mice. Rearrangements of both c‐myc and bcl‐2 confirmed the involvement of both oncogenes in the translocations which lead to abundant c‐myc and bcl‐2 transcripts. Two JH rearrangements and one Cα rearrangement were observed which did not co‐migrate with either c‐myc or bcl‐2 rearrangements. This is the first report of a cell line bearing both t(8;14) and t(14;18) derived from a follicular lymphoma after documented transformation into a centroblas‐tic lymphoma without leukemic features. U 2904 provides further evidence for the involvement of c‐myc in the progression of follicular lymphomas. © 1995 Wiley‐Liss, Inc.
Suppression by amiloride of bombesin‐enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane
Authors: Iishi Hiroyasu , Tatsuta Masaharu , Baba Miyako , Yano Hiroyuki , Uehara Hiroyuki , Nakaizumi Akihiko
Published: February 2007

The effects of concomitant administration of bombesin and of the diuretic drug amiloride on the development of large and small intestinal tumors induced by azoxymethane (AOM), the incidence of their metastasis to the peritoneum and the labeling index of intestinal adenocarcinomas were investigated in inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM for 10 weeks and s.c. injections of bombesin and/or a higher or lower dose of amiloride hydrochloride (amiloride) every other day until the end of the experiment in week 45. Administration of bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal adenocarcinomas. Although administration of both doses of amiloride with bombesin had little or no influence on the enhancement of intestinal tumorigenesis by bombesin, the location, histological type, depth of involvement or labeling index of intestinal adenocarcinomas, a higher dose of amiloride significantly reduced the incidence of cancer metastasis to the peritoneum. Our findings indicate that amiloride possesses an anti‐metastatic activity. © 1995 Wiley‐Liss, Inc.
A zinc metalloproteinase is responsible for the release of cd30 on human tumor cell lines
Authors: Hansen Hinrich P. , Kisseleva Tatiana , Kobarg JÖRg , Horn‐Lohrens Ottmar , Havsteen Bent , Lemke Hilmar
Published: February 2007

The activation marker CD30 is expressed on the cell surface of the malignant cells in Hodgkin's disease and a few non‐Hodgkin lymphomas. We have analyzed the regulation of membrane‐bound CD30 and found that the binding of a variety of anti‐CD30 antibodies induced down‐regulation of CD30 on cell lines. In addition, such down‐modulation was also observed after treatment of the cell surface proteins with the sulfhydryl reagent iodoacetamide or after stimulation of the second messenger pathway with phorbol ester or calcium ionophore. This modulation was abolished at 4°C and strongly inhibited by chelators like EDTA or 1, 10‐phenanthroline, whereas EGTA, a selective inhibitor of Ca2+‐dependent proteinases and other inhibitors of serine, thiol and acid proteinases, showed no effect. The down‐modulation was strengthened by Zn2+ or Cd2+, but not by other divalent cations such as Fe2+, Mn2+, Mg2+, Ca2+ or Co2+, thus indicating the involvement of a zinc metalloproteinase in CD30 modulation which can be activated by protein kinase C and by alkylation of sulfhydryl groups. Pulse‐chase experiments, analysis of the CD30 glycosylation and specific measurement of the 90‐kDa soluble form of CD30 (sCD30) with a sandwich radioimmunoassay revealed that CD30 down‐modulation results from enhanced release of 90‐kDa sCD30 by the site‐specific cleavage of CD30 accomplished by a zinc metalloproteinase. This release occurs at the cell membrane without prior endocytosis. © 1995 Wiley‐Liss, Inc.
Mutated human kirsten ras, driven by a thyroglobulin promoter, induces a growth advantage and partially dedifferentiates rat thyroid epithelial cells in vitro
Authors: Monaco Carmen , Califano Daniela , Chiappetta Gennaro , Mineo Alba , De Franciscis Vittorio , Vecchio Giancarlo , Santelli Giovanni
Published: February 2007

We have earlier shown that expression of the human activated Ki‐ras, directed by the rat thyroglobulin (TG) promoter in the thyroid gland of transgenic mice, is able to induce thyroid benign tumors, albeit at low incidence. A likely explanation of our results is that the low levels of exogenous Ki‐ras transcripts are not sufficient to induce multifocal tumors in the thyroid gland. We have performed experiments to analyze the effects of a similar construct in vitro upon thyroid‐cell proliferation and differentiation. Transfection of FRTL‐5 rat thyroid cells with the human Ki‐rasval 12 fused to the rat TG promoter is rapidly followed by reduced expression of the differentiation markers thyroglobulin, thyroperoxydase and thyrotropin receptor, but not by fully malignant cell transformation. The data reported support the hypothesis that Ki‐ras mRNA levels are critical to the process of complete neoplastic transformation of thyroid epithelial differentiated cells in vitro. © 1995 Wiley‐Liss, Inc.
Incidence of cutaneous childhood melanoma in Queensland, Australia
Authors: Whiteman David , Valery Patricia , McWhirter William , Green Adele
Published: February 2007

The incidence of cutaneous melanoma in children aged 0–14 years was examined in Queensland, Australia. Details of notifications were collected from the population‐based Australian Paediatric Cancer Registry. Between 1987 and 1994, the age‐adjusted incidence rates of invasive cutaneous melanoma occurring in Queensland children were estimated at 8.5/million for males and 7.1 /million for females. Incidence rates rose steeply in both sexes with increasing age, from less than 1/million in the 0–4 age group, to nearly 30/million in the 10–14 age group. To assess the uniformity of the anatomical distribution of lesions, relative tumour densities (RTDs) were calculated compared with the body as a whole. In both sexes, melanomas were most common on the trunk (RTD > 3), while lower limb lesions were less common (RTD < 0.6) and no melanomas were reported on the buttocks or external genitalia. Although not statistically significant, there was a tendency for truncal lesions in males to occur on the back, while in females, truncal melanomas were more evenly distributed across the chest, back and shoulders. No consistent relationship between latitude and melanoma incidence was observed, with higher rates reported in the subtropical than the tropical regions of Queensland. These are the first reported incidence rates of cutaneous melanoma in Australian children and are the highest ever reported in the world in this age group. Our findings provide baseline data from which to monitor changes in the occurrence of cutaneous melanoma in children. © 1995 Wiley‐Liss, Inc.
Differential expression of 70–kDa heat shock‐protein in human oral tumorigenesis
Authors: Kaur Jasbir , Ralhan Ranju
Published: February 2007

To understand the biological events underlying the multistep process of oral tumorigenesis we have studied the expression of 70–kDa heat‐shock protein, HSP70, in human normal, pre‐malignant and malignant oral tissues. Expression of HSP70 was assessed in oral‐tissue specimens using a mouse monoclonal antibody against HSP70 by immunostaining and immunoblot‐ting analysis. Strong nuclear and cytoplasmic HSP70 immunostaining was observed in oral squamous‐cell carcinomas (30/ 38). Mild to moderate HSP70 expression was observed in oral dysplastic lesions (19/30) and basal low level of HSP70 was observed in normal oral tissues. The results were corroborated by immunoblotting analysis. The wide variation in HSP70 expression in normal, pre‐malignant and malignant oral lesions suggests that it is differentially expressed during oral carcinogen‐esis and may be implicated in tumor development. © 1995 Wiley‐Liss, Inc.
Influence of food groups and food diversity on breast cancer risk in Italy
Authors: Franceschi Silvia , Favero Adriano , La Vecchia Carlo , Negri Eva , Dal Maso Luigino , Salvini Simonetta , Decarli Adriano , Giacosa Attilio
Published: February 2007

Although debate on breast cancer and diet has been concentrated on nutrients, assessment of the role of specific foods and food groups and variety of food intake retains a considerable importance. To further elucidate the role of dietary habits, 2,569 women with incident breast cancer (median age 55 years) and 2,588 control women (median age 56 years), hospitalised with acute non‐neoplastic diseases, were interviewed between 1991 and 1994 in 6 different Italian areas. The validated food frequency questionnaire included 79 food items and recipes, which were grouped into 18 food groups (5 for “diversity” analyses purpose). After allowance for non‐dietary confounding factors and total energy intake, significant trends of increasing breast cancer risk with increasing intake emerged for the following food groups: bread and cereal dishes, pork and processed meats, and sugar and candies. Conversely, high intake of milk, poultry, fish, raw vegetables, potatoes and coffee and tea seemed to exert a protection against the development of breast cancer. Intake of soups, eggs, other meats, cheese, cooked vegetables, citrus fruits, other fruits and cake and desserts were not significantly related to breast cancer risk. The variety of vegetable types consumed weekly seemed to have a beneficial effect beyond the advantage of high vegetable intake per se. © 1995 Wiley‐Liss, Inc.
Childhood cancer in Victoria, Australia, 1970–1989
Authors: Giles Graham , Waters Keith , Thursfield Vicky , Farrugia Helen
Published: February 2007

The incidence of cancer between 1970 and 1989 in children aged less than 15 years and resident in the state of Victoria, Australia, was ascertained using records held by the Victorian Cancer Registry. Altogether, 1,189 children in the 1970s and 1,261 children in the 1980s were registered with new diagnoses of cancer and these were followed up until 30 June 1993. Between 1970–1979 and 1980–1989 the incidence of childhood cancer rose by 14%, but this was not statistically significant. Part of this apparent increase may have been due to improved registration of cases in the 1980s, particularly of certain tumour types, and of tumours in older children who may have been treated outside the major paediatric treatment centres. Between the 2 decades, 5–year survival increased from 49% to 67%, with improvements in almost all tumour types. Only in Ewing's sarcoma did survival proportions decrease, and this may be related to histological misclassification and to an increased proportion of Ewing's arising in the pelvis during the 1980s. There is evidence already that with new treatment regimens introduced during the 1980s survival in the 1990s will show increased gains. © 1995 Wiley‐Liss, Inc.
High rate of MDR‐1 and heterogeneous pattern of MRP expression without gene amplification in endometrial cancer
Authors: Esteller Manel , Martinez‐Palones Josep M. , García Angel , Xercavins Jordi , Reventós Jaume
Published: February 2007

The present study was undertaken to determine the pattern of expression of 2 molecular markers of multidrug resistance, the MDR‐I and MRP genes, in endometrial carcinomas from 50 untreated patients using a PCR semi‐quantitative assay. In addition, PCR analysis of MDR‐I and MRP gene amplification was obtained in each case. High rate of MDR‐I expression without gene amplification was detected in all endometrial‐carcinoma samples, as well as in 10 adenomatous hyperplasias and 50 samples of normal endometrium. On the other hand, MRP appeared to be expressed at moderate levels in normal endometrial tissue, while relatively high levels of MRP expression without gene amplification were occasionally observed in endometrial‐carcinoma samples. © 1995 Wiley‐Liss, Inc.
Low efficiency of cytologic screening for cancer in situ of the cervix in older women
Authors: Gustafsson Leif , Sparen Par , Gustafsson Margit , Pettersson Birgitta , Wilander Erik , Bergstrom Reinhold , Adami Hans‐Olov
Published: February 2007

Cytologic screening for cervical cancer has proven to be beneficial in many countries, although the value of this intervention in women older than 50 years remains controversial. The purpose of this study was to investigate the efficiency of detecting cancer in situ by means of a cytologic smear at different ages, with special emphasis on the benefit of screening in women above the age of 50. We analyzed 466,275 smears taken in an open cohort of 118,890 women in Sweden between 1969 and 1988. The number of cancers in situ detected per 1,000 smears, the detection ratio, was used as an outcome measure in univariate analyses and in multivariate regression models. Cancer/n situ was detected in 1,076 women in the study cohort. The detection ratio peaked at ages 30 to 34 and decreased heavily during the next 15 years of age. The efficiency of taking smears at ages above 50 was only 20 per cent (OR, 0.19; 95% Cl, 0.14–0.26) of that at ages 30 to 34. These results were not changed when adjusting for time period and time interval since the previous smear. In spite of a high incidence of invasive cervical cancer in older women, the benefit of cytologic screening to detect cancer in situ above the age of 50 is uncertain. © 1995 Wiley‐Liss, Inc.
Uptake by cells and photosensitizing effectiveness of novel pheophorbide derivatives in vitro
Authors: Dagan Arie , Gatt Shimon , Cerbu‐Karabat Sara , Maziere Jean‐Claude , Maziere Cecile , Santus René , Engelhardt Edward L. , Yeh Karen A. , Stobbe Corinne C. , Fenning Matthew C. , Chapman J. Donald
Published: February 2007

Pheophorbide a prepared from the algae Spirulina was derivatized at the C(7)‐carboxylic group by linking amino alkyls of various lengths and terminal functional groups. The compounds were purified by thin‐layer chromatography (TLC) and by high‐pressure liquid chromatography (HPLC). Solubilization of compounds by serum lipoproteins, the kinetics of compound uptake into mammalian cells, and photosensitizing effectiveness when activated by 673 nm laser light have been studied. Optimal photosensitizer uptake into cells and the greatest photosensitizing activity were observed with compounds having side‐chain lengths of 4–6 carbon atoms which terminated in OH and CH3 groups. The most effective compounds were 3 orders of magnitude more potent than Photofrin in the degree of photoinactivation of cultured EMT‐6 tumor cells. HDL and LDL significantly promoted the efflux of these photosensitizing drugs from cells, suggesting that their long‐term retention in normal tissues in vivo would be minimal and produce little phototoxicity. © 1995 Wiley‐Liss, Inc.
On the relationship between the probenecid‐sensitive transport of daunorubicin or calcein and the glutathione status of cells overexpressing the multidrug resistance‐associated protein (MRP)
Authors: Versantvoort C. H. M. , Bagrij T. , Wright K. A. , Twentyman P. R.
Published: February 2007

Cells exposed to calcein acetoxymethyl ester (calcein AM) in the growth medium become fluorescent following cleavage of calcein AM by cellular esterases to produce the fluorescent derivative calcein. It has previously been shown by others that multidrug resistant cells which overexpress P‐glycoprotein accumulate much less fluorescent calcein than the corresponding parental cells. We have now examined the transport of calcein in multidrug resistant cells which overexpress an alternative transporter, the multidrug resistance‐associated protein (MRP). Accumulation of calcein fluorescence was greatly reduced in the MRP‐overexpressing human lung cancer cell lines COR‐L23/R and MOR/R compared with their parental lines. Energy depletion resulted in a considerably increased accumulation in the resistant lines. Treatment of resistant cells with buthionine sulfoximine (BSO), which depletes cellular glutathione (GSH), did not affect calcein accumulation, in marked contrast to our previous results for daunorubicin or the fluorescent probe rhodamine 123. Genistein, verapamil, cyclosporin A and oua‐bain were also each able to modify, to some extent, accumulation of daunorubicin, whilst having essentially no effect on calcein accumulation. However, the organic anion transport inhibitor probenecid was able to increase accumulation of both calcein and daunorubicin in the resistant cells. Genistein and verapamil treatment preferentially reduced the GSH content of resistant cells, whilst probenecid did not. However, probenecid caused a clear decrease in release of GSH from resistant cells into the medium. © 1995 Wiley‐Liss, Inc.