bluuebunny/crossref_metadata_2025 huggingface dataset:
The high lysability by lak cells of colon‐carcinoma cells resistant to doxorubicin is associated with a high expression of ICAM‐1, LFA‐3, NCA and a less‐differentiated phenotype
Authors: Rivoltini Licia , Cattoretti Giorgio , Arienti Flavio , Mastroianni Antonio , Melani Cecilia , Colombo Mario P. , Parmiani Giorgio
Published: February 2007

A human colon‐carcinoma ceil subline resistant to doxorubicin (LoVo/Dx), previously shown to be more lysed than the chemosensitive subline LoVo/H by different immune effectors, is reported here to be similarly susceptible to direct, anti‐proliferative effect of soluble cytokines (TNF‐α and/or IFN‐γ). More adhesion molecules ICAM‐1, LFA‐3 and NCA were expressed on LoVo/Dx than on LoVo/H, while no significant amounts of CEA were detectable on the cell surface or in culture supernatant of either tumor subline. Anti‐ICAM‐1, anti‐LFA‐3 and anti‐NCA monoclonal antibodies (MAbs) caused a marked reduction of lysis by interleukin‐2 (IL‐2) activated lymphocytes (LAK) of LoVo/Dx, whereas a lower effect was evident on LoVo/H. A pool of these antibodies was able to further increase the inhibition of the LAK lysis of both sublines. LoVo/Dx displayed a less differentiated phenotype as assessed by morphology, in vitro growth and altered or increased expression of markers such as desmoplakin and vimentin respectively, and disappearance of mucin. Treatment of LoVo sublines with differentiating agents (dimethylformamide and retinoic acid) led to a decreased expression of all adhesion molecules studied, accompanied by increased resistance to LAK‐mediated lysis. These data indicate that sensitivity of chemoresistant tumor cells to cytotoxic effectors depends on the level of expression of adhesion molecules, including NCA, and is related to differentiation stage.
Type‐II insulin‐like growth‐factor receptor in conditioned medium from HT‐29 human colon carcinoma cell line
Authors: Garrouste Françoise , Remacle‐Bonnet Maryse , Culouscou Jean M. , Marvaldi Jacques , Pommier Gilbert
Published: February 2007

The HT‐29 human colon cancer cell line has previously been shown to secrete high amounts of insulin‐like growth factor II (IGF‐II). The recent demonstration that soluble IGF‐II/ mannose 6‐phosphate receptor was present in fetal serum prompted us to search for a release of type‐II IGF receptor by these human colonic carcinoma cells. Serum‐free conditioned medium from the HT‐29 cell line was gel filtered on Sephadex G‐200. There was significant binding of [125I]IGF‐II to the void volume fractions in addition to binding to the 40‐kDa IGF‐binding protein (IGF‐BP) fractions. Competitive binding studies using [l25I]IGF‐II and the void volume pool showed a pattern typical of the type‐II receptor. It exhibited a high affinity for IGF‐II (KD = 0.4 nM), but had a low affinity for IGF‐I (KD = 6.8 nM), and no detectable affinity for insulin. Additional evidence was provided by affinity cross‐linking of [l25I]IGF‐II to the same high‐molecular‐weight material which demonstrated a major specific band at 250kDa after reduction of disulfide bonds. In contrast, the type‐I IGF receptor was undetectable. The extracellular type‐II IGF receptor was not a significant carrier for IGF‐II since virtually all IGF‐II secreted by HT‐29 cells was associated with IGF‐BP. The presence of a soluble IGF‐II/mannose 6‐phosphate receptor in the culture medium from colonic cancer cells suggests that it may play an important role in tumor pathogenesis.
Somatostatin analogue rc‐160 inhibits the growth of transplanted colon cancer in rats
Authors: Qin Yunfeng , Schally Andrew V. , Willems Gerard
Published: February 2007

The effect of somatostatin analogue RC‐160 on the growth of DHD/K12 rat colon cancer has been investigatedin vivoas well asin vitro.Twenty syngeneic BDIX rats with s.c. implanted tumors were divided randomly into 2 groups. The rats from each group received a daily s.c. injection of either RC‐160 (100 μg/kg/day) or injection vehicle as control for 37 days starting from the day of tumor inoculation. Tumor volumes were measured every 3‐4 days. At the end of the treatment, the mean tumor volume was 504.5 ± 97.0 mm3in the control group and 177.8 ± 60.5 mm3in the RC‐160 treated group (p< 0.01). The tumor volume doubling time was calculated to be 11 days in the control group and 13.5 days in the RC‐160 group, respectively. The tumor growth delay time was 18 days. Using bromodeoxyuridine labellingin vivo, the mean labelling index in the tumors was decreased by 35% (p<0.01) after RC‐160 treatment. Total protein and total DNA contents in the tumors were decreased by 70.1% (p< 0.05) and 68.7% (p< 0.05), respectively. The data indicate that somatostatin analogue RC‐160 inhibits the growth of DHD/K12 colon cancerin vivo.In 2 studiesin vitro, DHD/K12 cells were cultured for 72 hr with RC‐160 and natural somatostatin‐14 (S‐S‐14) at concentrations ranging from 62.5 ng/ml to 2,000 ng/ml. Tumor‐cell growth was measured spectrophotometrically by the crystal violet staining assay. No direct effect on tumor cell growthin vitrowas observed with either RC‐160 or S‐S‐14, possibly because of the loss of somatostatin receptors in previous passages of the DHD/K12 cell line.
Differences in patterns of allelic loss between two common types of adult cancer, breast and colon carcinoma, and Wilms' tumor of childhood
Authors: Devilee P. , Van Den Broek M. , Mannens M. , Slater R. , Cornelisse C. J. , Westerveld A. , Khan P. Meera
Published: February 2007

Several chromosomal regions exhibit loss of heterozygosity (LOH) in different types of human tumor, and on this basis are presumed to carry‐suppressor genes. We studied 7 of such chromosome regions, including 3p, 5q, 11p, 13q, 17p, 18q and 22q, using a selected set of DNA markers in 44 Wilms' tumors, 64 breast and 83 colon carcinomas. In Wilms' tumor only the short arm of chromosome II was preferentially involved (38% of the informative cases), whereas in breast and colorectal carcinomas all investigated chromosome regions showed allelic loss at frequencies ranging from 19‐61% and 12‐55%, respectively. We tried to explain this difference in terms of developmental stages and tissue homeostasis of the organs involved. We postulate that more widespread occurrence of allele loss in colorectal and breast carcinomas compared to Wilms' tumor is associated with a difference in the differentiation status of the tissues at the time of tumor initiation.
Hodgkin's disease in adults in Saudi Arabia. Clinical features, prognostic factors and an analysis of therapy. Outcome of combination chemotherapy only, for both localized and advanced disease
Authors: Al‐Idrissi Hassan Y. , Ibrahim Ezzeldin M.
Published: February 2007

Fifty evaluable, previously untreated, adult patients with clinically staged (CS) early and advanced Hodgkin's disease were treated with chemotherapy alone, using various regimens. Their mean age was 31.9 years. Fifteen patients (30%) had CS I or II and 35 (70%) had CS III or IV Eighty‐eight per cent of patients had one or more of the B symptoms and 64% had an unfavorable histology. Complete remission (CR) was achieved in 43 out of 50 patients (86% with 95% confidence interval of 76% to 96%), partial remission in 3 (6%) and treatment failure in 4. Adjusted analysis, using all possible subset regression, showed that unfavorable histology, bulky disease and receiving a total dose‐intensity (TDI) ⩽ 0.80 were negatively associated with the likelihood of achieving CR. At a median follow‐up of 36 months (range, 6‐90), 84% of patients were alive and 82% were disease‐free. The overall median survival has not been reached, but the projected 5‐year survival probability was 79%. Time‐to‐relapse was also estimated for those who achieved initial CR. The estimated 5‐year relapse‐free survival was 87%. The Cox proportional hazards model predicted that unfavorable histology, bulky disease and TDI ⩽ 0.80 had an independent, adverse influence on survival. We conclude that the results of chemotherapy alone are encouraging and the rationale is practical and acceptable in those countries where the availability of radiotherapy units is limited.
Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging
Authors: Gaze M. N. , Huxham I. M. , Mairs R. J. , Barrett Ann
Published: February 2007

The targeted radiotherapy of neuroblastoma with 131I‐labelled metaiodobenzyl guanidine (mIBG) is now the subject of several clinical studies. The precise intracellular localization of mlBG, necessary for nuclear microdosimetry, has not previously been described. We report the use of electron‐energy‐loss spectroscopy and electron spectroscopic imaging to establish the intracellular distribution of mlBG in cells from the human neuroblastoma line NBI‐G which had been incubated with the drug by mapping iodine in ultra‐thin sections of tumours. Most of the iodine is found within the mitochondria, with lesser amounts in the vesicles and on the nuclear membrane. The use of alternative radionuclides with different physical characteristics has been suggested to optimize the efficacy of this therapeutic strategy. The lack of penetration of mIBG into the nucleoplasm means that ultra‐short‐range Auger electron emitters such as 125I are not likely to prove more cytotoxic than 131I.
Characterization, isolation and amino terminal sequencing of a rat colon carcinoma‐associated antigen
Authors: Chadeneau Corinne , Denis Marc G. , Blottière Hervé M. , Grégoire Marc , Douillard Jean‐Yves , Meflah Khaled
Published: February 2007

Monoclonal antibodies have been raised against a cell line derived from a dimethylhydrazine‐induced rat colon carcinoma. One of these antibodies (MAb E4) has previously been shown to react slightly with normal small intestine and colon, and not with other normal tissues as determined by immunohistochemistry. Using Western immunoblotting we confirmed this tumor specificity. Therefore, the Mr of approx. 66,000 glycosylated antigen (pE4) recognized by MAb E4 appeared to be a potential marker of colon carcinoma. Fifteen human tumor cell lines were tested by flow cytometry for the expression of pE4. This antigen was not detected on these cells. In the rat colon carcinoma cell, pE4 was exclusively found on the cell membrane. pE4 was purified to near homogeneity by immunoaffinity chromatography. The first 20 N‐terminal amino acids were identified. Comparison with the NBRF data bank did not reveal a complete homology with known sequenced proteins but similarities were found with the mouse L3T4 precursor, the env polyprotein of human immunodeficiency virus type I, flagellin from Halobacterium halobium and the gp30 from hepatitis B surface antigen. Homology was always found in transmembranous or hydrophobic domains of these proteins. By indirect immunofluorescence analysis of adherent cells and size exclusion chromatography under native conditions, pE4 was found to interact with other molecules and perhaps to be involved in intercellular contact.
Prognostic value of morphometry and DNA flow‐cytometry features of invasive breast cancers detected by population screening: Comparison with control group of hospital patients
Authors: Uyterlinde Anne M. , Baak Jan P. A. , Schipper Nellie W. , Peterse Hans J. , Meijer Jos W. R. , Vooys Peter G. , Matze Erna
Published: February 2007

Using the prognostic value of morphometric and flow‐cytometric features, a group of patients with invasive breast cancers detected with population screening (PS, n = 70) has been evaluated and compared with a random control group in 2 hospitals (H group, n = 225) diagnosed in the same period. The results show that the PS patients had smaller tumors, less positive lymph nodes, better differentiated tumors with a lower mitotic activity index (MAI) and lower values of the morphometric prognostic index (MPI). Furthermore, the women more frequently had diploid tumors and tumors with small nuclei. The second purpose was to evaluate whether quantitative microscopical features, in comparison with other prognostic features such as size of primary tumor, nodal status and histologic grade, are as strong prognosticators in PS tumors as in H‐detected breast cancers. In comparison with H tumors, morphometric and flow‐cytometric features, as well as tumor size, had the same prognostic value for the PS tumors. In contrast, nodal status was not significant within the PS group, and the same phenomenon was found in a sub‐group of H patients with similar sized tumors. Of all quantitative microscopical features (MPI, MAI, mean nuclear area (MNA) and DNA Index (DI)), the MAI had the strongest prognostic value. Dl showed additional prognostic value to the MAI for patients with small tumors and with small tumor‐cell nuclei, because a diploid pattern in these cases (this combination occurred in 21 patients of the total group = 30%) was correlated with a 95% 10‐year survival rate. Histologic grade, although significant within the large H group, was of no prognostic value within the PS group, and also not as in the H sub‐group with small tumors. It is concluded from morphometric and DNA flow‐cytometric criteria that these prognostic features in invasive breast cancers detected by PS were all more favorable than in randomly detected hospital breast cancers. This may account for the reported better survival rate of PS patients. Furthermore, the prognosis of patients with small invasive breast cancers detected by population screening can be more accurately deduced by quantitative microscopical features than by axillary‐lymph‐node status.
Clustering of aberrations to specific chromosome regions in benign neoplasms
Authors: Sreekantaiah Chandrika , Sandberg Avery A.
Published: February 2007

Cytogenetic analyses of benign tumors in the past 2 decades have established consistent and recurrent abnormalities in a large proportion of these tumors. In particular, chromosomal analyses of meningiomas, adenomas of the salivary gland, uterine leiomyomas and lipomas have led to the identification of cytogenetic subtypes characterized by specific structural or numerical abnormalities. A comparison of these consistent changes shows a clustering of aberrations to specific regions on chromosomes 12, 1, 2, 6, 11, 13 and 22. The specificity of the involvement of these chromosome regions in the various benign neoplasms suggests that genes of importance in growth regulation rather than those related to malignant transformation are located at these sites.
Dietary factors in cancer of the lower urinary tract
Authors: Nomura Abraham M. Y. , Kolonel Laurence N. , Hankin Jean H. , Yoshizawa Carl N.
Published: February 2007

This dietary study was based on 195 male and 66 female cases of lower urinary tract cancer, identified in Hawaii between 1977 and 1986. Each case was matched for sex, age, and ethnic group (Caucasian or Japanese) to 2 population‐based controls. There was a decrease in risk with increasing levels of consumption of vitamin C in women (p =0.03) and dark green vegetables in men (p =0.02). When examined by quartile, the odds ratios for the highest quartile of intake compared to the lowest quartile were 0.4 for women and 0.6 for men, respectively. Although dark green vegetables are a source of carotenoids, the intake of total carotenoids, retinol and total vitamin A was weakly and inconsistently related to risk in both sexes. Among women only, there was also an inverse association with the consumption of regular ground coffee (p ‐0.02) but not with other types of coffee. Finally, there were no statistically significant or consistent differences between cases and controls in the intake of artificial sweeteners and tea.
Alpha‐smooth‐muscle actin and desmin expressions in human neuroblastoma cell lines
Authors: Sugimoto Tohru , Ueyama Hisao , Hosoi Hajime , Inazawa Johji , Kato Taiji , Kemshead John T. , Reynolds C. Patrick , Gown Allen M. , Mine Hiroshi , Sawada Tadashi
Published: February 2007

The neural crest gives rise to a variety of tissues, including peripheral neurons, Schwann cells, melanocytes and ectomes‐enchymal cells, which include the smooth‐muscle cells of large arteries. Cell lines derived from neuroblastoma (a neural‐crest tumor) exhibit at least 2 distinct morphological cell types, a neuroblastic phenotype (N‐type) and an epithelial‐like phenotype (S‐type) with characteristics of substrate‐adhesiveness. We have analyzed 17 human neuroblastoma cell lines using a panel of monoclonal antibodies (MAbs) against cytoskeletal proteins. Three neuroblastoma cell lines (KP‐N‐SI, KP‐N‐YN and SMS‐KCN) bound an α‐smooth‐muscle actin antibody. In addition, one of these lines (KP‐N‐SI) bound anti‐desmin MAbs as determined by indirect immunofluorescence. A total of 8 cioned cell lines were obtained from the above parent cell lines. These were composed of either N‐or 5‐type cells and were confirmed to have the same neuroblastoma origin as each parent cell line by chromosomal analysis. Alpha‐smooth‐muscle actin and desmin were demonstrated In the 5‐type cloned cells by indirect immunofluorescence, as well as by 2‐dimensional Western blot analysis. These results were confirmed by Northern blot analysis using a specific probe (pSHαSMA‐3′UT) to human α‐smooth‐muscle actin mRNA. These ascertain the presence of α‐smooth‐muscle actin and desmin in neuroblastoma cell lines. These data show that, in addition to giving rise to cells with neural, Schwann‐cell and melanocyte markers, neuroblastoma can also give rise to the cells expressing smooth‐muscle cell markers.
Differentiating effect of sodium butyrate on human hepatoma cell lines PLC/PRF/5, HCC‐M and HCC‐T
Authors: Saito Hidetsugu , Morizane Toshio , Watanabe Tetsu , Kagawa Tatehiro , Miyaguchi Shingo , Kumagai Naoki , Tsuchiya Masaharu
Published: February 2007

The in vitro effect of sodium butyrate (SB) on human hepatoma cell lines PLC/PRF/5, HCC‐M and HCC‐T was investigated. SB was added at the non‐toxic but cytostatic concentration of I mM. In all these cell lines, SB reduced cell proliferation and changed the morphology of the cells into a fibroblast‐like shape. In PLC/PRF/5, alpha‐fetoprotein production and c‐myc expression were inhibited. In contrast, gene expression of albumin, one of the normal liver‐cell products, Mid that of integrated hepatitis B virus genome, was increased. In HCC‐M and HCC‐T, c‐myc expression, which was enhanced In the naive state, was reduced. In HCC‐M, fos expression was inhibited but the expression of N‐ and K‐ras genes did not change. SB seemed to induce normal or mature properties of hepatocytes in human hepatoma cell lines.
Altered protein glycosylation of rat 3Y1 cells induced by activated c‐myc gene
Authors: Hiraizumi Sen , Takakasaki Seiichi , Shiroki Kazuko , Kobata Akira
Published: February 2007

N‐linked sugar chains of rat 3Y1 cells and tumorigenic cells derived by transfection with activated c‐myc gene were quantitatively released as oligosaccharides from membrane preparations by hydrazinolysis. Structural analyses revealed that cells of both types contain bi‐, tri‐ and tetra‐antennary complex‐type oligosaccharides as well as high‐mannose‐type oligosaccharides. However, the c‐myc‐transfected cells showed an increase in tri‐ and tetra‐antennary oligosaccharides having the GIcNAcβI→4Manαl→ and/or the GlcNAcβl→ 6Manαl→ linkages with a decrease in biantennary oligosaccharides compared to control 3Y1 cells. The data suggest that c‐myc gene has a potential role in the regulation of cellular protein glycosylation and that an elevated expression of c‐myc gene in the cells leads to increased branch formation of outer chains in N‐linked oligosaccharides concomitant with the acquisition of tumorigeniclty.
A case‐control study of gastric cancer and diet in Italy. III. Risk patterns by histologic type
Authors: Buiatti Eva , Palli Domenico , Bianchi Simonetta , Decarli Adriano , Amadori Dino , Avelum Claudio , Gpriani Francesco , Cocco Pierluigi , Giacosa Attilio , Lorenzini Letizia , Marubini Ettore , Puntoni Riccardo , Saragoni Ariele , Fraumeni Joseph F. , Blot William J.
Published: February 2007

In a case‐control study of gastric cancer (GC) in high‐risk and low‐risk areas of Italy, 923 GCs were systematically categorized by one pathologist according to the Lauren classification distinguishing 2 main histologic types, intestinal (55%) and diffuse (23%). Intestinal types outnumbered diffuse types by a 3 to I margin in high‐risk regions in the north‐central part of the country, while both types occurred at nearly equal rates in low‐risk areas. Intestinal types also occurred relatively more frequently at older ages and among males. Relative risks of each type of GC were evaluated In relation to dietary and other data obtained from interviews with the cancer patients and controls. The risk patterns for intestinal and diffuse types were remarkably similar. Increased risks of both types were associated with high intake of meat, salted/dried fish, seasoned cheeses and traditional soups, while decreased risks of both types were found among heavy consumers of fresh vegetables and fruits. Correspondingly similar patterns were seen with indices of nutrients, with risks of both intestinal and diffuse GC rising with animal protein Intake and declining with consumption of vitamins C and E. Both types were inversely related to socio‐economic status, and neither was associated with cigarette smoking. A familial history of GC was reported more frequently by patients with each type than by controls, although the highest risk was for unclassified GC, a group of poorly differentiated and medullary carcinomas accounting for 15% of all GCs in this study. The findings suggest that, despite differences in geographic and demographic patterns, the intestinal and diffuse types of GC have etiologic factors in common.
Ras mutations in united kingdom examples of oral malignancies are infrequent
Authors: Chang Sidney E. , Bhatia Pradeep , Johnson Newell W. , Morgan Peter R. , McCormick Frank , Young Bryan , Hiorns Lynne
Published: February 2007

Point mutations in codons 12, 13 or 61 of the oncogenes Ha‐ras, Ki‐ras or N‐ras have been identified in human malignancies of many types. Using the PCR (polymerase chain reaction) technique for DNA amplification in vitro and stringent probing of the amplified DNA on dot blots with a library of specific oligonucleotides, we have screened for the presence of ras mutations in oral and para‐oral malignancies and some associated lesions. The material, from UK patients, consisted of 22 oral squamous‐cell carcinomas including 5 neck metastases, I oral mucosal dysplasia, I proliferative verrucous leukoplakia, I antral and I tonsillar carcinoma, I basal‐cell carcinoma, I salivary adenocarcinoma, I salivary adenoid cystic carcinoma and I lung adenocarcinoma metastatic to the gingiva. Genomic DNA was extracted from tissues which were fresh or preserved in liquid nitrogen. Two DNA samples contained point mutations in codon 61 of Ki‐ras. One of these mutations was in the lymphocytes infiltrating a retromolar SCC. The other mutation (CAA to CAU; substitution of glutamine by histidine) was in the lung adenocarcinoma metastasis. The absence of ras mutations in the epithelium of primary oral squamous‐cell carcinomas is of considerable interest as other work in our Department on Indian cases of oral carcinomas associated with chewing tobacco (quid) revealed that 35% of these had a codon 12, 13 or 61 mutation in Ha‐ras. While ras activations arising from point mutations may occur in a high proportion of oral malignancies associated with chewing tobacco (quid), this was not the case in UK oral malignancies, even where tobacco was smoked.
Significance of freshly cultured fibroblasts from different tissues in promoting cancer cell growth
Authors: Mukaida Hidenori , Hirabayashi Naoki , Hirai Toshihiro , Iwata Takashi , Saeki Syuuji , Toge Tetsuya
Published: February 2007

The interactions between human cancer cells and primary cultured human fibroblasts without cell‐to‐cell contact were investigated using double soft‐agar culture. Human fibroblasts obtained from different organs were cultured in monolayers and used after the 3rd or 4th passage. In double softagar culture, colony formations of cancer cells in the ‐over‐layer were stimulated or inhibited by the presence of various kinds of fibroblast in the underlayer. The growth of all cancer cells tested was always stimulated by the presence of fibroblasts obtained from an organ In which cancer cells had already developed, and inhibited by those from skin. However, fibroblast‐conditioned media failed to affect cancer cell growth, either in MTT assay or in soft‐agar culture. These results suggest that mutual growth reliance exists between human cancer cells and primary cultured fibroblasts by diffusible factors secreted by both cells (paracrine growth) and that mutual growth enhancement occurs between cancer cells and fibroblasts derived from tissues in which cancer cells had originated.
The role of both specific cellular adhesion and growth promotion in liver colonization by F9 embryonal carcinoma cells
Authors: Rusciano Dario , Lorenzoni Patrizia , Burger Max M.
Published: February 2007

Unselected F9 murine embryonal carcinoma cells preferentially colonize the liver upon injection into tail veins of syngeneic mice, while the lungs are only very rarely colonized. Here we show that F9 cells attach better to fibronectin than to laminin in an adhesion assay, like other liver‐colonizing cell lines. Moreover, assays of adhesion to extracellular matrix (ECM) prepared from rat organs (liver, lung and kidney) demonstrate that, in the absence of serum, F9 cells adhere better to liver‐than to kidney‐or lung‐derived ECM. Even in the presence of FCS, the adhesion to lung ECM remains very low. This very low adhesiveness of F9 cells to lung‐derived ECM correlates well with the finding that, in an organ distribution assay, tail‐vein‐injected F9 cells are very rapidly released from the lungs, when compared to the retention times of the lung‐specific murine melanoma cell line B16‐F10. Yet another property appears to contribute to organ‐specific colonization of these cells: extracts of liver promote the growth of F9 cells, in contrast to extracts of lung or kidney which have no effect. These data suggest that preferential formation of metastases in the liver following the intravenous injection of F9 cells is the result of both their adhesive abilities and their growth response to local microenvironment.
Drug effects on CA125 antigen expression and antibody binding to cancer cells
Authors: Nakai Toshiharu , Endo Keigo , Hosono Makoto , Saga Tsuneo , Watanabe Yuji , Sakahara Harumi , Imai Kozoh , Yachi Akira , Kivozuka Yasuhiko , Ishiwata Isamu , Konishi Junji
Published: February 2007

CA125 is a high‐molecular weight glycoprotein expressed on most serous‐type ovarian cancer and some lung adenocar‐cinoma tissues. The effects of various drugs on the release of CA125 antigen into culture medium and on monoclonal antibody (MAb) binding to cancer cells were studied using 8 human cancer cell lines, all of which expressed CA125 on their cell surfaces. The effect of dexamethasone was seen at as low a concentration as 10–9 M dexamethasone, and the release of CA125 and the binding of radiolabelled anti‐CA125 antibody were completely inhibited after exposure to 10–7 M dexamethasone. The number of antibody binding sites markedly decreased. In contrast, sodium butyrate increased CA125 expression. These findings were clearly detected in only 3 cancer cell lines and a significant effect was not seen in the 5 other cancer cell lines. Interferon‐γ, examined in 3 cell lines, suppressed in a dose‐dependent manner in 2 CA125 expression cell lines, but enhanced it in one line. No apparent effects were seen after exposure to tissue necrosis factor or interleukin‐2. These results suggest that drugs may regulate the CA125 antigen expression in some, but not all, cancer cells and may affect the biodistribution of radiolabelled MAbs.
Plasminogen activator inhibitor 1 in human carcinoma tissues
Authors: Tanaka Nobuya , Fukao Hideharu , Ueshima Shigeru , Okada Kiyotaka , Yasutomi Masayuki , Matsuo Osamu
Published: February 2007

The content of PAI‐1 was measured in carcinoma tissues from the stomach and colorectum divided macroscopically into 3 portions: the central part of the carcinoma, the marginal part of the carcinoma containing some normal mucosa, and the normal mucosa. Among these tissues, the highest levels of PAI‐1 antigen were found in the central part of the carcinoma. On the other hand, no PAI‐1 antigen or activity was observed in the normal mucosae. The PAI‐1 produced in the stomach and colorectal carcinoma tissues showed a non‐lytic zone with a molecular weight of 54 kDa by reverse fibrin autography, and this 54‐kDa band reacted with anti‐PAI‐1 IgG on an immunoblotted nitrocellulose membrane by the avidinbiotin complex method. The contents of PAI‐2 in the carcinoma tissues were not significantly different from those in the normal mucosa of the stomach and colorectum. In both the stomach and colorectal carcinomas, the highest value of u‐PA/total PA (sum of u‐PA and t‐PA) was observed in the central part of the carcinoma, followed by the marginal part of the carcinoma, and was lowest in the normal mucosa. We conclude that increased levels of PAI‐1 in malignant tissue of the stomach and colorectal tract may serve to modulate extra‐cellular proteolysis by u‐PA.
DNA adducts in bronchial biopsies
Authors: Dunn Bruce P. , Vedal Sverre , San Richard H. C. , Kwan Wan‐Fung , Nelems Bill , Enarson Donald A. , Stich Hans F.
Published: February 2007

To investigate the feasibility of measuring DNA‐carcinogen adducts in the lungs of non‐surgical patients, endobronchial biopsies were obtained from 78 patients undergoing routine diagnostic bronchoscopy. Lung cancer was present in 37 (47%) of the patients. DNA was isolated from the tissues and analyzed by HPLC‐ or nuclease‐PI ‐enriched 32P‐postlabelling, using procedures selective for aromatic adducts. Chromatograms from all 28 current smokers showed a distinctive diagonal adduct zone which was present in only 24 of 40 ex‐smokers and 4 of 10 lifetime non‐smokers. Adduct levels and chromatographic patterns were similar in bronchial tissue from different lobes of the lung, in bronchial and alveolar tissue, and in tumor and non‐tumor bronchial tissue taken from the same subject. Bronchial DNA adduct levels were strongly associated with cigarette smoking status and dropped rapidly after smoking ceased. Higher levels of DNA adducts seen in the lung‐cancer patients were mainly due to cigarette smoking. Frequent alcohol intake was the only dietary factor associated with higher levels of bronchial DNA adducts. We conclude that the level of bronchial DNA adducts is strongly associated with cigarette‐smoking history and with alcohol intake, but is not associated with lung cancer independently from its relation to smoking. The results indicate the feasibility of using 32P‐postlabelling to detect and quantitate genetic damage in bronchial biopsy specimens.
Expression of leucocyte adhesion molecules on 66 clinical neuroblastoma specimens
Authors: Favrot Marie C. , Combaret Valérie , Goillot Evelyne , Tabone Eric , Bouffet Eric , Dolbeau Dominique , Bouvier Rolande , Coze Carole , Michon Jean , Philip Thierry
Published: February 2007

LFA‐3, ICAM‐1, HLA.ABC and HLA.DR expression was analyzed on 66 neuroblastoma specimens. HLA.ABC was expressed on 26 specimens, HLA.DR on 2, LFA‐3 on 20 and ICAM‐1 on 10. HLA.ABC and LFA‐3 were positive on ganglioneuroblastoma or ganglioneuroma, but they were negative on neuroblastoma, independently of the clinical staging; HLA.ABC and LFA‐3 were induced in vivo by chemotherapy in parallel with tumoral cell differentiation, in both the primary and the metastases. The expression of ICAM‐1 was restricted to 5 of the 10 low‐grade stage‐1 or stage‐2 specimens, 1 stage‐3 specimen, and the primary tumors of 2 patients with stage‐4 disease, analyzed hence at diagnosis and after chemotherapy (4 specimens); metastatic cells obtained in 1 of these patients were negative. HLA.ABC and LFA‐3 expressed on both myc N‐negative and ‐positive specimens, whereas ICAM‐1 was restricted to MYCN‐negative specimens. LFA‐3 diffusely stained partially differentiated neuroblasts, Schwann cells and ganglion cells. The expression of HLA.ABC on differentiated neuroblasts varied from one sample to another and within the same tumor; Schwann cells were strongly positive, but ganglion cells were negative. In positive samples, ICAM‐1 was expressed on differentiated neuroblasts and Schwann cells, but negative on ganglion cells; however, most of the differentiated tumors were ICAM‐1‐negative, suggesting ICAM‐1 induction by unknown local signal. The 4 markers were negative on undifferentiated neuroblasts. The distribution of these 4 markers on clinical specimens was in agreement with their reactivity on fetal tissues, as well as with results obtained on neuroblastoma cell lines before and after in vitro treatment with IFN‐γ.
Laminin receptors, collagenase IV and prognosis in node‐negative breast cancers
Authors: Daidone Maria Grazia , Silvestrini Rosella , D'Errico Antonia , Fronzo Giovanni Di , Benini Elvira , Mancini Antonio M. , Garbisa Spiridione , Liotta Lance A. , Grigioni Walter F.
Published: February 2007

In 187 node‐negative breast cancers, the expression of laminin receptors and collagenase IV was directly related in 52% of cases, independently of pathological (tumor size and histology) and biological (estrogen receptors and proliferative activity) features. Moreover, the presence of laminin receptors and collagenase IV did not appear to influence tumor proliferative activity, evaluated as 3H‐thymidine labelling index. In this case series, relapse‐free survival and overall survival at 6 years were significantly affected by tumor size, hormone receptor status and proliferative activity. Conversely, high levels of laminin receptors and collagenase IV failed to influence relapse‐free or overall survival, whereas they were strong indicators of local‐regional diffusion of the disease.
Estrogen and progesterone receptors in cervical human papillomavirus related lesions
Authors: Monsonego Joseph , Magdelenat Henri , Catalan François , Coscas Yves , Zerat Laurent , Sastre Xavier
Published: February 2007

According to recent studies showing that human papilloma‐ virus (HPV) infections can be influenced by sex steroid hormones, we performed estrogen (ER) and progesterone (PgR) receptor assays in fresh frozen biopsies of genital‐HPV‐related lesions. Seventy‐three women with normal cervix, condyloma, low‐ and high‐grade CIN and squamous carcinoma were evaluated in comparison with 15 persons with vulvar and 9 with penile papillomavirus‐assoclated lesions. HPV genotypes were determined by dot‐blot hybridization. Non‐cervical lesions did not express HR. Condyloma on squamous metaplasia of the cervix and high‐grade CIN expressed high levels of HR, particularly PgR (mean 4,086 and 4,518 fmoles/g tissue, respectively). Cervical squamous carcinoma expressed very low concentrations of PgR in a limited number of cases. High levels of PgR were correlated with high‐grade CIN(p <0.05),HPV16–18‐associated lesions (p <0.01) and ER were correlated to HPV6–11‐related lesions (p < 0.01). The levels were independent of age, cycle stage and oral contraception. Morphological localization of PgR, using an immunocytochemical method using a monoclonal antibody (MAb) (PR‐ICA), showed intense homogeneous staining in the nuclei of the stromal fibroblasts underlying dysplastic epithelium and condyloma on squamous metaplasia. These results suggest that, under in vivo conditions, sex steroid hormones, particularly progesterone, may act indirectly on HPV‐infected epithelial cells and be implicated as co‐factors in HPV‐related cervical neoplasia. They could explain the relative predisposition to malignant transformation of the cervix as compared with vulvar and penile mucosa.
Expression of collagenase‐related metalloproteinase genes in human lung or head and neck tumours
Authors: Muller D. , Breathnach R. , Engelmann A. , Millon R. , Bronner G. , Flesch H. , Dumont P. , Eber M. , Abecassis J.
Published: February 2007

We address the question as to whether increased metalloproteinase production might be related to the high regional recurrence rate of some carcinomas, and particularly head and neck squamous‐cell carcinomas (SCC). Northern blot of total RNA prepared from 26 lung carcinomas, 107 head and neck carcinoma samples and corresponding normal tissue samples demonstrates the frequent and sometimes concomitant over‐expression of the 2 stromelysin genes, the type‐1 collagenase gene and the pump‐1 gene in the head and neck tumour tissue samples. In these SCC, over‐expression of the 2 stromelysin genes and the type‐1 collagenase gene (but not the pump‐1 gene) is associated with a high degree of tumour differentiation. Moreover, a tumour with high levels of the stromelysin mRNAs is more likely to show high local invasiveness, suggesting that the stromelysins may be implicated in the clinical course of head and neck tumours. Evaluation of the corresponding mRNA levels may prove a useful indicator for predicting the clinical aggressiveness of these tumours.
Altered expression of P‐glycoprotein and cellular adhesion molecules on human multi‐drug‐resistant tumor cells does not affect their susceptibility to NK‐ and LAK‐mediated cytotoxicity
Authors: Scheper Rik J. , Dalton William S. , Grogan Thomas M. , Schlosser Arno , Bellamy William T. , Taylor Charles W. , Scuderi Phil , Spier Catherine
Published: February 2007

Drug resistance has been associated with resistance to NK‐ and LAK‐cell‐mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi‐drug‐resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226/MR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7/Mitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR‐patterns of resistance, with the P‐glycoprotein pump (P‐170) detected only in the doxorubicin‐selected sublines. Flow cytometric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM‐1 and LFA‐3, and MHC‐Class‐1 (MCF7/D40 only), to be decreased in the doxorubicin‐selected MDR‐sublines, whereas expression of CD56 (Leu 19) was strongly up‐regulated in 8226/Dox40. Lysis of P‐170‐positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effector: target‐cell adhesion pathways. Mitoxantrone‐selected tumor cells did not display P‐170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to NK or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment.
Vascular anatomy and organ‐specific tumor growth as critical factors in the development of metastases and their distribution among organs
Authors: Arguello Francisco , Baggs Raymond B. , Eskenazi Allen E. , Duerst Reggie E. , Frantz Christopher N.
Published: February 2007

We have examined with 19 tumor cell lines the discrete roles that vascular anatomy and tumor‐cell‐organ‐affinity play in the development of metastases and their distribution among organs. Spontaneous metastases of B16‐G3.26 melanoma cells from a primary tumor growing in the foot pad of mice, or experimental metastases 21 days after intravenous tumor‐cell injection resulted in tumor colonies only in the lungs. In contrast, when the lung microvasculature was bypassed, and the same cells given by systemic intra‐arterial (s.i.a.) injection, large tumor colonies developed selectively in the ovaries, adrenal glands and bones, but rarely in the lungs. When animals injected i.v. were allowed to live with lung metastases for a long period of time, small tumor colonies began to develop in extra‐pulmonary organs with a distribution identical to that seen after s.i.a. injection. Seven murine tumor cell lines (previously characterized by their ability to colonize primarily the lungs after i.v. injection) and 7 of the 8 studied human tumor cell lines colonized different specific extra‐pulmonary organs after s.i.a. injection, frequently producing metastatic syndromes commonly described in patients with cancer, but rarely seen in animal models of metastasis. These results suggest that metastatic cells, even those capable of colonizing specific organs, do not freely circulate in the blood stream and lodge in specific tissues. In contrast, the cells must establish a vascular route of access to the target organ, e.g., through the systemic circulation from metastatic tumors in the lungs. Two cell lines considered to be tumorigenic but non‐metastatic failed to colonize the lungs or extra‐pulmonary organs after i.v. injection, but readily colonized specific organs after s.i.a. injection. Thus, tumor cells considered to be non‐metastatic may be indeed metastatic if they are provided with vascular access to an organ more congenial to their growth requirements.
In vitro and in vivo modulation of multi‐drug resistance with amiodarone
Authors: Van Der Graaf W. T. A. , De Vries E. G. E. , Uges D. R. A. , Nanninga A. G. , Meijer C. , Vellenga E. , Mulder P. O. M. , Mulder N. H.
Published: February 2007

The modulating effect on drug resistance of amlodarone (AM) and its metabolite desethylamiodarone (DEA) was studied in a P‐glycoprotein‐positive human colon carcinoma cell line COLO 320, and a human small‐cell lung carcinoma cell line GLC4 and its adriamycin (Adr)‐resistant subline GLC4‐Adr (both P‐glycoprotein‐negative). AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VP16) In COLO 320 cells, while in the GLC4 and GLC4‐Adr cell line no effect was seen. In the COLO 320 cell line, AM caused more intracellular, and especially intranuclear, fluorescence of Adr and more Adr‐induced DNA strand breaks as compared to Adr alone. Moreover, an increase in VP16‐induced topoisomerase II‐DNA complexes was observed when AM was added. Competition between AM and Adr for the same efflux pump was suggested In efflux studies. The colony‐forming unit granulocyte macrophage (CFU‐GM) assay showed no increase In cytotoxicity of Adr when AM was added. Fourteen patients with Adr‐resistant tumors were treated with Adr and AM. In these patients, peak serum levels of AM plus DEA of 10 μ.M were reached. Patient serum (20%) obtained after the first i.v. AM infusion induced in vitro significantly more cell kill of Adr in COLO 320 cells. Apart from a transient first‐degree AV block In one patient, no cardiac toxiclty was observed with the combination of Adr and AM. Bone‐marrow toxicity was the same as expected from Adr alone in these patients. One of the 13 evaluable patients obtained a partial remission.
Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo
Authors: Tanaka Juichi , Teicher Beverly A. , Herman Terence S. , Holden Sylvia A. , Dezube Bruce , Frei Emil
Published: February 2007

In an effort to improve the additive anti‐tumor efficacy of commonly used alkylating agents, the topoisomerase‐II inhibitor etoposide was used in combination with either the mitochondrial poison and energy‐depleting agent lonidamine or the hemorheologic agent and tumor‐blood‐flow‐increasing agent pentoxifylline. In the FSallC murine fibrosarcoma system, these modulators were evaluated for modulation of whole‐tumor cell killing vs. bone‐marrow CFU‐GM toxicity with the alkylating drugs CDDP, CTX, L‐PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor‐cell and bone‐marrow killing, except for BCNU, where a substantial increase in tumor‐cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone‐marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor‐cell vs. bone‐marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor‐cell killing of 0.5 to 1.0 log were observed. Hoechst‐33342‐defined tumor‐cell sub‐population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.
c‐erbB‐2 proto‐oncogene expression and its relationship to survival in gastric carcinoma: An immunohistochemical study on archival material
Authors: Jain S. , Filipe M. Isabel , Gullick W. J. , Lineman Jacqueline , Morris R. W.
Published: February 2007

The c‐erbB‐2 proto‐oncogene encodes a growth factor receptor which is over‐expressed in a variety of human adenocarcinomas. Recent reports suggest that it may be of value in arriving at prognosis in breast and ovarian cancer. In this study, c‐erbB‐2 expression was investigated in 93 routinely processed cases of gastric carcinoma, using an immunohisto‐chemical technique. c‐erbB‐2 membrane immunoreactivity was observed in 11% (10/93) of tumours, all of whkh were of the well differentiated intestinal type (p< 0.01). Overall, patients with tumours expressing this proto‐oncogene had a significantly improved prognosis (p< 0.05). Within the group of intestinal‐type tumours, those that were c‐erbB‐2‐positive formed a distinct sub‐population which had a better prognosis (p< 0.02), suggesting possible differences in aetiology.
Trisomy 12 and K‐ras‐2 Amplification in human ovarian tumors
Authors: Yang‐Feng Teresa L. , Li Shi‐Bo , Leung Wah‐Ying , Carcangiu Maria L. , Schwartz Peter E.
Published: February 2007

Cytogenetic analysis was performed on 11 benign and borderline ovarian tumors. Trisomy 12, identified as a sole abnormality in 6 tumors, is likely a specific karyotypic change in different benign and borderline tumors and may well be a primary chromosomal lesion in these tumors. The possible association between amplification of the proto‐oncogene K‐ras‐2 which Is located on chromosome 12 and trisomy 12 was Investigated. DNA blotting analysis of 64 tumors indicates that trisomy 12 does not seem to be related to K‐ras‐2 amplification in ovarian tumors. K‐ras‐2 amplification was observed in 3 high‐grade tumors from 3 patients with metastases.