bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of O6‐methylguanine‐DNA methyltransferase activity on chloroethylnitrosourea chemotherapy in brain tumors
Authors: Mineura Katsuyoshi , Izumi Ichiro , Watanabe Katsuo , Kowada Masayoshi
Published: February 2007

Chloroethylnitrosoureas (CENUs) alkylate DNA at specific sites and inhibit DNA replication in tumor cells. O6‐Alkylguanine moieties resulting from alkylation of guanine bases are thought to be one of most lethal adducts in living cells. Effectiveness of CENUs is known to relate well with an enzymic activity of the DNA repair enzyme O6‐methylguanine‐DNA methyltransferase (MGMT), which recognizes and removes O6‐alkylguanine. To improve therapeutic results of CENUs, we have measured MGMT activity of human brain tumors and studied the relationship between MGMT activity and clinical responsiveness to 1‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl‐3‐(2‐chloroethyl)‐3‐nitrosourea hydrochloride (ACNU). Thirty‐seven patients with brain tumors were entered into the study. The neoplasms included gliomas, non‐glial tumors, and brain metastases. The MGMT activity of gliomas was significantly lower than that of non‐glial tumors and brain metastases. No significant difference in the enzyme activity was noted between low‐ and high‐grade gliomas. Out of the 22 gliomas 5 tumors indicated a value below 60 fmol/mg, suggestive of a methyl excision repair minus (Mer−) tumor. Two out of 3 evaluable patients with a Mer− tumor responded well to post‐operative ACNU adjuvant chemotherapy. Our results suggest that brain tumors include a certain percentage of Mer− phenotype tumors, and that CENUs such as ACNU should be applied selectively on tumors with a low MGMT activity in order to increase the therapeutic effectiveness. © 1993 Wiley‐Liss, Inc.
Immunohistochemical study of mucin carbohydrates and core proteins in hepatolithiasis and cholangiocarcinoma
Authors: Yamashita Kaneteru , Yonezawa Suguru , Tanaka Sadao , Shirahama Hiroshi , Sakoda Koro , Imai Kohzoh , Xing Pei‐Xiang , McKenzie Ian F. C. , Hilkens John , Kim Young S. , Sato Eiichi
Published: February 2007

The expression of mucin carbohydrates [Tn, sialosyl‐Tn(STn), and T antigens] and core proteins [MUCI‐apomucin‐related antigen (ARA) and MUC2‐ARA] was examined immunohisto‐chemically in tissues from 40 patients with hepatolithiasis and 26 patients with intrahepatic bile‐duct carcinoma. Tn and STn antigens were expressed in most of the carcinomas, and were also often expressed in the atypical bile‐duct epithelium of the patients with hepatolithiasis or carcinoma, whereas they were rarely or never expressed in the normal bile duct, suggesting that they are effective tumor markers. T antigen was less useful as a marker for intrahepatic bile‐duct carcinoma or the atypical epithelium, because it was expressed in normal bile‐duct of some cases. Regarding the expression of ARAs in the carcinomas, non‐invasive bile‐duct cyst adenocarcinomas with favorable prognosis either expressed no MUCI‐ARA with [DF3(‐), MUSE11(‐) and 139H2(‐)] staining pattern or expressed MUCI‐ARA with [DF3(‐), MUSE11(+) and 139H2(+)] staining pattern. However these tumors often expressed MUC2‐ARA with [anti‐MRP(+) and CCP58(+)] staining pattern. In contrast, most invasive non‐papillary cholangiocarcinomas with poor prognosis expressed MUCI‐ARA with [DF3( + ), MUSE 11(+) and 139H2(+)] staining pattern, but expressed no MUC2‐ARA with [anti‐MRP(‐) and CCP58(‐)] staining pattern. These results suggests that different apomucins are produced by bile‐duct cystadenocarcinomas and cholangiocarcinomas with differing prognosis. Furthermore, expression of Tn and STn antigens is a useful indicator of malignancy in the intrahepatic duct. © 1993 Wiley‐Liss, Inc.
Modification of TNF‐α pharmacokinetics in SA‐1 tumor‐bearing mice
Authors: Kus Breda , Serša Gregor , Novaković Srdjan , Urbančič Janja , Štalc Anton
Published: February 2007

Fibrosarcoma‐SA‐1‐tumor‐bearing mice were treated s.c. in the vicinity of tumors (peri‐tumorally) or intravenously, with recombinant human TNF‐α lacking 1to 3 amino acids from N‐terminal part (TNF‐αNv3). Tumor growth delay, observed after both routes of TNF‐αNv3 application, was statistically significant, though a better anti‐tumor effect was achieved after peri‐tumoral application. TNF‐αNv3 serum levels were determined in these animals and compared with TNF‐αNv3 serum levels in healthy animals, which were treated with TNF‐αNv3 either s.c. or i.v. The peak serum levels of TNF‐αNv3 applied peri‐tumorally/s.c. were significantly higher in tumor‐bearing than in healthy mice, whereas smaller differences in peak serum levels were found after i.v. application, which might correlate with anti‐tumor activity. Whatever the route of application, TNF‐αNv3 elimination from the serum of tumor‐bearing mice was slower than that in healthy animals. Also, comparison of TNF‐αNv3 pharmacokinetic parameters for tumor‐free and sarcoma‐ or melanoma‐bearing mice has demonstrated that the pharmacokinetics of TNF‐αNv3 are modified in tumor‐bearing animals. © 1993 Wiley‐Liss, Inc.
Characterization of cytotoxic activity of saporin anti‐gp185/HER‐2 immunotoxins
Authors: Tecce R. , Digiesi G. , Savarese A. , Trizio D. , Natali P. G.
Published: February 2007

The oncogene HER‐2/neu encodes a trans‐membrane receptor of 185 kDa with tyrosine‐kinase activity. Over‐expression of this molecule has been reported in a significant proportion of human breast and ovarian carcinomas, characterized by a poor clinical prognosis. Two monoclonal antibodies (MAbs), recognizing distinct epitopes of the gp 185 extracellular domain, have been utilized in the present study for the production of immunotoxins (ITs) by conjugation to the type‐1 RIP (ribosome‐inactivating protein) plant toxin saporin 6 (SAP). These ITs have been shown to retain tumor‐specificity and specifically to inhibit protein synthesis in the gp 185HER‐2(+) SK‐BR‐3 breast‐carcinoma cell line with IC50 values lower then I nM. Kinetics of the cytotoxic activity of the ITs are characterized by a slow rate, since incubation times ranging from 24 to 60 hr, depending on the different degree of expression of the receptor, are required to determine > 90% inhibition in the incorporation of radiolabeled leucine. However, the cytotoxic activity of these ITs, as evaluated by a more sensitive clonogenic assay, appears highly potent, since we have observed that 3 to 4 logs of cells are killed upon exposure to the ITs for short times at concentrations ranging from 1 to 5 × 10−8 M. © 1993 Wiley‐Liss, Inc.
Sequential process of blood‐borne lung metastases of spontaneous mammary carcinoma in C3H mice
Authors: Sugino Takashi , Kawaguchi Takanori , Suzuki Toshimitsu
Published: February 2007

We examined the correlation between growth characteristics and the incidence of lung metastases of spontaneous mammary tumors in C3H mice. The growth pattern of the mammary tumors was composed of initial rapid growth, declining growth, and further exponential growth (re‐growth). The “re‐growth” was closely associated with loss of differentiation and progressive increase of the incidence of lung metastases. In addition, we observed the sequential process of blood‐borne lung metastases. The findings involved (i) “passive” intravasation: carcinoma nests encased in newly formed endothelial cells are released into sinusoidal vessels within primary tumors; (ii) “mechanical” arrest and proliferation of multicellular tumor emboli in pulmonary arterioles; (iii) “active” extravasation: carcinoma cells rushed out to the lung parenchyma through the arteriolar walls ruptured by initial minimal penetration of carcinoma cells and intravascular pressure. The results indicate a stable progression in the natural history of C3H mouse mammary carcinomas characterized by growth characteristics, the incidence of lung metastases, and histological change generating a poorly differentiated clone which can successfully complete a sequential process of blood‐borne lung metastasis. © 1993 Wiley‐Liss, Inc.
Complete local tumor remission after therapy with extra‐corporeally applied high‐energy shock waves (HESW)
Authors: Gamarra Fernando , Spelsberg Fritz , Dellian Marc , Goetz Alwin E.
Published: February 2007

High‐energy shock waves (HESW) have recently been proposed as a means of non‐invasive tumor therapy. Here we report the first successful local treatment of experimental tumors by means of multifocal and repeated application of HESW. The experiments were performed on 29 Syrian golden hamsters bearing amelanotic hamster melanomas in the dorsal skin. HESW, generated electrohydraulically, were applied multifocally to the center and to 5 sites on the margin of the tumors. A group of animals undergoing surgical resection and an untreated group served as controls. Complete remission of local tumor was achieved in more than 90% of the HESW‐treated hamsters and in the same number of surgically treated animals, while untreated tumors continued to grow. Frequency of metastasis was the same in both groups after HESW treatment or surgery. Tumor therapy with multifocally and repeatedly applied HESW was thus as successful as surgery. © 1993 Wiley‐Liss, Inc.
Mouse mammary‐tumor virus activates Fgf‐3/Int‐2 less frequently in tumors from virgin than from parous mice
Authors: Clausse Nathalie , Smith Rosalind , Calberg‐Bacq Claire‐Michelle , Peters Gordon , Dickson Clive
Published: February 2007

Tumorigenesis by mouse mammary‐tumor virus (MMTV) involves proviral disruption and transcriptional activation of a number of cellular oncogenes, generically termed Int. The frequencies with which different Int genes are activated in different mouse strains can be quite variable, and previous surveys have suggested that insertions at int‐2/Fgf‐3 occur primarily in strains that develop pregnancy‐dependent mammary tumors. To address this issue, we have determined the relative contributions of 5 known Int genes (Wnt‐1, Wnt‐3, Fgf‐3, Fgf‐4 and Int‐3) in mammary tumors from virgin BR6 and multiparous BR6, BALB/cfBR6 and RIII mice. Whereas Fgf‐3 was implicated in 66%, 80% and 92% of the tumors from the respective parous animals, only 20% of the tumors from virgin mice expressed Fgf‐3. This reduced involvement of Fgf‐3 was compensated by proviral insertions in Fgf‐4, Int‐3 and Wnt‐3, but the frequency of Wnt‐1 activation was relatively constant. These data strengthen the link between Fgf‐3 and a pregnancy‐dependent phenotype and suggest that, in the strains analyzed, the frequency of Int‐gene activation was influenced more by the hormonal status than by the genetic background. © 1993 Wiley‐Liss, Inc.
Risk of cancer revealed by follow‐up of families with hereditary non‐polyposis colorectal cancer: A population‐based study
Authors: De Leon Maurizio Ponz , Benatti Piero , Pedroni Monica , Sassatelli Romano , Roncucci Luca
Published: February 2007

Hereditary non‐polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by susceptibility to large‐bowel cancer, frequently with early onset and localized in the right colon. Several tumours of other sites may also occur with increased frequency in these families. During the period 1984‐1989, 28 families with HNPCC were identified in our Health Care District through a population‐based colorectal cancer registry. Moreover, 61 additional families were selected and classified as having “suspected” HNPCC. The objective of the present study is to report the occurrence of new cases of cancer in the 5‐ to 6‐year follow‐up of individuals at risk of tumour development in either HNPCC or “suspected” families. There were 374 family members at risk in HNPCC and 468 in “suspected” families, contributing, respectively, 2,377 and 2,712 persons/year at risk. Thirty‐four new tumours developed among HNPCC family members vs. 29.3 expected; however, the occurrence of colorectal cancer in this group was significantly higher than expected, and this excess was particularly evident in the age‐groups 41‐50 and 51‐60. In “suspected” HNPCC, 38 new tumours developed vs. 24.5 expected; at variance with the other group, besides colorectal neoplasms, lung, liver and brain tumours also occurred significantly in excess. Moreover, the increased risk was uniformly distributed among different age‐groups. In conclusion, HNPCC family members are at increased risk of developing colorectal cancer, with an earlier onset than the general population; in contrast, high‐risk individuals in “suspected” HNPCC families seem to be prone to a broader neoplastic spectrum, and risk of tumours does not seem to be limited to any particular age‐group.
Quantitation of HTLV‐I provirus among seropositive blood donors: Relation with antibody profile using synthetic peptides
Authors: Matsumura Masayuki , Kushida Shigeki , Ami Yoshihiro , Suga Tetsuya , Uchida Kazuhiko , Kameyama Tsuneo , Terano Akira , Inoue Yukiko , Shiraki Hiroshi , Okochi Kazuo , Sato Hiroyuki , Miwa Masanao
Published: February 2007

To study the pathophysiological state of HTLV‐1 carriers and the quantitative aspect of the risk of HTLV‐1 infection, we measured the absolute amounts of HTLV‐1 provirus in 39 seropositive blood donors. The amount of provirus varied from less than one to more than 104 molecules per 105 peripheral‐blood mononuclear cells (PBMC). The average amount of HTLV‐1 provirus among seropositive blood donors was estimated as 3.7 × 103 molecules per 105 PBMC. The titer of the antibody against only the synthetic peptide (aa 100 to 130) of the gag p19 region of the HTLV‐1 provirus showed a weak but significant correlation with the amount of the provirus.
Analysis of antigens recognized on human melanoma cells by A2‐restricted cytolytic t lymphocytes (CTL)
Authors: Wölfel T. , Hauer M. , Klehmann E. , Brichard V. , Ackermann B. , Knuth A. , Boon T. , Zum büschenfelde K. H. Meyer
Published: February 2007

We have pursued our analysis of potential tumor‐rejection antigens recognized on human melanoma by autologous cytolytic T lymphocytes (CTL). We reported previously that 3 distinct antigens (A,B,C) were recognized on melanoma cell line SK29‐MEL in association with HLA‐A2. Selection for melanoma‐cell variants resistant to anti‐A CTL revealed that antigen A consists of at least 2 determinants (Aa, Ab) which can be lost separately. Genetic linkage between Aa and Ab was suggested by concomitant loss of Aa and Ab in an immunoselected tumor‐cell variant. This variant was also resistant to an autologous CTL clone restricted by HLA‐B45, indicating that this CTL may also recognize a determinant of antigen A. Of 11 allogeneic HLA‐A2 melanoma cell lines that were tested, 5 expressed both Aa and Ab, I expressed only Aa, and I only Ab. None of them was lysed by anti‐B or anti‐C CTL clones. A CTL clone derived from another HLA‐A2‐melanoma patient was found to have exactly the same lytic pattern as the anti‐Ab CTL of the first patient. This suggested that it may be possible to elicit an anti‐Ab response in many HLA‐A2 patients. We conclude that there are at least 2 distinct antigens presented in association with HLA‐A2 that are common to many melanomas and therefore constitute promising targets for specific immunotherapy.
Low doses of radiation induce systemic production of cytokines: Possible contribution to leukemogenesis
Authors: Tartakovsky Boris , Goldstein Orly , Krautghamer Rita , Haran‐Ghera Nechama
Published: February 2007

Experiments were conducted to explore the possible effect of low‐dose irradiation on cytokine production in mice. SJL/J and C57BL/6J mice were exposed to 3 Gy and 4 Gy respectively. At various time intervals thereafter, lung‐conditioned media, bone‐marrow‐conditioned media and sera were collected. Interleu‐kin‐6 and macrophage‐colony‐stimulating‐factor activities were tested, lnterleukin‐6 in lung‐conditioned media from both strains was found to be significantly induced by irradiation. Macrophage‐colony‐stimulating‐factor activity was greatly enhanced in sera of irradiated SJL/J mice as well as in bone‐marrow‐conditioned media of both strains. The kinetics of the radiation‐induced interleukin 6 and macrophage‐colony‐stimulating‐factor activity differed in the 2 strains. SJL/J and C57BL/6J mice have been previously shown to be susceptible to low‐dose‐radiation‐induced leukemia. The coleukemogenic effects of both cytokines in 3 different models of experimental leukemogenesis is demonstrated.
Over‐expression of the S13 ribosomal protein in actively growing cells
Authors: Denis Marc G. , Chadeneau Corinne , Lecabellec Marie‐Thérèse , Lemoullac Béatrice , Lemevel Bernard , Meflah Khaled , Lustenberger Patrick
Published: February 2007

In order to define biological markers of aggressiveness, 2 rat colon‐carcinoma cell lines differing by their tumorigenicity were used to clone genes over‐expressed in colon carcinoma as compared with normal epithelial cells. A progressive rat colon‐carcinoma clone (PROb) cDNA library was hybridized with 32P‐cDNA synthesized from mRNA prepared from these PROb cells, or from regressive cells (REGb) derived from the same tumor. Several clones were isolated after the initial screening. The specificity of each clone was confirmed by RNA blotting. One of these (B9) was found to hybridize to an mRNA 30‐fold more abundant in PROb cells than in normal adult rat colon, and was therefore selected for further study. No gene amplification was detected by Southern blot analysis, indicating that the difference in mRNA content was most likely due to an increased transcription of this gene. Sequencing of the cDNA revealed approximately 98% homology with the rat S13 ribosomal protein. The expression level of this gene was determined in a series of rat cell lines with different growth rates. A good correlation was found between these 2 parameters. Our data suggest that the S13 ribosomal‐protein gene can be used to evaluate the growth rate of tumor cells, which might be correlated with their aggressiveness. In an initial trial experiment, S13 ribosomal‐protein mRNA was detected in a series of human colorectal tumors by in situ hybridization. A strong signal was seen in the 4 tumors analyzed.
Evaluation of S9788 as a potential modulator of drug resistance against human tumour sublines expressing differing resistance mechanisms In Vitro
Authors: Hill Bridget T. , van der Graaf Winette T. A. , Hosking Louise K. , De vries Elisabeth G. E. , Mulder Nanno H. , Whelan Richard D. H.
Published: February 2007

Significant activity has been identified using S9788, a triazineaminopiperidine derivative, as a new modulator of multidrug resistance against a series of drug‐resistant human tumour‐cell lines in vitro. Maximal non‐cytotoxic concentrations (i.e., those resulting in ≤ 10% cytotoxicity) of S9788 or verapamil were tested in combination with vinblastine, Adriamycin or vincristine and cytotoxicity was evaluated using a clonogenic assay, or the metabolic dye reduction MTT assay, or by monitoring growth inhibition. Under these conditions, the extent of resistance modulation by verapamil and by S9788 was comparable in the various tumour cell lines tested, although a definite concentration‐dependent modulation was noted with both compounds. The highest dose‐modification factors were noted in the highly vinblastine‐resistant classic multi‐drug‐resistant subline CEM/VLB 100, although resistance reversal was only partial. Resistance modulation by both verapamil and S9788 was noted in 4 drug‐selected resistant sublines and 4 “intrinsically” resistant human tumour cell lines, which all exhibited significant P‐glycoprotein expression. In contrast, in 2 drug‐resistant human tumour sublines (GLC4/ADR and CEM/ VM‐I) characterized by altered topoisomerase‐II activity and proving to be P‐glycoprotein‐negative, no resistance modulation relative to parental cells was observed. These data are consistent with the proposal that resistance modulation is mediated by interaction between S9788 and P‐glycoprotein and support its clinical evaluation in patients with P‐glycoprotein‐positive tumours.
UICC/CRC conference on targeted cancer therapy
Authors: Begent R. H. J.
Published: February 2007

Selective delivery of therapy to tumour cells has been a goal of cancer therapy since the beginning of this century. Progress has been slow until recently when a host of technical developments has made effective therapy of cancer appear to be within reach. Different technologies are contributing in several clinical areas. The UICC Committee for Future Prospects in Cancer Therapy and the Cancer Research Campaign held a meeting at the Royal Free Hospital School of Medicine in London to bring together diverse groups working on aspects of targeted cancer therapy.

Targeted therapy depends on tumour recognition, a delivery system and a therapeutic modality for tumour killing.
Growth‐regulatory mechanism of two human esophageal‐cancer cell lines in protein‐free conditions
Authors: Iihara K. , Shiozaki H. , Oku K. , Tahara H. , Doki Y. , Oka H. , Kadowaki T. , Iwazawa T. , Inouh M. , Mori T.
Published: February 2007

We investigated the growth‐regulatory mechanism of 2 esophageal squamous‐cancer cell lines, TE2‐NS and TE3‐OS cells, both of which can grow stably in protein‐free conditions in vitro. Protein‐free conditioned media from TE2‐NS and TE3‐OS cells stimulated the growth of these cells. Exogenous epidermal growth factor (EGF), transforming growth factor‐alpha (TGF‐α), insulin‐like growth factor (IGF)‐I and ‐II enhanced cell proliferation by 2.2‐ to 3.8‐fold in protein‐free conditions, as compared with an untreated control. Receptor‐binding assays showed that both TE2‐NS and TE3‐OS cells possessed a single class of high‐affinity binding sites for IGF‐I and 2 classes of binding sites for TGF‐α, as confirmed on the cell membrane by immunochemistry. These results suggest that EGF, TGF‐α and IGFs are candidates for the autocrine growth factor in cancer cells. The addition of inhibitory monoclonal antibodies against TGF‐a and EGFR, but not those against either EGF or IGF‐IR, significantly inhibited growth of the cells. Immunocytochemical staining and ELISA of the conditioned media both confirmed the production of TGF‐α protein, but not EGF protein, in these cell lines. The data for a protein‐free culture system strongly suggested that TGF‐α, but not EGF or IGF, is biologically important as an autocrine growth factor in the growth of these cell lines in vitro.
High levels of NM23‐H1 and NM23‐H2 messenger RNA in human squamous‐cell lung carcinoma are associated with poor differentiation and advanced tumor stages
Authors: Engel Matthias , Theisinger Birgit , Seib Thomas , Zang Klaus D. , Welter Cornelius , Dooley Steven , Seitz Gerhard , Huwer Hanno
Published: February 2007

Expression of the candidate metastasis‐suppressor gene nm23‐H1 has been shown to correlate inversely with metastatic potential in some human tumors, but not in all. Until now, few studies have been carried out on the activity of the homologous nm23‐H2 gene in human cancer. No nm23 transcription studies exist for human lung cancer so far. To determine whether the nm23 genes could have a metastasis‐suppressor function in non‐small‐cell lung carcinoma (NSCLC), pulmonary sarcoma and carcinoids, we analysed both nm23‐H1 and nm23‐H2 mRNA levels in 37 tumor samples obtained from patients who underwent potentially curative resection between 1986 and 1990, and in 4 metastatic tumors obtained from autopsy. As compared to corresponding healthy lung parenchyma, both nm23‐H I and nm23‐H2 transcript levels were elevated in 37 of 41 tumors. The increases in nm23 mRNA expression were stronger in advanced stages of squamous‐cell carcinoma, large‐cell carcinoma, sarcoma and carcinoids than in early stages of the respective tumor types. Within stages I and II of squamous‐cell carcinoma, significantly higher nm23 mRNA levels were found in poorly differentiated tumors than in moderately differentiated ones. Moreover, an inverse correlation between nm23 expression and disease‐free survival of the patients was observed. In conclusion, our results indicate that the increased nm23 expression in the analysed tumors is not consistent with the proposed metastasis‐suppressor function, but the 2 nm23 genes nevertheless may be implicated in the mechanism of tumor progression.
Refined‐sugar intake and the risk of colorectal cancer in humans
Authors: Vecchia Carlo La , Franceschi Silvia , Bidoli Ettore , Barbone Fabio , Dolara Piero
Published: February 2007

The relationship between sugar added to coffee and other hot beverages‐‐as an indicator of taste for sugar and sugar intake outside main meals‐‐and the risk of colorectal cancer was investigated using data from a case‐control study conducted in Northern Italy on 953 cases of histologically confirmed colon cancer, 633 of rectal cancer and 2845 controls admitted to hospital for acute, non‐neoplastic, non‐digestive tract disorders. Compared with subjects who reported adding no sugar to their beverages, the multivariate relative risks (RR) of colon cancer were 1.4 for those adding one spoonful of sugar, 1.6 for those adding 2 spoonsful, and 2.0 for those adding 3 or more. The corresponding RRs for rectal cancer were 1.3, 1.5 and 1.4. For combination of colorectal cancer the RRs were 1.4, 1.5 and 1.8. All the trends in risk were significant, and the results were consistent across strata of study centre, sex and age, and were not appreciably modified by allowance for a number of major identified potential distorting factors, including an estimate of total calorie intake. These findings, if confirmed, would suggest that taste for sugar is a relevant indicator of colorectal cancer risk, and could be interpreted either in terms of a role of sugar in colorectal carcinogens, or of a specific influence of even limited amounts of sugar taken outside meals, which may stimulate the proliferation of the bowel epithelium, and hence enhance colorectal carcinogenesis.
Y chromosome loss and rearrangement in non‐small‐cell lung cancer
Authors: Center Rob , Lukeis Robyn , Vrazas Vickie , Garson O. Margaret
Published: February 2007

While loss of the Y chromosome from the karyotype of tumor cells has frequently been found in a number of human malignancies of different types, structural alterations are a much less common finding. Prompted by the high frequency of cytogenetic Y chromosome loss found in primary non‐small‐cell lung cancer (NSCLC), and the fact that NSCLC karyotypes usually contain marker chromosomes of unidentified origin, we have determined the Y chromosome status of 12 NSCLC samples (7 cell lines and 5 primary tumors) at a molecular level. Of the 9 cases which did not have a cvtogenetically detectable Y chromosome, 4 were negative for all the Y sequences tested. The other 5, in contrast, retained some Y chromosome sequences. In I case (H520), only Yq heterochromatic sequences were detected, whereas in the remaining 4 (L162, L93, L125 and L71) both Yq heterochromatic sequences and Y euchromatic sequences were retained. The region of common overlap for loss of Y euchromatin was Yp distal to the Y centromere. We hypothesize that deletion of Yp sequences may play a role in tumor progression in NSCLC due to loss of a tumor‐suppressor gene.
Incidence of colorectal cancer following adenomatous polyps of the large intestine
Authors: Levi Fabio , Randimbison Lalao , Vecchia Carlo La
Published: February 2007

An association between adenomatous polyps of the large bowel and colorectal cancer has been reported, in the absence, however, of population‐based estimates of risk. Subjects with histologically confirmed first diagnosis of large‐bowel polyps notified to the population‐based Cancer Registry of the Swiss Canton of Vaud (about 600,000 inhabitants) during the calendar period 1979‐1990 were actively followed up to the end of 1990 for the subsequent occurrence of malignant neoplasms. Among 2,496 individuals with intestinal polyps, followed for a total of 10,310 person‐years at risk (6,201 among males and 4,109 among females), 150 malignant neoplasms were registered versus 152 expected. Thus, the standardized incidence ratio (SIR) for all cancers combined was 0.99. A significant excess was observed for colorectal cancer, with 35 cases observed (19 males, 16 females) versus 17.0 expected (SIR = 2.1; 95% CI: 1.5–3.0). There was also an excess, although not significant, for small‐bowel cancer (2 cases observed vs. 0.4 expected; SIR = 5.4). In none of the other cancer sites was SIR significantly or appreciably elevated: in subjects with colorectal polyps the SIR was 1.6 for stomach, 1.0 for lung, 0.9 for breast and 1.2 for prostate. The SIR of colorectal cancer was 3.1 in the first year since polyp registration, and declined thereafter to 1.8, in the absence, however, of any further trend with time since diagnosis. The cumulative risk of colorectal cancer in subjects with colorectal polyps was 2% at 5 years and 3% at 10 years. The quantitative estimates of this study are of interest for their population‐based nature, and are potentially useful for defining and targeting screening colonoscopy programmes.
Cytogenetic analysis of 52 colorectal carcinomas‐‐non‐random aberration pattern and correlation with pathologic parameters
Authors: Bardi Georgia , Johansson Bertil , Pandis Nikos , Mandahl Nils , Mitelman Felix , Heim Sverre , Bak‐Jensen Elisabeth , Lindström Clas , Törnqvist Anders , Frederiksen Hans , Andrén‐Sandberg Åke
Published: February 2007

Cytogenetic analysis of short‐term cultures from 52 colorectal carcinomas revealed a normal karyotype in 13 and clonal chromosome aberrations in 39 tumors. In the abnormal group, 13 tumors had simple numerical changes only, whereas 26 had at least one structural rearrangement with or without concomitant numerical changes. The most common numerical abnormalities were, in order of decreasing frequency, +7, −18, −Y, +8, +13 and −14. The most common structural rearrangements affected, again in order of decreasing frequency, chromosomes 8, 1, 6, 7, 17, 3, 11, 13, 14, 16, 2 and 10. The chromosome bands most frequently involved in the structural changes were 8q 10, 17p11, 11q13, 8p11, 6q21, 7p15, 7q36, 12q13, 13q10, and 16q13. The most frequent genomic imbalances brought about by the structural rearrangements were losses from chromosome arms 8p, 1 p, 6q, 17p, 7p, and 16q, as well as gains of 7q, 8q, 13q, and 11 q. A statistically significant (p < 0.05) correlation between the karyotypic pattern and tumor grade was found, with the poorly differentiated carcinomas generally having more massive chromosomal abnormalities.
Enhancement of cisplatin and etoposide cytotoxicity after all‐trans retinoic‐acid‐induced cellular differentiation of a murine embryonal carcinoma cell line
Authors: Guchelaar H.‐J. , Uges D. R. A. , Timmer‐Bosscha H. , De Vries E. G. E. , Mulder N. H. , Dam‐Meiring A. , Oosterhuis J. W.
Published: February 2007

The potential of a combination of differentiation induction and chemotherapy was analyzed. Treatment of the murine embryonal carcinoma (EC) cell line PCC4 in vitro with all‐transretinoic acid (RA) was followed by exposure to cisplatin (CDDP) or etoposide (VP‐16). The expression of EC‐cell‐specific markers decreased upon 96 hr exposure to 10−9, 10−8, 10−7and 10−6M RA, indicating a loss of embryonal phenotype of the cells, whereas expression of markers specific for cytokeratins and neurofilaments was increased after this treatment. These data suggest early somatic differentiation of PCC4 cells upon treatment with RA. Cellular growth rate of PCC4 cells was not affected by preincubation with RA at 10−9 M for 96 hr, but was reduced at 10−8 and 10−7 M RA and inhibited at 10−6 M RA. Culture of PCC4 cells in the presence of 10−7 M RA for 96 hr led to accumulation in G1 of the cell cycle, whereas at 10−8 M RA cell‐cycle distribution was not affected. RA‐treated and ‐untreated PCC4 cells were compared for CDDP and VP‐16 sensitivity. Pre‐treatment with 10−9, 10−8 and 10−7 M RA increased CDDP sensitivity, resulting in a 1.9‐, 2.7‐ and 2.6‐fold decrease in the concentrations inhibiting survival by 50% (IC50s) respectively. Pre‐treatment with 10−8 and 10−7 M RA increased VP‐16 sensitivity 2.5‐ and 3.0‐fold, respectively. Enhanced CDDP sensitivity at RA concentrations not affecting cell‐cycle distribution was not attributable to changes in cellular platinum (Pt) accumulation, or to changes of Pt‐DNA binding. Enhanced VP‐16 sensitivity also occurred while topoisomerase‐II activity was unchanged and topoisomerase‐I activity was increased 2‐fold. Furthermore, there was a 2.0‐ to 4.5‐fold increase in the cellular concentration of VP‐16 after 10−8 and 10−7 M RA pre‐treatment. In conclusion, this study shows that in PCC4 cells the rationale for combining RA and VP‐16 or CDDP is 2‐fold: RA induces differentiation and increases CDDP and VP‐16 sensitivity.
Epidermal growth factor elevates the activity levels of glycolipid sulfotransferases in renal‐cell‐carcinoma cells
Authors: Kobayashi Takahiko , Honke Koichi , Gasa Shinsei , Kato Naoyuki , Makita Akira , Miyazaki Tamotsu
Published: February 2007

Accumulation of sulfoglycolipids associated with markedly elevated levels of glycolipid‐sulfotransferase activity was previously demonstrated in human renal‐cell‐carcinoma cells. To elucidate the regulatory mechanisms of sulfoglycolipid metabolism in renal‐cell carcinoma, effects of various growth factors on the sulfotransferase‐activity levels were investigated using a human renal‐cell‐carcinoma cell line, SMKT‐R3. Exogenous epidermal growth factor (EGF) significantly increased the activity levels of the sulfotransferases in a dose‐dependent manner, but did not change that of arylsulfatase A, which hydrolyzes sulfoglycolipids. Furthermore, metabolic labeling with 35S‐sulfate revealed that the addition of EGF to the culture medium of the cells resulted in an increment of sulfoglycolipid synthesis. The expression of the EGF receptor on SMKT‐R3 cells was demonstrated by affinity cross‐linking with 125l‐EGF. These observations suggest that EGF can regulate sulfotransferase‐activity levels in renal‐cell‐carcinoma cells, and function as one of the regulatory factors of sulfoglycolipid synthesis in these carcinoma cells.
Induction of tumor‐cell lysis by bi‐specific antibody recognizing ganglioside GD2 and T‐cell antigen CD3
Authors: Bernhard Helga , Karbach Julia , Büschenfelde Karl‐Hermann Meyer Zum , Strittmatter Wolfgang , Knuth Alexander
Published: February 2007

Human tumor cells expressing ganglioside GD2 were lysed by various effector populations targeted with an anti‐CD3‐anti‐GD2 bi‐specific antibody (BAb CD3 x GD2). This antibodyheteroconjugate was prepared by chemically cross‐linking the OKT‐3 monoclonal antibody (MAb) reactive with CD3 antigen on T lymphocytes with the ganglioside MAb ME 361, which binds preferentially to the tumor‐associated ganglioside GD2. The specificity of target‐cell lysis by the cytotoxic T cells (CTL) was mediated by the specificity of the targeting antibody: GD2‐negative cells were not lysed in the presence of the CD3 x GD2 BAb. A dose‐dependent response was observed in a range of 10 to 10,000 ng/ml. In contrast, 2 other BAbs recognizing the tumor‐associated antigens EGF‐R and TKB‐2 had greater potency to mediate tumor‐cell lysis than the GD2 x CD3 BAb. Peripheral‐blood cells (PBL) stimulated with OKT‐3 MAb or with irradiated tumor cells in a mixed lymphocyte culture (MLTC) could be induced to lyse GD2‐positive tumor cells in the presence of CD3 x GD2 BAb. The tumor‐cell lysis could be mediated by autologous or allogeneic effector cells. NK cells had no influence on the BAb‐induced cytotoxicity.
The anti‐tumor arotinoid RO 40‐8757 protects bone marrow from the toxic effects of cyclophosphamide
Authors: Eliason James F. , Inoue Tomoaki , Kubota Akiko , Horii Ikuo , Teelmann Kampe , Hartmann Diethelm
Published: February 2007

The arotinoid Ro 40‐8757 is a novel compound that has significant therapeutic activity against chemically induced breast tumors in rats. The results of combination therapy with cyclophosphamide, plus the arotinoid showed that the anti‐tumor effects were additive. However, all of the rats given CPA alone died between week 6 and week 10 of treatment. None of the animals in the group treated with the combination died. Administration of a single dose of Ro 40‐8757 to non‐tumor bearing mice resulted in a transient increase in bone‐marrow‐progenitor cells after 2 days and a decrease in splenic progenitors at day 4. Treatment of mice with the combination demonstrated that the marrow progenitors were protected from the toxic effects of CPA by the arotinoid. Direct addition of Ro 40‐8757 to mouse bone‐marrow cells in clonogenic assay cultures containing WEHI‐3‐conditioned medium plus erythropoietin showed no significant enhancement by the arotinoid. The results suggest that this compound may exert its protective effect through the hemopoietic micro‐environment.
Inhibitory effects of 3′‐methyl‐3‐hydroxy‐chalcone on proliferation of human malignant tumor cells and on skin carcinogenesis
Authors: Satomi Yoshiko
Published: February 2007

3′‐methyl‐3‐hydroxy‐chalcone (3Me‐3‐C), a derivative of chalcone, inhibited the proliferation of various kinds of human malignant tumor cells, such as HGC‐27 (gastric cancer), HeLa (cervical carcinoma), PANC‐1 (pancreatic cancer) and GOTO (neuroblastoma). Flow‐cytometric analysis of HGC‐27 cells revealed that 3′Me‐3‐C perturbed the cell cycle, i.e., it delayed passage through the S phase, and/or caused arrest in the G0/G1 phase. 3′Me‐3‐C inhibited the binding of [6,7‐3H]estradiol to type‐II estrogen‐binding sites dose‐dependently, and altered the pattern of protein synthesis and phosphorylation, which may explain 3Me‐3‐C‐induced inhibition of cell proliferation. In addition, 3Me‐3‐C also suppressed the promoting activity of 12‐0‐tetradecanoylphorbol‐13‐acetate on skin carcinogenesis in 7,12‐dimethylbenz[a]anthracene‐initiated mice.
Liposarcoma: A population‐based epidemiologic and prognostic study of features of 43 patients, including tumor DNA content
Authors: Gustafson Pelle , Rydholm Anders , Willén Helena , Åkerman Måns , Baldetorp Bo , Fernö Mårten
Published: February 2007

Different conceptions exist regarding the epidemiology and prognosis of liposarcoma, and several classification systems are in use. We analyzed a population‐based, 25‐year series of 43 patients with liposarcoma of the extremity or trunk wall. Follow‐up was complete. The annual incidence was 0.12/10s. The thigh was the most common location. One of 6 tumors was subcutaneous. Deep‐seated tumors were larger than s.c. tumors. Among the 42 surgically treated patients, grade II (4‐grade scale) was the most common malignancy grade. Four tumors were well‐differentiated, 24 were predominantly myxoid, 4 predominantly round‐cell, and 10 were predominantly of pleomorphic type. The 5‐year metastasis‐free survival rate was 69%. By univariate analysis increasing malignancy grade, tumor necrosis, vascular invasion, mitotic count, subtype other than well‐differentiated, and high cellularity were prognostic for metastatic disease. However, in the multivariate analysis only tumor necrosis was an independent risk factor. Tumor necrosis should be considered when prognosis of liposarcoma of the extremity and trunk wall is evaluated.
Lack of allelic deletion and point mutation as mechanisms of p53 activation in human malignant melanoma
Authors: Castresana Javier S. , Rubio Mari‐Paz , Seizinger Bernd R. , Vàzquez J. Jaime , Idoate Miguel , Sober Arthur J. , Barnhill Raymond L.
Published: February 2007

To investigate the role of the p53 tumor‐suppressor gene in the development of human melanoma, loss of heterozygosity (LOH) of p53 was studied in 46 cases of melanoma by a polymerase‐chain‐reaction/restriction‐fragment‐length polymorphism (PCR/RFLP) analysis, and p53 mutations were assessed in 51 cases of melanoma by a polymerase‐chain‐reaction/ single‐strand‐conformation polymorphism (PCR/SSCP) analysis. Frozen tumors and paraffin samples were used in the study. We were not able to detect any allelic loss in 12 BstU1 informative cases or any single mutation in exons 5 to 8 of the p53 gene. Our results, together with other findings at the DNA level, suggest that the p53 gene appears not to be commonly involved in the development of melanoma, at least by its most frequent mechanisms of deletion of one allele and/or mutation in the other.
Tumor‐cell proliferation and prognosis in renal‐cell carcinoma
Authors: Larsson Per , Ljungberg Börje , Roos Göran , Stenling Roger
Published: February 2007

In the present study the prognostic value of tumor S‐phase fraction was evaluated in 69 patients with renal‐cell carcinoma. The proportion of S‐phase cells was calculated from DNA histograms by flow cytometry in multiple samples from each tumor. The mean tumor S‐phase percentage varied between 1.0 and 17.0%, mean 7.5%, with a significant difference between diploid and non‐diploid tumors. Stage‐I tumors showed significantly lower S‐phase values than tumors of stages II/III and IV. Histopathological grade correlated with fraction of cells in S‐phase. Nineteen tumors were homogeneously diploid, I was tetraploid and 49 were aneuploid. Heterogeneity concerning S‐phase values was found in 46 of the 69 tumors and concerning DNA ploidy in 34 tumors. Survival time was longer for patients with diploid tumors than for those with aneuploid tumors. Patients with S‐phase values <7.5% had a longer survival time than patients having tumors with S‐phase values >7.5%. Within the group of aneuploid tumors, patients with S‐phase values <7.5% had a significantly better prognosis. In multivariate analysis, only tumor stage and S‐phase gave significant independent prognostic information. The S‐phase fraction seems to be an additional prognostic parameter for patients with renal‐cell carcinoma.
Correlation of epithelial proliferation and squamous esophageal histology in 1185 biopsies from linxian, china
Authors: Liu Fu‐Sheng , Wang Guo‐Qing , Li Jun‐Yao , Dawsey Sanford M. , Rao Madhusudan , Taylor Philip R. , Lipkin Martin , Lewin Klaus J. , Li Bing
Published: February 2007

Epithelial proliferation is an active area of research in gastrointestinal cancer, but only a few studies have examined the relationship of esophageal epithelial proliferation and squamous histologic findings in populations with high rates of squamous esophageal cancer. In order to study this correlation, tritiated thymidine labeling was performed on 1185 esophageal biopsies from 745 residents of Linxian, China, a county with some of the highest esophageal‐cancer rates in the world. Total labeling index (TLI = total labeled cells/total cells counted) was used to measure the amount of proliferation, and the proportion of labeled cells found in cell layers 4 to 10 (labeled cell fraction 4 plus, LF4+ = labeled cells in layers 4‐10/total labeled cells) was used to measure the vertical distribution of proliferation. Of the biopsies, 979 were histologically normal, 51 showed acanthosis, 35 showed esophagitis, 116 showed squamous dysplasia, and 6 showed invasive squamous cancer. The mean values of both proliferation variables, stratified by histologic diagnosis, showed the following relationships: normal = acanthosis < esophagitis = dysplasia < cancer. The ranges of proliferation values overlapped extensively in all biopsy categories, so that measuring proliferation could not substitute for histologic diagnosis. It remains to be seen whether proliferation values, histologic diagnoses, or some combination of these methods is most predictive of subsequent esophageal cancer.
E‐cadherin expression in head and neck squamous‐cell carcinoma is associated with clinical outcome
Authors: Mattijssen Vera , De Mulder Pieter H. M. , Peters Herman M. , Schalkwijk Lia , Van't Hof‐Grootenboer Bep , Ruiter Dirk J. , Manni Johannes J.
Published: February 2007

The cell‐cell adhesion molecule E‐cadherin has been shown to suppress invasive growth of epithelial cells in vitro, and loss of its expression is thought to be important in invasion and metastatic potential of epithelial tumors in vivo. We retrospectively studied the level of E‐cadherin expression in 50 primary head and neck squamous‐cell carcinomas (HNSCC) by immunohistochemical methods, on frozen sections, using anti‐E‐cadherin monoclonal antibody (MAb) 6F9. It concerned patients with different stages of carcinoma of larynx or oral cavity who had been treated with curative intention 30 months or more before. Percentages of membranous stained tumor cells were scored in 1 of 5 categories. Scores were generally low, as in 11/50 lesions ≤5% cells were stained, and in 19/50 lesions only 6‐25% cells showed membranous staining. In 9 lymph‐node metastases evaluated, E‐cadherin expression was in the same range as in the primary tumors. There was a significant correlation between the level of membranous E‐cadherin expression in the primary tumor and the degree of differentiation. No relation was found with tumor size (pT) or regional lymph‐node classification (pN). Nevertheless, 29 patients surviving ≥30 months without evidence of disease had significantly higher levels of membranous E‐cadherin expression in their primary tumors than 10 patients with unfavorable clinical course clearly related to recurrent and/or metastatic HNSCC. Moreover, this could only partially be explained by distinctions in differentiation grade between both groups. Our results suggest that membranous E‐cadherin expression has prognostic importance in patients with HNSCC.
Possible regulation of soluble icam‐1 levels by interleukin‐1 in a sub‐set of breast cysts
Authors: Lai L. C. , Kadory S. , Cornell C. , Lennard T. W. J.
Published: February 2007

There are 2 main groups of breast cysts characterized by their intracystic sodium‐to‐potassium ratios. Women who have intracystic Na/K < 3 may have a higher risk of developing breast cancer than those who have intracystic Na/K > 3. The cell adhesion molecule, ICAM‐1, has been shown to be inducible by interleukin‐1 (IL‐1). Furthermore, ICAM‐1 may be involved in the progression of metastasis in certain malignancies. The aim of this study was to measure intracystic soluble ICAM‐1 (sICAMu‐l) and IL‐1 α/β levels and to assess the relationships between these substances. Wide‐ranging concentrations of sICAM‐1, IL‐1α and IL‐1β were found in breast‐cyst fluid. The high‐electrolyte‐ratio group had intracystic levels of sICAM‐1 and IL‐1β which were significantly higher than those of the low‐electrolyte‐ratio group. No significant difference was found between IL‐1α concentrations in the 2 groups of breast cysts. Strong positive correlations were found between sICAM‐1 and IL‐1α, sICAM‐1 and IL‐1β, and IL‐1α and IL‐1β. The significance of the higher concentrations of sICAM‐1 in the high‐electrolyte‐ratio group remains to be determined, but the results of this study suggest that sICAM‐1 levels in the high‐electrolyte‐ratio group may be regulated in part by IL‐1α and IL‐1β.