bluuebunny/crossref_metadata_2025 huggingface dataset:
Immortalization of normal human fibroblasts by treatment with 4‐nitroquinoline 1‐oxide
Authors: Bai L. , Mihara K. , Kondo Y. , Honma M. , Namba M.
Published: February 2007

Normal human fibroblasts (the OUMS‐24 strain), derived from a 6‐week‐old human embryo, were transformed (into the OUMS‐24F line) and immortalized by repeated treatments (59 times) with 4‐nitroquinoline 1‐oxide (4NQO). Treatment began during primary culture and ended at the 51st population doubling level (PDL). At the 57th PDL (146 days after the last treatment), morphologically altered, epithelial‐type cells appeared, began to grow and became immortal (now past the 100th PDL). However, the control fibroblasts, which were not treated with 4NQO, senesced at the 62nd PDL. The finding that extensive, repeated treatments with 4NQO are required for the immortalization of normal human cells, indicates that multiple mutational events are involved in the immortalization of human cells in general. In other words, immortalization itself seems to be a multi‐step process. Karyotypic analysis showed that many cells were hypodiploid before immortalization, but that afterwards chromosomes were distributed broadly in the diploid to tetraploid regions. The immortalized cells showed amplification and enhanced expression of c‐myc. Two‐dimensional electrophoretic analysis showed that the number of disappearing cellular proteins was greater than the number of the newly appearing ones after the cells became immortalized. Since the immortalized cells showed neither anchorage‐independent growth nor tumorigenicity, they are useful for studying factors that can contribute to multi‐step carcinogenesis in human cells. In addition, genetically matched normal (OUMS‐24) and immortalized (OUMS‐24F) cells will be useful for analyzing the genes related to cellular mortality and immortalization.
Phenotypic and molecular analysis of ph1‐chromosome‐positive acute lymphoblastic leukemia cell lines
Authors: Miyagi T. , Ohyashiki J. , Yamato K. , Koeffler H. P. , Miyoshi I.
Published: February 2007

We have established 2 Philadelphia chromosome (Ph1)‐positive acute lymphoblastic leukemia (ALL) cell lines, designated PALL‐1 and PALL‐2, from distinct adult Ph1‐positive ALL patients. PALL‐1 was established in nude mice, and PALL‐2 was established in culture. Both retained the Ph1 chromosome and expressed the ALL type bcr/abl chimeric mRNA containing the junction of the first exon of BCR gene (eI) and second exon of c‐abl gene (a2). PALL‐1 and PALL‐2 expressed CD34 surface antigen which is characteristic of early hematopoietic progenitor cells. PALL‐2 expressed antigens for both pre‐B and early myeloid cells and had rearrangements of both the heavy chain of immunoglobulin gene and the β chain of T‐cell‐receptor gene. Both PALL‐1 and PALL‐2 expressed detectable levels of p53 gene RNA. Polymerase‐chain‐reaction‐single‐strand conformation polymorphism (PCR‐SSCP) analysis of the p53 gene showed a normal pattern of mobility in both cell lines. Taken together, the 2 cell lines had features of Ph1‐positive ALL (i) hematopoietic progenitor cells with pre‐B‐cell phenotype and, (ii) activation of el‐a2 type bcr/abl oncogene without alterations of p53 gene. These unique lines should provide a valuable tool for studying the pathogenesis of Ph1‐positive ALL.
Activators of coagulation in cultured human lung‐tumor cells
Authors: Seitz R. , Heidtmann H.‐H. , Maasberg M. , Immel A. , Egbring R. , Havemann K.
Published: February 2007

Tumor matrix generation and tumor cell growth are supported by coagulation processes within the tumor tissue. Activators of coagulation were searched for in suspensions of 9 permanent human squamous‐cell lung‐cancer (EPLC 32MI, U1752), large‐cell lung‐cancer (LCLC 97TMI, LCLC 103H, U 1810), and small‐cell lung‐cancer (N‐592, H‐526, DMS79, 86MI) cell lines. Incubation with these cells shortened the recalcification time in normal plasma (also in the presence of antibodies against tissue factor) or coagulation‐factor‐VII‐, VIII‐,IX‐or X‐deficient plasmas. The activators of coagulation in the 2 most active cell lines (U1752 and LCLC 103H) were further characterized in purified systems: the cleavage of chromogenic substrates, and the generation of markers of pro‐thrombin activation were assessed. Three activators of coagulation were found in intact or sonicated cell suspensions and culture supernatants: (i) a tissue factor (TF)‐like activity; (ii) an activity activating factor X, which in contrast to “cancer pro‐coagulant” was not inhibited by iodoacetamide; and (iii) an activity‐ activating pro‐thrombin, which was inhibited by the serine protease inhibitor PMSF and appeared to require plasmatic co‐factor(s). The heterogeneous expression of coagulation activators by lung‐tumor cell lines might be of significance for tumor biology and response to therapy.
Review article: Epidemiology of male breast cancer. A meta‐analysis of published case‐control studies and discussion of selected aetiological factors
Authors: Sasco Annie J. , Lowenfels Albert B. , Jong Pieternel Pasker‐De
Published: February 2007

Male breast cancer is a rare tumour in all parts of the world. About 1% of all breast cancers occur in men, but the male/female ratio is higher among black than among white populations. This effect can be seen in US cancer registries and even more markedly in African data. A positive correlation exists on a population scale between male breast cancer and prostate cancer. Seven case‐control studies of male breast cancer are available, and a pooled analysis was conducted of the most commonly suspected risk factors. Male breast cancer appears to be associated with marital status: Mantel‐Haenszel exposure odds ratio (EOR) for never married = 1.6; 95% confidence limits (CL) = 1.1, 2.3, religion (EOR for being Jewish = 2.1; 95% CL = 1.4, 3.2), previous breast pathology (EOR for positive history of benign breast disease = 2.7; 95% CL = 1.7, 4.2), gynaecomastia (EOR for positive history = 6.2, 95% CL = 3.4, 11.4), previous testicular pathology (EOR for positive history = 2.2; 95% CL = 1.5, 3.3), previous liver diseases (EOR for positive history = 1.6; 95% CL = 1.0, 2.4) and family history of breast cancer (EOR for first‐degree relative with breast cancer = 2.5; 95% CL = 1.7, 3.7). No association is found with smoking history. Other potential risk factors such as reproductive history, education, occupation, anthropometric variables, association with various diseases, and specific exposures such as drug use, were not systematically evaluated in all studies and provide sometimes contradictory results, possibly due to small numbers of exposed subjects. Overall, the analytical epidemiology of male breast cancer presents similarities with the epidemiology of female breast cancer, with a potential role of factors related to hormonal status, relative hyperoestrogeny in men being potentially linked to increased risk of disease. Genetics may also play a role, with high risk linked to a familial history of breast cancer, and with a major risk in patients with Klinefelter's syndrome.
Prognostic significance of the proliferative potential of intracranial gliomas measured by bromodeoxyuridine labeling
Authors: Hoshino Takao , Ahn David , Prados Michael D. , Lamborn Kathleen , Wilson Charles B.
Published: February 2007

The growth potential of 174 intracranial gliomas was estimated by calculating the bromodeoxyuridine labeling index (BUdR LI). Each patient received a 30‐min infusion of BUdR, 200 mg/m2, before tumor removal. Excised tumor specimens were stained immunohistochemically to determine the BUdR LI, or percentage of S‐phase cells. A Cox proportional‐hazards stepwise model was used to determine the correlation between the BUdR LI and survival. Among patients with glioblastomas, the BUdR LI did not improve the prediction once age was entered in the model. Among patients with malignant or low‐grade astrocytomas, the BUdR LI was the best single predictor of survival. The relative predictive abilities of BUdR LI and histopathology were determined by analyzing malignant astrocytoma and glioblastomas together. Distinguishing between malignant astrocytomas and glioblastomas did not significantly improve the prediction of survival once the BUdR LI and age were entered into the model. Equations derived from the model indicate that the probability of survival is a function of age and BUdR LI in patients with glioblastoma or malignant astrocytoma, but is a function of BUdR LI alone in patients with low‐grade astrocytoma. The equations also show a substantial difference in the impact of increased BUdR LI on survival among patients with glioblastoma or malignant astrocytoma and those with low‐grade astrocytoma. Without highly effective treatments for specific tumor phenotypes, the survival of a patient with an intracranial glioma appears to depend strongly on the proliferative potential of the tumor. Thus, accurate estimates of the proliferative potential are important in predicting the survival of individual patients with gliomas as well as in evaluating the effectiveness of various types of treatment.
Trends in non‐melanocytic skin cancer treated in Australia: The second national survey
Authors: Marks R. , Staples M. , Giles G. G.
Published: February 2007

An Australia‐wide survey in 1985 recorded the highest rates of medically treated non‐melanocytic skin cancer (NMSC) ever reported. We report the findings of a repeat survey conducted in 1990. This second survey confirmed the differences, by age, sex, body site, latitude, country of birth and skin reaction to strong sunlight, that were observed in 1985. Over the 5‐year period certain changes were noted: the incidence of NMSCs increased by 19%, of basal‐cell carcinomas (BCC) by 11% and of squamous‐cell carcinomas (SCC) by 5%. With advancing age, men and women differed in their incidence, and this difference was greater for SCC than for BCC. Log‐linear modelling, however, failed to detect either a cohort or a survey effect between the 2 surveys. The proportional distribution of BCCs and SCCs by body site indicated an increase in BCCs on the trunk in both men and women, and half the proportion of SCCs on the head and neck in women as compared with men. The latitudinal gradients observed in 1985 were even stronger in 1990; the population living north of 37°s experienced a 30% increase in the incidence of treated NMSC between 1985 and 1990, while the population living south of 37s had a 25% decrease. The implications of these findings for cancer‐control initiatives are discussed.
Serological responses to HPV 16 in cervical dysplasia and neoplasia: Correlation of antibodies to E6 with cervical cancer
Authors: Ghosh Anna K. , Smith Nigel K. , Stacey Simon N. , Glew Susan S. , Connor Mary E. , Arrand John R. , Stern Peter L.
Published: February 2007

Sera from patients with cervical cancer, cervical intraepithelial neoplasia (CIN) and non‐genital cancers, and from healthy individuals, were investigated for antibodies to human papilloma virus (HPV) early proteins E4, E6 and E7 and the major capsid protein LI by Western blot analysis of recombinant HPV proteins. There was a significantly higher prevalence of sera with antibodies to E6 in cervical cancer patients than in healthy individuals or in CIN or non‐genital‐cancer patients. Antibodies to E7 were detected in 25% of cervical‐cancer patients, which is significantly higher than in HPV‐associated cervical lesions or in control populations, but not significantly different from the incidence in patients with non‐genital cancers. Antibodies to L I were found more frequently in CIN, while antibodies to E4 had a similar prevalence in cervical‐cancer, cervical‐dysplasia and non‐genital‐cancer groups, with 24% in the controls. The inability to detect antibodies to E6 and E7 in the majority of cervical‐cancer patients limits the application of this methodology to the monitoring of HPV infection and the development of cervical cancer. However, the latter approach may be useful in combination with other assay systems which allow detection of different, including conformational, epitopes of HPV E6 and/or E7 recombinant proteins.
Orthotopic transplantation of histologically intact clinical specimens of stomach cancer to nude mice: Correlation of metastatic sites in mouse and individual patient donors
Authors: Furukawa Toshiharu , Kubota Tetsuro , Watanabe Masahiko , Kitajima Masaki , Hoffman Robert M.
Published: February 2007

Fresh surgical specimens derived from 36 patients with advanced stomach cancer were orthotopically transplanted in nude mice using histologically intact tissue. Twenty of 36 patient tumors gave rise to locally growing tumors in the mice. All 20 patients whose stomach tumors resulted in local growth in the nude mice had clinical lymph‐node involvement, whereas 8 of the other 16 patients whose tumors were rejected had lymph‐node involvement. There was a statistical correlation(p <0.01) between local tumor growth in nude mice and clinical lymph‐node involvement. Of the 20 cases resulting in local growth in the nude mice, 5 had clinical liver metastases and all 5 cases resulted in liver metastases in the nude mice. Of the 20 cases, 6 had clinical peritoneal involvement of their tumor, and of these 5 resulted in peritoneal metastasis in the nude mice. There were statistical correlations (p < 0.01) for both liver metastases and peritoneal involvement between patients and mice. These results indicate that, after orthotopic transplantation of histologically intact stomach cancers from patients to nude mice, the subsequent metastatic behavior of the tumors in the mice closely correlated with the course of the tumors in the patients.
Correlation between the lung distribution patterns of Lu‐Ecam‐1 and melanoma experimental metastases
Authors: And Duzhang Zhu , Pauli Bendicht U.
Published: February 2007

Lu‐ECAM‐1 is a 90‐kDa lectin‐like, melanoma‐cell‐binding endothelial‐cell adhesion molecule that mediates colonization of the lungs by B16‐FIO melanoma cells. The well‐known formation of pleural and sub‐pleural B 16‐F10 melanoma colonies is correlated quantitatively with prominent histochemical staining of endothelia of pleural capillaries and sub‐pleural venules with anti‐Lu‐ECAM‐I MAb 6D3. The less frequent endothelial staining of perivenous and peribronchial venules is associated with fewer B16‐F10 colonies in these locations, and the occasional segmental staining of pulmonary veins coincides with rare tumor nodules which usually expand in an asymmetric fashion around these veins. Lu‐ECAM‐I is also expressed on endothelia of some tumor vessels, indicating that these vessels are recruited from the same host blood vessels that originally caused the arrest of blood‐borne B16‐F10 melanoma cells. The close association between the lung distribution patterns of Lu‐ECAM‐I‐positive blood vessels and experimental melanoma metastases is further evidence of the importance of endothelial‐ cell adhesion molecules in the formation of metastases.
Detection of a progression‐linked DNA restriction fragment in rat hepatoma cells probed with a hexokinase CDNA
Authors: Wigley W. Christian , Corson Gary E. , Nakashima Richard A.
Published: February 2007

We have compared genomic DNA isolated from a series of rat hepatomas and from normal rat liver tissue by restriction fragment analysis. Our objective was to identify a tumor‐specific restriction fragment that would be present in rapidly growing tumors and missing in normal tissues. Using a cDNA probe specific for the C‐terminal half of rat brain hexokinase, we have identified several changes in DNA restriction fragment lengths in rat hepatoma vs. normal rat liver. Most of these involved restriction fragments that were present in normal rat DNA and missing in tumor DNA. However, one Hinfl fragment of Mr = 13.4 kilobase pairs (kb) was found to be present in rapidly growing rat hepatomas, but missing in normal rat tissue and in hepatomas of slow or intermediate growth rate.
The development and characterization of vinca alkaloid‐resistant Caco‐2 human colorectal cell lines expressing mdr‐1
Authors: Hoskins Joann , Deherdt Sonja V. , Moore Robert E. , Bumol Thomas F.
Published: February 2007

Several novel cell lines with variable resistance to Vinca alkaloids have been derived from the Caco‐2 human colorectal carcinoma cell line. Parental Caco‐2 cells were found by PCR analysis and immunofluorescence studies to produce a low amount of the mdr‐1 gene product (P‐glycoprotein) that may well be clinically significant. These cells, which were initially highly sensitive to desacetylvinblastine sulfate (DAVLB sulfate) were selected, without mutagenesis, through continuous culture with increasing concentrations of DAVLB sulfate over a 335‐day period. This selection resulted in cell lines that displayed an mdr (multiple‐drug‐resistance) cross‐resistance profile that could be reversed with agents such as verapamil and vindoline. During the selection process the amount of mdr‐I mRNA present, the extent of gene amplification and the amount of gp 170 expressed all correlated well with the level of drug resistance. However, this correlation does not hold in the absence of selective pressure for the more resistant cell lines where gene amplification and the amount of P‐glycoprotein present remained constant while the level of drug resistance and the amount of mdr‐l mRNA present declined. These cell lines are potential models for studying mdr‐1 gene expression and drug resistance in human epithelial malignancies.
Expression of autocrine motility factor receptor in serum‐ and protein‐independent fibrosarcoma cells: Implications for autonomy in tumor‐cell motility and metastasis
Authors: Watanabe Hideomi , Shinozaki Tetsuya , Raz Avraham , Chigira Masaki
Published: February 2007

The motile response of serum‐dependent (Gc‐4 SD) and protein‐independent (Gc‐4 PF) murine fibrosarcoma cells to monoclonal antibody (MAb) that binds to gp78 a cell‐surface receptor (M, 78,000) for an autocrine motility factor (AMF) was analyzed. The Gc‐4 PF cells responded to the anti‐gp78 by increased motility in vitro (3‐fold) and increased lung colonization in vivo (8‐to 20‐fold), while the serum‐dependent counter‐part failed to respond to motile stimulation both in vitro and in vivo. Immuno‐analysis of cell‐surface expression and cell extracts revealed a smaller amount of gp78 in Gc‐4 SD cells than in Gc‐4 PF cells. Both cell lines secrete an equal amount of AMF to the culture media. Our results suggest that protein‐free culture of Gc‐4 PF cells is associated with high response to AMF and with high expression of its receptor, and that autonomous motile regulation may play a role in tumor dissemination.
Effect of monoclonal antibody 17‐1A and gm‐CSF in patients with advanced colorectal carcinoma—long‐lasting, complete remissions can be induced
Authors: Ragnhammar Peter , Fagerberg Jan , Frödin Jan‐Erik , Hjelm Anna‐Lena , Lindemalm Christina , Magnusson Inger , Masucci Giuseppe , Mellstedt Håkan
Published: February 2007

Antibody‐dependent cellular cytotoxicity (ADCC) is considered to be one of the effector functions of unconjugated monoclonal antibodies (MAbs) in tumor therapy. The antitumor activity of MAbs might therefore be augmented if the cytotoxic capability of the effector cells could be increased. In an in vitro system, the killing capacity of MAb was significantly enhanced by pre‐treatment of the effector cells with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Based on these findings, the therapeutic effect of the combination of mouse MAb 17‐IA (IgG2a) and GM‐CSF was evaluated in 20 patients with metastatic colorectal carcinoma (CRC). The patients received GM‐CSF for 10 days and a single i.v. infusion of MAb 17‐IA on day 3 of the cycle. Four cycles were given at 1‐monthly intervals. There was a continuous increase in blood monocytes and lymphocytes during all 4 GM‐CSF cycles. Neutrophils and eosinophils were also significantly augmented but in a biphasic manner and the cell counts on day 10 of cycle IV were significantly lower than in cycles I and II. GM‐CSF‐related side‐effects were of no major clinical importance. During the third cycle, an immediate‐type allergic reaction (ITAR) against MAb 17‐ IA occurred in most patients, necessitating reduction of the MAb dose as well as of the infusion rate. Two patients achieved complete remission. One patient had a minor response, and 3 other patients were considered to have stable disease >3 months.
Cancer incidence trends in Urban Shanghai, 1972‐1989
Authors: Jin Fan , Devesa Susan S. , Zheng Wei , Blot William J. , Fraumeni Joseph F. , Gao Yu‐Tang
Published: February 2007

Incidence data pertaining to more than 250,000 cancer cases diagnosed during the years 1972‐1989 among residents of urban Shanghai, China, were analyzed to determine the relative importance of the various malignancies and to discover changes over time. In the most recent 3‐year period, lung cancer was the most frequent cancer among men (57.0 per 100,000 person‐years, age‐adjusted world standard), followed by cancers of the stomach (50. 1), liver (29.6), esophagus (13.3), colon (11.2) and rectum (9.4). Among women, breast cancer leads (25.1), followed by cancers of the stomach (23.2), lung (18.8), liver (10.9), colon (10.2) and rectum (7.3). The most impressive increases in incidence rates from 1972‐74 to 1987‐89 were observed for cancers of the gallbladder (119% and 101% among men and women, respectively), colon (85% and 78%), and brain and other nervous system (71% and 60%). In addition, increases of 20‐50% occurred for cancers of the pancreas, male lung, female breast, corpus uteri, kidney, and for non‐Hodgkin's lymphoma. Rates declined notably for cancers of the esophagus (‐54% and ‐53%), cervix uteri (‐86%), and to a lesser extent (10‐20%) cancers of the male stomach and liver. These observed trends can be explained only partly by improvements in cancer diagnosis and completeness of the cancer registry, and most likely reflect changes in the prevalence of risk factors in this population.
int‐2 Amplification in breast cancer: Association with decreased survival and relationship to amplification of c‐erbb‐2 and c‐myc
Authors: Henry J. A. , Hennessy C. , Leveit D. L. , Nard T. W. J. Len , Westley B. R. , May F. E. B.
Published: February 2007

Amplification of the int‐2 oncogene was measured in a series of breast tumours and related to amplification of the c‐myc and c‐erbB‐2 oncogenes, histopathological features and relapse‐free and overall survival. int‐2 was amplified in 11%, c‐myc in 20% and c‐erbB‐2 in 27% of the tumours assessed. int‐2 amplification was associated with large tumour size (p < 0.05) and reduced relapse‐free (p < 0.05) and overall (p < 0.0005) survival. c‐myc amplification was associated with poor tumour differentiation p < 0.05) but had no association with prognosis. c‐erbB‐2 amplification was associated with low levels of expression of oestrogen receptor mRNA (p < 0.05), poor tumour differentiation (p < 0.05) and shortened relapse‐free (p < 0.OOOl) and overall survival (p < 0.0001). This is the first report of an association between amplification of the int‐2 oncogene in breast tumours and a significantly increased risk of death from breast cancer, and suggests that int‐2 may be useful for identifying breast‐cancer patients having a poor prognosis.
Differences in the post‐translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells
Authors: Beninati Simone , Abbruzzese Alberto , Cardinali Massimo
Published: February 2007

The identification of (γ‐glutamyl)polyamines in proteolytic digest of proteins from the cytosolic and particulate fractions of B16‐F10 and B 16‐F1OLr6 cell lines, originating from a spontaneous tumor in C57BL/6 mice, indicates that polyamines are incorporated into melanoma cell proteins by transglutaminases (TGases‐EC 2.3.2.13). The levels of spermidine‐derived protein cross‐links were found to be inversely related with the meta‐static potential of the 2 melanoma lines. Characterization of TGase activity in the 2 tumor cell lines showed 3 types of enzyme. The soluble cellular TGase activity (TGase C) was higher, and increased more, during the growth of the least metastasizing clone B16‐F10Lr6 than in the B16‐F10 line, which is the most metastasizing. Consistently, NN8‐bis(γ‐glutamyl) spermidine, which is responsible for protein cross‐link formation, was present in greater amount in B16‐F10Lr6 cells. The enhancement by theophylline of soluble‐TGase activity and spermidine‐dependent protein cross‐links of B16‐F10 cells reduced, with linear dose dependence, the ability of these cells to penetrate through human fibronectin‐coated membrane in an in vitro assay of invasiveness. Our data confirm and extend earlier observations indicating that the propensity of a tumor to metastasize can be indirectly related to intracellular levels of TGase activity, and provide the basis for some speculation concerning the role of polyamines as modifiers of murine melanoma cell proteins in metastasis.
Effects of all‐trans retinoic acid as a potential chemopreventive agent on the formation of azoxymethane‐induced aberrant crypt foci: Differential expression of c‐myc and c‐fos mrna and protein
Authors: Stopera Shelley A. , Bird Ranjana P.
Published: February 2007

The main objectives were to determine the modulating effects of all‐trans retinoic acid on the number, size and multiplicity of aberrant crypt foci as well as the in vivo expression of the genes c‐myc and c‐fos. These foci, which are hypothesized to be the pre‐malignant lesions of colon cancer, were induced in Sprague‐Dawley rats with a single injection of azoxymethane. Rats were fed either a control diet (AIN‐76) or the control diet to which had been added 75 mg/kg or 150 mg/kg all‐trans retinoic acid. Within 4 weeks, we observed that the diets containing all‐trans retinoic acid reduced the total number and multiplicity of aberrant crypt foci in the colon. However, all‐trans retinoic acid increased the size of the lesions that persisted, possibly due to a greater proportion of lesions with dilated crypts. In situ hybridization and immunohistochemistry were performed on the colons for the in vivo analysis of gene expression in these lesions. The expression of myc‐specific mRNA and protein in aberrant crypt foci significantly decreased with both levels of all‐trans retinoic acid. In contrast, fos‐specific mRNA and protein in aberrant crypt foci significantly increased when 150 mg/kg all‐trans retinoic acid was added to the diet. The most important findings of this investigation are that intervention with all‐trans retinoic acid in the pre‐malignant stage of colon carcinogenesis is effective in decreasing the number and growth of aberrant crypt foci and altering the expression of the c‐myc and c‐fas genes.
Combined therapy with IL‐6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas
Authors: Katz Anne , Shulman Lester M. , Revel Michel , Feldman Michael , Eisenbach Lea
Published: February 2007

We investigated the anti‐tumor effects of human recombinant interleukin‐6 (hrlL‐6) on the highly metastatic Lewis lung‐carcinoma clone, D122. These cells express high‐affinity IL‐6 receptors at numbers comparable to the IL‐6‐dependent murine hybridoma B9 cells; however, IL‐6 did not affect D122 cell proliferation or expression of MHC‐class‐1 antigens in vitro. In vivo, treatment of mice bearing D122 tumors in the footpads, with a low dose of IL‐6 in 3 daily injections, 4 days a week for 3 weeks, significantly decreased spontaneous metastases. However, only combined treatment of IL‐6 and irradiated tumor cells resulted in almost complete protection against spontaneous metastases. Histological analysis confirmed the absence of micrometastases in most of the animals treated by this combination protocol. Analysis of the cytolytic activity of splenocytes at various time points during combined IL‐6 and immunotherapy of tumor‐bearing mice revealed significant and sustained lysis of the poorly immunogenic D122 carcinoma cells, while splenocytes of control mice could not lyse D122 target cells. Activation of specific immunity was also demonstrated when mice were pre‐immunized with hrlL‐6 and inactivated D122 cells and challenged with live carcinoma cells 10 days later. Significant growth inhibition of the primary tumor was observed.
Tumor‐necrosis factor can enhance radio‐antibody uptake in human colon carcinoma xenografts by increasing vascular permeability
Authors: Folli Silvio , Épèlegrin Andr , Chalandon Yves , Yao Xiaofei , Buchegger Franz , Lienard Danielle , Lejeune Ferdi , Mach Jean‐Pierre
Published: February 2007

Marked differences in the tumor uptake of a 125I‐labeled monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) were observed in 4 serially transplanted human colorectal carcinomas in nude mice. A comparative study showed that elevated values of measurable tumor vascular parameters, such as permeability, blood flow and blood volume, correlated better with high MAb tumor uptake than the concentration of target antigen in the tumor. In an attempt to modify the vascular parameters and to determine if this could increase antibody uptake by the tumor, rhTNFα (TNF) was injected i.t. or i.v. and antibody localization experiments were performed immediately thereafter. Results showed that the permeability of the tumor vessels increased 8 to 10 fold 1 hr after i.t. injection of TNF as compared to control tumors injected with saline. Tumor uptake of 125I‐labeled anti‐CEA MAb, was 3 times higher 2 hr after i.v. injection and still 27% higher 22 hr later, as compared to results from controls. Intravenous injection of TNF simultaneously with the l25I‐ labeled anti‐CEA MAb also resulted in a 2‐fold increase in tumor uptake 4 hr after injection, but the increase was no longer significant 24 hr after injection. Interestingly after i.v. injection of TNF, the MAb concentration in the blood and other normal tissues, such as liver, kidneys, lungs and heart was decreased, resulting in significantly higher ratios of tumor to normal tissue. Taken together the results demonstrate that injection of TNF can increase tumor vascular permeability and improve radioantibody uptake. This raises the possibility of increasing the radiation dose delivered by antibody to the tumor in the course of radioimmunotherapy.
Antigen processing and presentation by EBV‐carrying cell lines: Cell‐phenotype dependence and influence of the EBV‐encoded LMP1
Authors: de Campos‐Lima Pedro O. , Torsteinsdóttir Sigurbjörg , Cuomo Laura , Klein George , Sulitzeanu Dov , Masuccii Maria G.
Published: February 2007

Burkitt's‐lymphoma (BL) lines which have maintained in vitro the tumor‐cell phenotype (group‐1 BLs) are poor antigen‐ presenting cells (APC), in spite of a relatively high surface expression of MHC class II. In order to investigate the mechanism of this deficiency, we have compared group‐1 BL lines, their sub‐lines which have progressed in vitro towards an LCL‐like phenotype (group‐III BL), and EBV‐transformed lymphoblastoid cell lines (LCLs), for their ability to bind and process tetanus toxoid (TT). The uptake and internalization of 125I‐labelled TT was equivalent in the 3 cell types. Only LCLs and group‐III BL lines were able to process the IT,as shown by the identification of discrete proteolytic products after separation of whole‐cell extracts in tricine‐SDS‐polyacrylamide gels, and by the recovery of TCA‐soluble radioactivity in the culture supernatant. Processing of TT was induced by expression of the EBV‐ encoded membrane protein LMPI in transfected group‐I BLs. The present findings suggest that the inability of group‐I BLs to act as APC is due to their failure to process exogenous antigens. This function appears to be related to phenotypic properties that can be modulated by the expression of LMPI.
Age distribution of histologic types of breast carcinoma
Authors: Stalsberg Helge , Thomas David B.
Published: February 2007

The large number of cases in the Surveillance, Epidemiology and End Results (SEER) program of the US National Cancer Institute allowed a detailed analysis of the age distribution of the histologic types of invasive breast carcinoma. Between ages 50 and 85 years in females, the age‐specific incidence rate shows little change for medullary, inflammatory and apocrine carcinomas; is about doubled for Paget's disease and for ductal, lobular, tubular and metaplastic carcinomas; and increases to 4 to 8 times the menopausal level for mucinous, papillary and signet‐ring‐cell carcinomas. The peri‐menopausal break on the age‐incidence curve is most marked for carcinomas of predominantly lobular origin and virtually absent for carcinomas of predominantly ductal origin. In males, the age distribution of papillary carcinoma is similar to that of all types combined, whereas that of mucinous carcinoma is skewed towards older ages, as in females.
Cancer in Kampala, Uganda, in 1989–91: Changes in incidence in the era of aids
Authors: Wabinga Henry R. , Mugerwa Joshua W. , Parkin D. Maxwell , Wabwire‐Mangen Fred
Published: February 2007

Re‐establishment of the cancer registry in Kyadondo County, Uganda, has allowed estimation of incidence rates for the period September 1989 to December 1991. The results are compared with earlier data from the same area, and from other African cancer registries. The most striking feature is the emergence of Kaposi's sarcoma as the leading cancer in males (almost half of all registered cases) and the second most frequent (17.9%) in females. This parallels the evolution of the epidemic of AIDS. There were also marked increases in the incidence of both oesophageal and prostatic carcinoma, while the incidence of cancer of the penis and the urinary bladder declined, possibly as a result of improved standards of hygiene. In females, the incidence of cancer of the cervix has more than doubled since the 1950s, and is now among the highest recorded in the African continent.
Expression of the neuroglandular antigen and analogues in melanoma. CD9 expression appears inversely related to metastatic potential of melanoma
Authors: Si Zhaoyi , Hersey Peter
Published: February 2007

Immunohistological methods were used to examine the relation between the metastatic potential of melanoma and expression of the neuroglandular antigen (CD63) and other members of this family of molecules, CD53, CD37, CD9 and the target of an anti‐proliferative antibody (TAPA‐1), as well as MHC‐class‐I and ‐II antigens. The criteria used to establish metastatic potential were their relation to thickness of the primary melanoma, and differences in expression between vertical and radial growth phases of primary melanoma and between primary and metastatic melanoma. Studies on basal‐cell carcinoma (BCC) and squamous‐cell carcinoma (SCC) were also included as controls for malignant skin cancers with low metastatic potential. Expression of CD9 and MHC‐class‐1 antigen was found to be inversely related to thickness of the primary tumor, and CD9 was expressed predominantly on primary rather than on metastatic tumors. CD9 expression correlated with MHC‐class‐1 expression on melanoma, and both were expressed on BCCs and SCCs having low metastatic potential, but not on compound nevi. CD63 and TAPA‐1 were expressed on nevi but not on SCC and BCC. Leu 13 is a molecule associated with TAPA‐1 in lymphomas, and was found to be expressed in sections from 5 out of 34 primary and 5 out of 21 metastatic melanoma. CD53 and CD37 were not detected on melanoma. Our results indicate that several members of the neuroglandular antigen are expressed in melanoma and that low expression of CD9 on primary melanomas might have prognostic significance with respect to the potential for metastasis.
Sex differences in lung‐cancer risk associated with cigarette smoking
Authors: Osann Kathryn E. , Anton‐Culver Hoda , Kurosaki Tom , Taylor Thomas
Published: February 2007

The importance of cigarette smoking as a risk factor for specific histologic types of lung cancer in men and women has been examined in a case‐control analysis of data from the Cancer Surveillance Program of Orange County, a population‐based registry. Smoking habits were abstracted from medical records for 1153 men and 833 women diagnosed with primary lung cancer in 1984–1986 and 1851 men and 1656 women aged 30 or older diagnosed with cancers not associated with smoking. Ninety‐six percent of men and 89% of women with lung cancer were current or former cigarette smokers, as compared with 55% of men and 34% of women with other cancers. The age and ethnicity‐adjusted odds ratios (OR) for ever‐smoking were 19.7 for men and 15.0 for women. Men and women who smoked 2 or more packs per day experienced nearly equal risks. Comparison of the most common cell types showed that women smokers had equal or lower ORs for squamous‐cell carcinoma and adenocarcinoma, but higher OR for small‐cell carcinoma, as compared with men smokers. While the smoking‐associated OR were equal for small‐cell and squamous‐cell carcinomas in men, the OR for women were significantly higher for small‐cell carcinoma than for squamous‐cell carcinoma.
Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF‐7 cell cultures
Authors: Santner S. J. , Ohlsson‐Wilhelm B. , Santen R. J.
Published: February 2007

Estradiol levels in breast tumors from post‐menopausal women are similar to those in pre‐menopausal women even though plasma estrogens are much lower after the menopause. In situ estrogen production by the tumor provides a potential means of maintaining high estradiol levels in post‐menopausal breast cancer tissue. The estrone sulfatase pathway has been proposed as the mediator of in situ estrogen production. A number of studies suggest that estrone sulfate may be converted into estradiol in breast tumors via the catalytic activity of estrone sulfatase and 17β‐hydroxysteroid dehydrogenase. However, these studies used pharmacologic levels of estrogen sulfates and have not shown that physiologic levels can support biologic effects. Accordingly, the present study examined the dose relationship of estrone sulfate to a variety of biologic endpoints in MCF‐7 breast cancer cells in culture. These cells converted physiologic concentrations of estrone sulfate to quantities of free estradiol capable of stimulating cell growth. Under these conditions, the nuclear steroids observed were free estrone and estradiol. Increase in cell number after 6 days of exposure to steroid required 100 nM estrone sulfate. However, S‐phase, a more sensitive measure of cell proliferation, was stimulated by 0.1 nM estrone sulfate, a clearly physiologic concentration. Stimulation of estrogen‐dependent protein markers such as pS2 and progesterone receptor required much higher concentrations of estrone sulfate. These effects were mediated through the estrogen receptor since the pure anti‐estrogen, ICI 164384, blocked all effects produced by estrone sulfate. While it has been suggested that anti‐estrogens may partly exert their effects by inhibition of sulfatase and 17β‐hydroxysteroid dehydrogenase, this did not occur under our experimental conditions. These data provide evidence of the relevance of the estrone sulfatase pathway since biologic effects can be demonstrated in response to physiologic concentrations of estrone sulfate.
N‐terminal peptide fragments of lipocortin‐1 inhibit a549 cell growth and block EGF‐induced stimulation of proliferation
Authors: Croxtall J. D. , Waheed S. , Choudhury Q. , Anand R. , Flower R. J.
Published: February 2007

Lipocortin‐1 mediates growth inhibition of glucocorticoids in A549 cells by suppressing the release of PGE2 necessary for their proliferation. We now show that 2 peptide fragments derived from the N‐terminal portion of lipocortin‐1 corresponding to amino‐acids 13–25 and 21–33 also inhibited A549 cell growth and suppressed release of PGE2, whereas peptides 1–12 and 13–25 (Phe21; in which the tyrosine at position 21 was replaced by a phenylalanine residue) were inactive. Similarly, peptide 21–33 (Phe21) and a scrambled sequence of 13–25 failed to inhibit cell growth. Moreover, the EGF‐induced stimulation of cell proliferation and PGE2 release in these cells was blocked by peptides 13–25 and 21–33, and also by peptides 1–12, 13–25 (Phe21) and 21–33 (Phe21), but not by a scrambled sequence of peptide 13–25.
Potentiation of dna‐adduct formation and cytotoxicity of platinum‐containing drugs by low pH
Authors: Atema Anita , Buurman Karin J. H. , Smets Lou A. , Noteboom Erik
Published: February 2007

The low interstitial pH of tumor tissue is an important modulator of various anti‐tumor modalities. In order to explore the optimal conditions for the potentiating action of low pH on the cytotoxic activities of cis‐ and carbo‐platin, we have investigated the temporal aspects of drug activity and pH modulation in L1210 murine leukemia cells in comparison with various other drugs. Extra‐ and intra‐cellular pH of L1210 cells was modulated before, during and after drug exposure and survival of L1210 cells was determined. During short exposures, cytotoxicity of cisplatin and alkylating drugs was potentiated by conditions of low pH in the ranking order of: cisplatin, mitomycin C., melphalan and chlorambucil. Low pH had no effect on the cytotoxic activity of carboplatin and cytosine arabinoside and it inhibited the action of doxorubicin. During prolonged incubation at low pH, potentiation of cisplatin was increased and a more than 3‐fold potentiation was induced in the case of carboplatin. Part of the latter effect was also manifested by 20 hr post‐incubation in drug‐free medium at low pH after a 4‐hr exposure to carboplatin. Post‐incubation did not increase the stimulating effect of low pH on the cytotoxic activity of melphalan and cisplatin. Acidification affected neither the uptake nor the extracellular hydrolysis of platinum‐containing drugs. Under all circumstances, potentiation of platinum‐containing drugs was accompanied by an increase in platinum‐induced DNA modification, as detected by immunocytochemistry.
Genital types of papillomavirus in children of women with HIV‐1 infection in Kinshasa, Zaire
Authors: Louis Michael E. St. , Kamenga Munkolenkole , Ryder Robert W. , Heyward William L. , Icenogle Joseph P. , Reeves William C. , Manzila Tarande
Published: February 2007

Increasing evidence indicates that infection with genital types of human papillomavirus (HPV) can occur prior to the onset of sexual activity, possibly by perinatal transmission. Evidence is also accumulating that women infected with the human immunodeficiency virus (HIV) more frequently express HPV. We conducted this study to measure HPV prevalence in HIV‐seropositive and ‐seronegative women in Kinshasa, Zaire and in their children. We collected cervico‐vaginal lavage specimens from 80 mothers (52 HIV‐seropositive and 28 HIV‐seronegative at the time of delivery) and oropharyngeal and perineal specimens from their 81 3‐year old children (21 HIV‐seropositive and 60 ‐seronegative). We used the ViraPap and ViraType assay to test specimens for HPV DNA by the dot‐blot technique. Detection of HPV in the mother was highly associated with HIV: 20 HIV‐seropositive women and one seronegative woman had HPV DNA. Ten children had HPV DNA. However, detection of HPV in the children was not associated with the mothers' HPV or HIV status or with the child's own HIV status. These findings document a substantial prevalence in young children of HPV DNA types that are linked to genital‐tract neoplasia in adults, but do not specifically support a hypothesis of mother‐to‐child transmission of genital HPV types.
Cytologic screening for esophageal cancer: Results from 12,877 subjects from a high‐risk population in China
Authors: Shen Q. , Wang D. Y. , Liu S. F. , Cao J. , Zhou B. , Cao S. G. , Zhao H. Z. , Li G. Y. , Guo W. D. , Liu F. S. , Li J. Y. , Li B. , Dawsey S. M. , Taylor P. R. , Blot W. J.
Published: February 2007

Linxian, China, has one of the highest esophageal‐cancer mortality rates in the world. In 1983, esophageal balloon‐cytology screening was performed to identify subjects eligible for 2 nutrition‐intervention trials in Linxian; 12,877 subjects had cytology slides which were satisfactory for diagnosis. Of the 12,649 subjects with squamous‐cell diagnoses, 31% were normal by Chinese cytologic criteria; 38% showed hyperplasia; 21% showed dysplasia 1; 6% showed dysplasia 2; 2% showed near‐cancer; and 2% showed cancer. Of the 1,471 subjects with columnar‐cell diagnoses, 31 % were normal; 44% showed hyperplasia; 16% showed dysplasia 1; 4% showed dysplasia 2; 2% showed near‐cancer; and 3% showed cancer. Squamous dysplasia and cancer were more common among females than males, while columnar dysplasia and cancer showed male predominance. The prevalence of dysplasia and cancer of both cell types increased with age. The prevalence of squamous dysplasia was significantly higher than in earlier balloon‐cytology screenings in Linxian, probably reflecting changes in cytologic classification.
Amplification and over‐expression of the EGFR and erbB‐2 genes in human esophageal adenocarcinomas
Authors: Al‐Kasspooles Mazin , Moore Jason H. , Orringer Mark B. , Beer David G.
Published: February 2007

Esophageal cancer is one of the 10 most prevalent human cancers worldwide. The incidence of esophageal adenocarcinoma is on the rise and patients with this disease typically have very poor prognosis. Informative biomarkers would benefit the clinical management of this disease. We examined 13 cases with esophageal adenocarcinomas and 5 cases with Barrett's esophagus for amplification of the EGFR and erbB‐2 genes. We detected multiple copies of the EGFR gene in 30.8% of the tumors and multiple copies of the erbB‐2 gene in 15.4% of the tumors. Of the cases with amplification of the erbB‐2 gene, co‐amplification of the EGFR gene was found. Multiple copies of the EGFR gene were also found in one case of Barrett's esophagus. Immunohistochemical staining of the tissues revealed increased expression of the erbB‐2 protein in Barrett's mucosa and adenocarcinoma, but no associations between staining intensity and degree of EGFR or erbB‐2 gene amplification, histology, or tumor stage were found. Differential polymerase chain reaction was examined as a method for pre‐operative detection of gene amplification in esophageal tumors and Barrett's mucosa.
Polarization of the α6β4 integrin in ovarian carcinomas
Authors: Bottini C. , Miotti S. , Fiorucci S. , Facheris P. , Ménard S. , Colnaghi M. I.
Published: February 2007

By immunizing a BALB/c mouse with a human ovary‐carcinoma cell line (IGROVI), grown intraperitoneally in nude mice, a monoclonal antibody (MAb), designated MAR6, was produced and characterized. Immunofluorescence on the immunizing cell fine showed a specific labelling by MAR6 at the cell‐to‐cell contact points. In addition, MAR6 was found to immunoprecipitate the α6β4 integrin complex. Competition tests with MAbs anti‐α6, anti‐β4, anti‐β1 sub‐units demonstrated that the recognized sub‐unit is α6. Indirect immunofluorescence on various cell lines gave MAR6 as positive only on α6‐positive lines (IGROVI, OVCAR3, SW626, SKOV3, ME4405, Calu3, N592, MDA468, A431 and HT29). Moreover, on IGROVI and OVCAR3 ovary‐carcinoma cells, which normally grow either adhering to the culture flask or forming clumps in suspension in the medium, MAR6 selectively stained the connection points between the cells in clumps, where, in the same position, the presence of the β4 sub‐unit, laminin and fibronectin was detected. On the contrary, the β1 sub‐unit was distributed over the whole cell membrane. The same pattern of labelling by these MAbs was observed in 2 cases of ovarian‐carcinoma cells present in ascitic fluids obtained from patients. Immunoperoxidase tests performed on cryosections of various normal tissues showed specific reactivity of MAR6 on basal or basolateral membranes of epithelial cells. On cryosections of ovarian tumors, MAR6 reactivity correlated with the degree of tumor differentiation. Indeed, in benign and well‐differentiated tumors, a strong basal or basolateral labelling only of cells surrounding the neoplastic nodules was found. On the contrary, on undifferentiated tumors the inner part of the tumor nodules was also progressively labelled, whereas the staining on the border was weak and discontinuous as a result of the α6 sub‐unit dispersion on the tumor cell surface.