bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrone sulfate stimulates growth of nitrosomethylurea‐induced breast carcinoma in vivo in the rat
Authors: Santner Steven J. , Levin Michael C. , Santen Richard J.
Published: February 2007

Concentrations of estradiol in human breast tumors from pre‐ and post‐menopausal women are similar whereas plasma levels are 5‐ to 60‐fold lower in post‐menopausal women. The mechanism for maintaining high tumor tissue estrogen levels in post‐menopausal women is unknown but could be related to the ability of plasma estrone sulfate to serve as a precursor for estradiol synthesis in tumor tissue. Estrone sulfate plasma levels are 30‐fold higher than free estradiol levels in postmenopausal women and estrone sulfatase is present in many tissues, including breast tumors, supporting this hypothesis. In this study, we examined the ability of exogenously administered estrone sulfate to stimulate growth of a carcinogeninduced, hormone‐dependent rat mammary tumor and measured the rate of conversion of estrone sulfate to free estrone and estradiol. Castrate rats bearing nitrosomethylurea‐induced mammary tumors were infused with estradiol as a control or estrone sulfate over a 14‐day period. Estradiol at low doses significantly increased tumor volume whereas higher amounts paradoxically inhibited growth. By comparison, estrone sulfate infusions significantly increased tumor volume over that observed in castrate animals on both days 7 and I4 of infusion. To determine whether estrone sulfate was converted to free estrone and estradiol during this protocol, 3H‐estrone sulfate was substituted for unlabelled steroid and castrate animals were again infused for 14 days. At 7, 10 and 14 days of infusion, 18‐26% of estrone sulfate was converted to free estrone and 9‐16% to free estradiol. There were no significant differences between the 2 doses used and the rates of conversion were stable over the infusion period. Conversion of estrone sulfate to free estradiol was also demonstrated by radioimmunoassay of free estradiol in plasma during estrone sulfate infusions. These data demonstrate that exogenously administered estrone sulfate can stimulate mammary tumor growth in castrate animals and support the possibility that estrone sulfate may serve as an important source of tumor tissue estradiol.
Increased fucosylation of high‐molecular‐weight glycoproteins accompanies retinoic‐acid‐induced differentiation of f‐9 embryonal carcinoma cells
Authors: Amos Brad , Lotan Dafna , Lotan Reuben
Published: February 2007

Retinoic acid (RA) treatment of F‐9 embryonal carcinoma cells resulted in cell flattening and increased production of laminin Bl chain, both indicating differentiation to endoderm‐like cells. In addition, RA caused a time‐ and dose‐ dependent decrease in growth rate in monolayer culture and a dose‐dependent decrease in the ability of the cells to form colonies in soft agarose. Differentiation was accompanied by an increase in the fucosylation of specific high‐molecular‐weight cellular and cell‐surface glycoproteins. The fucosylation of glycoproteins of Mr 175,000 (gp175), 250,000 (gp250), and 400,000 (gp400) increased as early as 24 hr after the addition of 5 ± 10−6 M RA to the culture medium. These changes preceded both growth inhibition and the induction of laminin BI expression, which were detected 48 to 72 hr after addition of RA. The increased fucosylation of these glycoproteins showed a distinct dose‐response relationship. Both gp 175 and gp250 showed the greatest increase in fucosylation at 10−5 M, which was also the dose at which RA induced laminin maximally, while the fucosylation of gp400 was greatest at 10−8 M RA and declined at higher concentrations. The overall synthesis of large fucosylated glycopeptides decreased in RA‐treated cells, in spite of the increases in the fucosylation of specific cellular glycoproteins. RA‐induced differentiation of F‐9 cells was also accompanied by a time‐ and dose‐dependent increase in fucosyltransferase activity. Although the functions of these glycoproteins are not currently known, the early increase in their fucosylation can be considered as a marker of differentiation in this system.
Establishment of highly metastatic variants of murine colon adenocarcinoma 26 under serum‐free conditions
Authors: Sugimoto Yoshikazu , Oh‐hara Tomoko , Heike Yuji , Watanabe Masahiko , Nakatsuru Yoko , Ishikawa Takatoshi , Tsuruo Takashi
Published: February 2007

Tumor cell variants were established in vitro by treating a metastatic variant of murine colon adenocarcinoma 26 (P‐26‐select) in serum‐free RPMI 1640 medium for 6 to 10 weeks. Five tumor cell lines were established from independent cultures and designated PS‐I to PS‐5. The PS cells showed higher growth potential in vitro under serum‐free or low‐serum conditions than the parental P‐26‐select. In comparison to P‐26‐select, the PS cell lines possessed enhanced lung‐colonizing ability after i. v. inoculation and metastasized spontaneously to the lung following s. c. inoculation into the flank or the right fore‐footpads of BALB/c mice. Metastatic nodules were also observed in the liver. Spleens and livers of the tumor‐bearing mice were enlarged mainly as a result of hematopoiesis, suggesting the production of CSF‐like substance(s) by the tumor cells. The PS cells secreted increased amounts of putative autocrine growth factor(s) and CSF‐like substance(s) in vitro. These characteristics might be related to the in vivo metastatic ability of the PS cells.
Cancer mortality in rio de janeiro
Authors: Pinto Cynthia Boschi , Coleman Michel P.
Published: February 2007

Cancer mortality data for 1979‐81 are presented for the state of Rio de Janeiro, Brazil. The population in 1980 was over II million, and more than 30,000 deaths (11% of the total) were certified as being due to cancer during the 3‐year period. Death certification was fairly complete, and for two‐thirds there was complementary medical evidence of the certified cause of death. Cancers of the stomach, lung and female breast accounted for one‐third of all cancers, and cancers of the oesophagus and liver ranked 4th and 5th, respectively, among both sexes combined. Lung cancer mortallty was higher in both sexes (ASR 27.9 in males, 6.1 in females) than elsewhere in Brazil. Mortality from liver cancer (ASR 5.9 in males, 4.5 in females) was more than 8 times higher than in the city of So Paulo. Cervix cancer mortality was only one‐third of that of Fortaleza, a rural state. The results confirm large regional differences in the pattern of cancer mortality within Brazil.
Possible prognostic value of pulmonary ah‐locus‐linked enzymes in patients with tobacco‐related lung cancer
Authors: Bartsch H. , Hietanen E. , Petruzzelli S. , Giuntini C. , Saracci R. , Mussi A. , Angeletti C. A.
Published: February 2007

As prognosis in breast cancer patients has been related to the AHH activity in their breast tissue, we have conducted a similar analysis on pulmonary drug metabolizing enzymes as prognostic markers for male lung cancer patients, primarily investigated for other reasons. A subset of 50 patients with lung cancer related to tobacco use, who had undergone thoracic surgery, was re‐analyzed. The activity of parenchymal aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH) that had been determined previously in homogenates of non‐neoplastic surgical lung specimens, was used for comparisons of the patients' survival after surgery. When the crude mortality percentages at 1 and 2 years by AHH or EH activity, subdivided into quarters of the distribution, were calculated, a lower mortality was related to lower enzyme levels. Subjects in the 1st and 4th quarters of the distribution showed significant differences in their 1‐year survival for AHH (p = 0.05) and EH (p < 0.01) activities. This relationship could not be accounted for by age, cumulative lifetime smoking, recent or continuing smoking, stage or histological type of disease. Thus, the levels of pulmonary AHH and EH may have some prognostic significance in tobacco‐related lung cancer.
Myelopoiesis‐associated suppressor‐cell activity in mice with lewis lung carcinoma tumors: Interferon‐γ plus tumor necrosis factor‐α synergistically reduce suppressor cell activity
Authors: Young M. Rita I. , Young Melvin E. , Wright Mark A.
Published: February 2007

The myelopoietic stimulation which occurs in mice bearing metastatic Lewis lung carcinoma (LLC‐C3) tumors is accompanied by immune suppression and the appearance of myelopoiesis‐associated immune suppressor cells in the bone marrow and spleen. Low doses of recombinant murine interferon‐γ (IFN‐γ) plus recombinant human tumor necrosis factor‐α (TNF‐α) were used to limit myelopoiesis and, in turn, reduce the presence of myelopoiesis‐associated immune suppressor cells in LLC‐C3 tumor bearers. Neither IFN‐γ nor TNF‐α alone had any effect in vitro on the growth of myeloid progenitor cells into colonies or on the suppressive activity of bone‐marrow cells from LLC‐C3‐bearing mice. However, the combination of low doses of IFN‐γ and TNF‐α synergistically inhibited both the growth of myeloid progenitor cells into colonies and the suppressive activity of bone‐marrow cells from tumor‐bearers. Similar results were obtained in vivo. When used alone, neither IFN‐γ nor TNF‐α had any effect on myelopoiesis or on suppressor‐cell activity. When combined, IFN‐γ plus TNF‐α synergistically suppressed myelopoiesis and the presence of immune suppressive cells both in the bone marrow and in the spleen of tumor bearers. T‐lymphocyte blastogenic and NK cytotoxic activities of the tumor‐bearers were restored only after treatment with both IFN‐γ and TNF‐α.
Coincident implantation, growth and interaction sites within the liver of cancer and reactive hematopoietic cells
Authors: Vidal‐Vanaclocha Fernando , Alonso‐Varona Ana , Ayala Ricardo , Boyano Maria‐Dolores , Barberá‐Guillem Emilio
Published: February 2007

We have examined the anatomical‐functional sites within mouse liver where phenylhydrazine (PHZ)‐induced hematopoietic foci, and M5076 reticulum cell sarcoma, B 16F10 melanoma and Lewis lung‐carcinoma cells specifically develop as colonies after intrasplenic injection. Cancer foci occurred predominantly in the 2. 4 to 4. 0 segment of the sinusoidal pathway, corresponding to hepatic acinar zone I. No significant differences were detected between different types of tumor, including their different tendencies to spontaneously metastasize liver, or as a result of the different procedures used for obtaining foci or metastases. In addition, PHZ‐treatment of mice previously injected with tumor cells, resulted in double colonization of the liver tissue by both hematopoietic and cancer cells, predominantly in zone I. This spatial coincidence indicates that non‐cancer‐specific mechanisms operate in zone I, either promoting implantation and/or growth of cell colonies or, alternatively, inhibiting these processes in the region surrounding the central vein (Rappaport zone 3). Our observations failed to reveal mutual displacement of cancer or hematopoietic foci by potential competition for development sites in zone I. Enumeration and diameter measurements of cancer foci in PHZ‐treated animals showed that the presence of hepatic hematopoietic foci coincided with a significant increase in the hepatic metastasis volume. However, the fact that no significant differences in pulmonary metastases occurred in both the PHZ‐treated and control mice given tail‐vein injection of cancer cells, and that PHZ reduces cancer cell proliferation in vitro, reveal evidence of local interactions with hematopoietic foci which promote growth of cancer foci in liver.
Modulation of type‐iv collagenase activity and invasive behavior of metastatic human melanoma (A2058) cells in vitro by monoclonal antibodies to type‐iv collagenase
Authors: Höyhtyä Matti , Hujanen Erkki , Turpeenniemi‐Hujanen Taina , Thorgeirsson Unnur , Liotta Lance A. , Tryggvason Karl
Published: February 2007

Monoclonal antibodies (MAbs) against human type‐IV collagenase were developed and used for studies on enzyme activity and tumor‐cell invasion in vitro. Fifteen MAb clones were generated against the enzyme purified from serum‐free culture medium of human melanoma cells (A2058). Five clones affecting the activity of type‐IV collagenase were selected for further characterization. All the selected clones could be used for a single‐step purification of type‐IV collagenase using IgG‐Sepharose affinity columns. One of the antibodies activated the enzyme when 3H‐proline‐labelled type‐IV collagen was used as substrate. The activation was dependent on the enzyme antibody ratio. Four clones caused more than 30% inhibition of the activity, maximal inhibition being 50%. Interestingly, the same antibody which activated the enzyme also increased the invasion of A2058 cells through a reconstituted basement membrane in an in vitro invasion assay. The 4 inhibitory antibodies decreased the penetration of A2058 cells through the reconstituted basement membrane. The results strongly support previous findings about the importance of type‐IV collagenase in tumor‐cell invasion.
Characterization, in some human breast cancer cell lines, of gastrin‐releasing peptide‐like receptors which are absent in normal breast epithelial cells
Authors: Giacchetti Sylvie , Gauvillé Christiane , Crémoux Patricia De , Bertin Laurent , Berthon Philippe , Abita Jean‐Pierre , Cuttitta Franck , Calvo Fabien
Published: February 2007

The binding of 125I‐Tyr4 bombesin was investigated on plasma membranes of 8 human breast cancer cell lines and 2 long‐term cultures of normal human breast epithelial cells. Scatchard plots were compatible with high‐affinity, single‐site class of receptors in 3 cell lines (KD of 0.75 ± 10−9 and 10−9 M, Bmax of 0.75 ± 10−13 and 9.7 ± 10−13 M/mg protein in MDAMB231 and in T47D cells, respectively) while no binding was observed in 5 other cell lines and normal epithelial cells. The neuropeptide and its structural analogues (natural or synthetic) inhibited the binding of 125I‐Tyr4 bombesin in the following order of potency: gastrin‐releasing peptide (GRP, EC50 = 1.7 ± −10 M) > BIM 26159 > bombesin, Tyr4 bombesin > BIM 26147 > litorin > neuromedin C. In contrast, 125I‐Tyr4 bombesin binding was not displaced by neuromedin B, somatostatin, bradykinin and insulin. In agreement with our binding data, SDS‐PAGE of the complex 125I‐Tyr4 bombesin‐receptor covalently linked by ethylene glycol‐bis succinimidyl succinate (EGS) identified after autoradiography a single band with a molecular weight of 75,000, which disappeared in the presence of bombesin in excess. No transcription of either GRP or neuromedin B mRNA could be shown in tumor or normal cells. Exogenous gastrin‐releasing peptide had no effect on growth of the cell lines when a serum‐free medium was used, implicating that in breast cancer cell lines this receptor does not mediate growth but has a functional role.
Anti‐retrovirus activity of 9‐(2‐phosphonylmethoxyethyl)adenine (pmea) in vivo increases when it is less frequently administered
Authors: Balzarini Jan , Naesens Lieve , Clercq Erik De
Published: February 2007

Different treatment schedules have been investigated when evaluating the inhibitory effect of 9‐(2‐phosphonylmethoxyethyl)adenine (PMEA) and 3′ ‐azido‐2′, 3′ ‐dideoxythymidine (AZT) on the replication of human immunodeficiency virus type I (HIV‐1) in MT‐4 cells, transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV), and MSV‐induced tumor formation in newborn NMRI mice. Shortening the exposure time of HIV‐1‐infected MT‐4 cells to PMEA or AZT led to an increase in the selectivity index of both compounds. PMEA proved markedly more efficient in suppressing MSV‐induced tumor formation in mice when administered as a single dose on the day of infection than when these doses were spread over 2, 4 or 7 administrations within 1 week after the virus infection. This was not observed when the total dose of AZT was fractionated. While the infrequent dosage regimen increased the anti‐retrovirus activity of PMEA, it did not increase its toxicity for the host. This unique property makes PMEA an attractive candidate for the treatment of retrovirus infections, including AIDS.
Immuno‐isotachophoretic determination of monoclonal immunoglobulin light chains produced by neoplastic b‐cells: Use in diagnosis, monitoring and detection of residual disease
Authors: Abelev G. I. , Karamova E. R. , Bragina E. G. , Andreeva N. E. , Kruglova G. V.
Published: February 2007

We suggest that countercurrent isotachophoresis performed on cellulose acetate membranes (ITP‐CAM) should be used for detecting trace amounts of Bence‐Jones protein (BJP) in urine of patients with chronic lymphocytic leukemia (CLL), non‐Hodgkin's lymphoma (NHL) and related diseases. ITPCAM allows simultaneous concentration and electrophoretic separation of proteins present in highly diluted solutions, as well as easy immunological detection of separated substances. BJP was found in 24 out of 42 patients with CLL, 33 of 56 with NHL and 3 of 3 with Waldenstrom macroglobulinemia. Twenty‐three patients were followed during the course of chemo‐ or radiotherapy. In 19 cases the BJP findings correlated well with clinical status. In no case of partial or complete clinical response did BJP completely disappear from the urine.
Serum hyaluronan (hyaluronic acid) in breast cancer patients
Authors: Delpech Bertrand , Chevallier Bernard , Reinhardt Nadine , Julien Jean‐Pierre , Duval Christian , Maingonnat Catherine , Bastit Philippe , Asselain Bernard
Published: February 2007

Eighty‐three women with breast cancer (57 with systemic metastasis, 26 without) were investigated for serum hyaluronan (HA) and compared to 50 patients with benign diseases of the breast. Hyaluronan was significantly increased in sera of metastatic patients compared to sera of non‐metastatic patients (p < 0.0001) and also in sera of non‐metastatic patients when compared to control sera (p < 0.01). The difference was not related to the number of metastatic sites involved. Three months after starting cytotoxic chemotherapy in metastatic patients, lower HA concentrations were observed in patients responding to chemotherapy. The initial level of serum HA had no predictive value concerning response to chemotherapy.
Parathyroid hormone‐related protein and hypercalcemia in pancreatic neuro‐endocrine tumors
Authors: Rizzoli R. , Sappino A. P. , Bonjour J. ‐P.
Published: February 2007

We investigated the possible involvement of parathyroid hormone‐related protein (PTHrP) in 2 cases of metastatic pancreatic neuro‐endocrine tumors associated with severe hypercaicemia. Both patients displayed biochemical alterations in renal tubular reabsorption of calcium and phosphate, as well as in urinary cAMP excretion, similar to those encountered in primary hyperparathyroidism, although plasma levels of parathyroid hormone were within the normal range. Tumor protein extracts stimulated cAMP production, which was inhibited by the PTH‐antagonist (8,18 Nle, 34 Tyr)bPTH‐(3‐34)amide, in the PTH‐responsive osteoblastic cell line UMR‐106. Northern blot analysis of tumor extracts revealed the presence of PTHrP mRNA transcripts, while PTH mRNA was undetectable. In contrast, neither PTHrP mRNA(s) nor cAMP‐stimulating activity was detectable in other neuroendocrine tumors not accompanied by hypercaicemia. These results demonstrate that certain pancreatic neuroendocrine tumors associated with hypercaicemia can synthesize and release PTHrP.
Restriction fragment length polymorphism analysis of the l‐myc gene locus in a case‐control study of lung cancer
Authors: Tamai Seiichi , Sugimura Haruhiko , Caporaso Neil E. , Resau James H. , Trump Benjamin F. , Weston Ainsley , Harris Curtis C.
Published: February 2007

The L‐myc DNA‐restriction fragment length polymorphism, revealed by EcoRI, has been studied in both a lung cancer case‐control framework and a cohort of 40 nondiseased unrelated individuals. No association was found between the L‐myc allelic frequencies and disease status, tumor stage or lung cancer histology. A strong association was, however, observed between the L‐myc allelic frequencies and ethnic origin (black or white) of the subjects. Among American whites the allelic distribution at the L‐myc proto‐oncogene locus was almost identical to that previously reported for Japanese subjects. Among the American black population there was a significantly higher frequency of the presence of the polymorphic EcoRI restriction site in the second intron of the L‐myc proto‐oncogene. These data emphasize the importance of conducting epidemiologic studies that control for ethnic factors and indicate that L‐myc EcoRI allelotypes do not appear to be predictive of lung cancer risk or disease status in American blacks and whites.
Diet, living conditions and nasopharyngeal carcinoma in tunisia—a case‐control study
Authors: Jeannel D. , Hubert A. , De Vathaire F. , Ellouz R. , Camoun M. , Ben Salem M. , Sancho‐Garnier H. , De‐Thé G.
Published: February 2007

We conducted a case‐control study of nasopharyngeal carcinoma (NPC) in Tunisia, on diet, dietary patterns and life style, the characteristics of which had been defined by an anthropological study. Eighty incident cases, diagnosed in Tunisia between November 1986 and November 1987, were each matched for sex, age and place of residence to 2 controls. The subjects were asked for dietary data referring to the year preceding the diagnosis of NPC and, with help of their families, during childhood and after weaning. After adjustment for an empirical living conditions score, the following food items were found to be associated with an increased risk for NPC: preserved spiced meat (quaddid), basic stewing preparation (mixture of red and black pepper, garlic, oil, caraway and coriander), and harissa (red pepper, olive oil, garlic, caraway, salt) taken with bread as a snack during childhood and youth. Moreover, subjects who had been directly weaned from mother's milk on to an adult diet were found to be at higher risk for NPC.
Contributions of vascularized lymph‐node metastases to hematogenous metastasis in a rat mammary carcinoma
Authors: Weiss Leonard , Ward Pamela M.
Published: February 2007

Rats received hind‐foot‐web (FWI) injections of MT‐ 100‐TC mammary carcinoma cells; the resultant tumor metastasized first to the popliteal lymph nodes. Over the course of 4 weeks, in association with increases in tumor weight, the blood‐flow to the popliteal nodes increased 18‐fold, and their vascular densities increased 2‐fold. In spite of this vascularization, cancer cells were detected in only 3 of 648 blood vessels associated with involved, ipsilateral lymph nodes compared with intravascular cells in 82 of 314 vessels associated with “primary” foot‐pad lesions. The presence of tumorigenic cancer cells in the right ventricular blood of animals bearing these tumors is, therefore, considered to result from their direct entry into blood vessels from the “primary” lesions, and/or from extra‐nodal invasion of vessels in tissues to which nodal tumors were adherent, as distinct from passage via lymphatico‐venous communications between tumors and nodal blood‐vessels. The reconstructed events occurring in the rat model, with effective restriction of regional node metastases to the nodes themselves for a time, could possibly account for the long‐term survival of some patients with breast cancer and regional‐node metastases, following surgery.
Selection and characterization of human melanoma lines with different liver‐colonizing capacity
Authors: Ladányi A. , Timár J. , Paku S. , Molnár G. , Lapis K.
Published: February 2007

Two human melanoma lines with low (HTI68) and high (HTI 68‐MI) liver metastatic capacity in immunosuppressed mice were selected in vivo from the A2058 cell line. After i. v. injection of the 2 tumor lines there was no significant difference either in the number of lung colonies or in the frequency and tissue distribution of extrapulmonary tumor deposits. These findings suggest that the selection in the spleen‐liver system did not result in an overall increase in the metastatic potential of the melanoma cells, but rather that it represented an organ‐preferential selection. The HT168‐MI cells did not acquire an increased growth rate in vitro or in vivo, suggesting that other phenotypic alterations are responsible for the enhanced metastatic capacity. The 2 tumor lines were characterized by similar expression of HLA‐A, B, C, transferrin receptor and melanoma‐associated proteoglycan antigen. HT168 contained more NGF receptor, while HLA‐DR appeared only on HT 168‐MI cells. This human metastasis model could be useful in studying the mechanisms of liver metastasis formation, as well as in revealing possible new targets of antimetastatic therapy.
Anti‐tumor protection induced in mice by fatty acid conjugates: Alkyl butyrates and poly(ethylene glycol) dibutyrates
Authors: Wakselman Michel , Cerutti Italina , Chany Charles
Published: February 2007

Simple fatty acids, especially butyrate salts, have interesting biological properties, since they are able to down‐regulate cell growth and promote various differentiated cellular functions. Their use for anti‐tumor treatment is, however, hampered by their over‐rapid diffusion in the blood, followed by a short‐lived biological action. We have therefore devised conjugates linking butyrate with either (i) aliphatic alcohols of increasing carbon numbers ranging from C4 to C12 or (ii) poly(ethylene glycols) of increasing molecular weights. In both cases, the resulting butyric esters can be hydrolysed by esterases which can release biologically active subunits from the synthetic compounds. As shown in the present study, only one conjugate in each series gave satisfactory anti‐tumor protection: namely, I‐octyl butyrate and poly(ethylene glycol 1000) dibutyrate respectively. A single immune‐stimulatory injection of purified Corynebacterium parvum extract prior to administration of the conjugates significantly increased the anti‐tumor potency.
Anti‐tumor effects of interferon in mice injected with interferon‐sensitive and interferon‐resistant friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases
Authors: Gresser Ion , Maury Chantal , Carnaud Claude , De Maever Edward , Maunoury Marie‐Thérése , Belardelli Filippo
Published: February 2007

DBA/2 mice were injected i. v. with IFN α/β‐resistant 3C18 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN α/β treatment of FLC‐injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN α/β in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The antitumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC‐injected DBA/2 mice were treated with antibodies to asialo‐GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN α/β treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN‐induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN α/β in this experimental model.
Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor β1 and β2
Authors: Chakrabarty Subhas , Fan Dominic , Varani James
Published: February 2007

We have previously characterized the diversity of cellular responses to transforming growth factor (TGF)‐βI from human colon carcinoma cells. We now show that morphological alteration and part of the growth‐inhibitory responses elicited by growth factor (GF) are associated with the secondary effect of the induction of synthesis of extracellular matrix (ECM) glycoproteins. Specifically, morphological alteration is associated with the ECM glycoprotein laminin, and growth inhibition is associated with both laminin and fibronectin. Both TGF‐βI and TGF‐β2 down‐modulate the expression of nucleolar protein B23 (also known as numatrin or nucleophosmin, a positive regulator of cell proliferation).

With one exception, the biological effects of both TGF‐βI and TGF‐β2 on these human colon carcinoma cell lines are identical. Both GFs up‐modulate the expression of carcinoembryonic antigen (CEA) and CEA‐related gene products. However, some of these products are differentially regulated by TGF‐β1 and TGF‐β2. The differences in the profile of the induction of these CEA and CEA‐related gene products, in the responsive cells, functionally distinguish TGF‐β1 from TGF‐β2. Finally, we identified and characterized some of the cellular proteins, the expression of which is up‐modulated by GF. These proteins are epithelium‐associated, differentiation‐related cytokeratins. Both TGF‐β1 and TGF‐β2 up‐modulate expression of the acidic and basic subtypes of human keratins in the responsive human colon carcinoma cells. Both the responsive and unresponsive cells, however, possess receptors for GFs.
Human melanoma cells with high susceptibility to cell‐mediated lysis can be identified on the basis of icam‐1 phenotype, vla profile and invasive ability
Authors: Anichini Andrea , Mortarini Roberta , Supino Rosanna , Parmiani Giorgio
Published: February 2007

Marked heterogeneity for susceptibility to lysis by autologous CTL clones and allogeneic IL‐2‐activated CD3‐ and CD3+ lymphocytes was found among 19 clones isolated from a human metastatic melanoma (Me665/2). A subset of 5 clones with the highest susceptibility to lysis had increased ICAM‐1 antigen expression. Phenotype analysis for the presence of extracellular matrix receptors in the β1‐ and β3‐integrin families revealed that the tumor clones with the highest susceptibility to lysis were also characterized by frequent expression or increased expression of multiple receptors in the β1 family including VLA‐1, ‐2, ‐3, ‐4 and ‐6. The correlation between phenotypic markers and susceptibility to lysis, seen at the clonal level, was confirmed by selection experiments on the uncloned metastasis Me665/2. In fact, the neoplastic population surviving 3 cycles of immunoselection with IL‐2‐activated lymphocytes exhibited, in comparison to the unselected metastasis: (1) reduced susceptibility to lysis and (2) reduced expression of ICAM‐1 and of VLA antigens. In contrast, enhanced susceptibility to lysis and up‐regulation of ICAM‐1, VLA‐1 and VLA‐3 antigens were observed on melanoma cells recovered after invading a reconstituted basement membrane. These data indicate that melanoma cells with enhanced susceptibility to cell‐mediated lysis can be identified on the basis of phenotypic characteristics (ICAM‐1 and VLA antigen profile) and functional features (invasive ability on reconstituted basement membranes).
Hormone sensitivity in vitro and in vivo of v‐ras‐transfected mcf‐7 cell derivatives
Authors: Van Roy F. , Mareel M. , Vleminckx K. , Beyaert R. , Fiers W. , Devleeschouwer N. , Muquardt C. , Legros N. , Bracke M. , Leclercq G.
Published: February 2007

Human mammary carcinoma cell lines (MCF‐7) were analysed for their hormone sensitivity before and after transfection with a v‐Ha‐ras oncogene or with a neomycin‐resistance gene followed by selection in vitro or in vivo. Our aim was to test how the expression of the ras oncogene would influence the estradiol sensitivity of MCF‐7 cells. In culture, MCF‐7 cells expressing the viral p21 oncogene product, as compared to parental MCF‐7 cells and their control derivatives, showed lower levels of a 67‐kDa estrogen receptor. Progesterone receptors, however, remained sensitive to up‐regulation by estrogens. The oncogene‐expressing cells were less sensitive than all controls to stimulation of proliferation by 10‐8M estradiol or to inhibition of proliferation by 2‐CH3‐4‐OH tamoxifen, and this was not dependent upon the type of culture medium used. After s. c. or i. p. injection into female athymic nude mice, ovariectomized or left intact, the growth of MCF‐7 cells expressing the ras oncogene product and of all control cells was sensitive to stimulation by estrogen supplementation. Conversely, cell lines derived from tumors generated with long latency in untreated athymic nude mice by v‐ras‐expressing MCF‐7 cells showed efficient formation of quickly growing tumors in the absence of estrogen supplementation. No differences were observed in invasion and metastasis of the different MCF‐7 cell types injected into athymic nude mice that were supplemented with estrogens or not.
Inflammation and anti‐tumor resistance. V. Production of a cytostatic factor following cooperation of elicited polymorphonuclear leukocytes and macrophages
Authors: Hevin Marie‐Brigitte , Friguet Bertrand , Fauve Robert M.
Published: February 2007

When Lewis tumor cells (3LL) included in a gel of polyacrylamide microbeads are injected into mice and recovered I day later, incorporation of 125I‐UdR is strongly reduced. In contrast, no reduction is observed in irradiated mice. The cytostatic effect is non‐existent in 6 hr‐old granuloma (granulocytes 909%, macrophages 10%), but is maximal in 48 hr‐old granuloma (granulocytes 50%, macrophages 50%). When 6 hr‐old granuloma cells (which are not cytostatic) are incubated with bone‐marrow‐derived macrophages (BMs) (which are slightly cytostatic), considerable cytostasis against 3LL is observed, such an effect being strongly reduced if the 2 cell populations are separated. This suggests that close contact of live polymorphs with macrophages is necessary for full expression of cytostasis. No increase in cytostasis of bonemarrow macrophages is observed when BMs are incubated with a cell‐free extract of freeze‐thawed 6‐hr‐old granuloma cells. Cell contact is not necessary between granuloma cells and 3LL since the cytostatic activity is found in the supernatant of incubated phagocytic cells. Cytostasis is also observed with B16, P815, J774 cells and normal mouse bone‐marrow cells. An active cytostatic fraction has been purified from the supernatant of 48‐hr‐old granuloma cells following molecular filtration and HPLC. The cytostatic factor has a low molecular weight (400–500 daltons), is not a peptide and presents maximum absorption at 267 nm.
The use of clonogenic assays in assessing the response of human lung cancer cell lines to α and γ interferons alone or in combination with adriamycin
Authors: Jabbar S. A. B. , Twentyman P. R.
Published: February 2007

The antiproliferative and cytotoxic effects of purified IFN‐α and recombinant IFN‐γ were investigated using both direct cell counting and a clonogenic assay on a panel of 5 established human lung cancer cell lines and for 2 of them also on their multidrug‐resistant counterparts. There was considerable heterogeneity in the response of the cell lines to the IFNs in terms of growth inhibition. Clonogenic assay of IFN‐treated cells indicated that, where a cell line had responded markedly to an IFN, only a small fraction of the cells remaining after IFN treatment were clonogenically viable. When cells were placed into the clonogenic assay in the presence of IFNs, the time course of colony formation was different from that seen in the control cultures for most of the cell lines. The measured “surviving fraction” was greatly dependent upon the time of colony counting. When the effects of IFNs in combination with ADM were studied, conclusions regarding the interaction of the effects of the agents also depended upon the time at which colonies were counted.
Specific chromosomal mutagenesis observed in stimulated lymphocytes from patients with S‐ANLL
Authors: Mamuris Zissis , Dumont Jeanine , Dutrillaux Bernard , Aurias Alain
Published: February 2007

An analysis of R‐banded PHA‐stimulated lymphocytes from 13 patients with secondary acute non‐lymphocytic leukemia (S‐ANLL) following breast cancer or lymphoma, and treatment by alkylating agents and/or radiotherapy, is reported. We found that chromosomes 5, 7, 11 and 17 are over‐involved in structural rearrangements. These anomalies are similar to those observed in the same categories of patients without S‐ANLL, and after in vitro treatment of normal lymphocytes by the alkylating agent melphalan. These anomalies are thus likely to be induced by treatment, independently of S‐ANLL. However, the same chromosomes (5, 7, 11 and 17) are recurrently deficient in leukemic S‐ANLL clones. In spite of these similarities, it remains unlikely that the deficiencies observed in leukemic clones were directly induced at the time of treatment. Probably, treatment of primary cancers induces nonrandom mutations of recessive genes located on these chromosomes as also indicated by chromosomal lesions. Various rearrangements including deletions of the homologous normal counterparts may then occur, unmasking mutated recessive genes. The latter stage would be concomitant with the leukemogenic process.
Gastrin‐releasing peptide in normal and neoplastic human lung: Measurement and biochemical characterization
Authors: McKillop Jane M. , McCann John P. , Gibbons John R. P. , Johnston Colin F. , Buchanan Keith D.
Published: February 2007

Levels of gastrin‐releasing peptide (GRP) were determined by radioimmunoassay in human normal main and lobar bronchus and parenchymal lung tissue extracts. It was found that the level of GRP differed significantly between all 3 areas. The concentration of GRP was statistically higher in main bronchus (median 6.74 ng/g) compared to both lobar bronchus (median 4.79 ng/g) and parenchymal lung (median 1.73 ng/g), and also statistically higher in lobar bronchus compared to parenchymal lung. Chromatographically, GRP‐immunoreactivity in both main and lobar bronchial extracts corresponded to GRP1‐27 and GRP18‐27, while in lung tissue only one major species was identified which corresponded in retention time to GRP18‐27. No significant difference was detected when the levels of GRP in normal lobar bronchus and normal lung tissue were compared to the levels in lobar bronchus and lung taken from patients with lung carcinoma, at a site adjacent to the carcinoma. However, a significant difference was observed between the GRP content of normal main bronchus compared to main bronchus from patients with carcinoma. GRP was measured in 26/56 lung carcinomas examined. The levels ranged from 42,000 ng/g in a carcinoid tumour to 0.18 ng/g in a squamous‐cell carcinoma, though only in 6 tumours were the levels outside the range determined for normal pulmonary tissue. Chromatography of selected tumour extracts of different histopathologies showed that there were differences in the GRP products present.
Age at first birth, parity and risk of breast cancer: A meta‐analysis of 8 studies from the nordic countries
Authors: Ewertz Marianne , Duffy Stephen W. , Adami Hans‐Olov , Kvåle Gunnar , Lund Eiliv , Meirik Olav , Mellemgaard Anders , Soini Irma , Tulinius Hrafn
Published: February 2007

Several large epidemiological studies in the Nordic countries have failed to confirm an association between age at first birth and breast cancer independent of parity. To assess whether lack of power or heterogeneity between the countries could explain this, a meta‐analysis was performed of 8 population‐based studies (3 cohort and 5 case‐control) of breast cancer and reproductive variables in the Nordic countries, including a total of 5,568 cases. It confirmed that low parity and late age at first birth are significant and independent determinants of breast‐cancer risk. Nulliparity was assoclated with a 30% increase in risk compared with parous women, and for every 2 births, the risk was reduced by about 16%. There was a significant trend of increasing risk with increasing age at first birth, women giving first birth after the age of 35 years having a 40% increased risk compared to those with a first birth before the age of 20 years. Tests for heterogeneity between studies were not significant for any of the examined variables. In the absence of bias, this suggests that several individual Nordic studies may have had too little power to detect the weak effect of age at first birth observed in the meta‐analysis.
Western blot analysis of serological responses following immunization with vaccinia viral lysates of melanoma cells
Authors: Hersey P. , Werkman H. , Edwards A. E.
Published: February 2007

Western blot analysis was used to characterize the antibody response of melanoma patients during immunization with vaccinia‐virus‐induced melanoma cell lysates (VMCL). Strong antibody responses were detectable within 4 weeks from commencement of immunization against different fractions (from 3 to 10) in blots of VMCL. The approximate MW of the main fractions identified were 100, 91, 85, 77, 64‐66, 49, 46, 43 and 34‐36 kDa. Comparison of the reactivity of the sera with extracts of vaccinia virus suggested that the reactivity against VMCL was not against viral antigens in the lysates. Studies on autologous extracts from 7 patients immunized with VMCL indicated that the majority of the fractions identified in extracts of VMCL were also identified in autologous extracts of melanoma cells. This indicated vaccine‐induced responses against the patients' tumor cells and not merely against alloantigens in the vaccine. Sera from the immunized patients appeared to identify a number of fractions of similar MW in extracts of colon and glioma cells, suggesting that the responses were not specific for melanoma. Possible exceptions were reactivity against melanoma fractions of 85, 64‐66 and 36 kDa. Our studies provide evidence for the effectiveness of VMCL in inducing antibody responses against autologous melanoma cells and form a basis for subsequent biochemical and genetic analysis of the antigens identified by antibody responses in immunized patients.
Induction of macrophage procoagulant expression by cisplatin, daunorubicin and doxorubicin
Authors: Wheeler Helen R. , Geczy Carolyn L.
Published: February 2007

Cisplatin, doxorubicin and daunorubicin (drugs which intercalate with DNA) influenced the membrane‐bound procoagulant potential of murine thioglycollate‐induced peritoneal exudate (TG‐PEC) macrophages and the monocytoid cell line WEHI 265, whereas the antimetabolites 5‐fluorouracil and methotrexate had no effect. Enhanced procoagulant was not caused by non‐specific toxicity of these agents. Cisplatin directly increased the procoagulant expressed on WEHI 265 cells, whereas MPCA on TG‐PEC was enhanced only when cisplatin was combined with a second stimulant, either bacterial lipopolysaccharide (LPS) or interferon (IFNγ). WEHI 265 cells failed to respond to the anthracycline drugs, either alone or in combination with LPS, whereas they enhanced the IFNγ response. Doxorubicin and daunorubicin increased the LPS response of TG‐PEC by approximately 4‐fold and the IFNγ response by approximately 10‐fold. Pulsing experiments suggested that the anthracyclines enhanced procoagulant expression by a mechanism different from cisplatin. Daunorubicin primed TG‐PEC within 4 hr to respond to low levels of LPS, whereas either LPS or cisplatin primed these cells to respond to cisplatin or LPS respectively. Furthermore, the procoagulant expressed by TG‐PEC stimulated by LPS/cisplatin had properties of tissue factor (TF: 50% total activity) and Factor VIIa (50% total procoagulant)‐like activities, whereas the predominant procoagulant on LPS/anthracycline activated TG‐PEC was TF‐like (70% total activity) with weak Factor VIIa and prothrombinase‐like properties.
Effect of plasma gangliosides on the growth of ehrlich ascites tumor
Authors: Saha Sandip , Ghosh Asit
Published: February 2007

Total plasma gangliosides of Ehrlich ascltes tumor‐bearing mice enhanced tumor growth when adoptively transferred with the same tumor cells in mice. However, individual gangliosides acted differently. Out of 6 gangliosides separated from plasma, 2 components enhanced tumor growth, whereas the remaining 4 inhibited tumor growth, Neither of the 2 enhancing components in various combinations with the 4 inhibitory components could restore the enhancing effect. The enhancing effect was restored only when both the enhancing components were mixed with the remaining 4 ganglioside components, i. e., with full/complete reconstitution.
Hyperplasia of mouse duodenal crypts and its control by NK cells during the initial phase of DMH carcinogenesis
Authors: Altmann G. G. , Parhar R. S. , Lala P. K.
Published: February 2007

The possible regulatory role of NK cells on early events in chemical carcinogenesis remains undefined. The present study examined whether NK cells control 1, 2‐dimethylhydrazine (DMH)‐induced hyperplasia of the duodenal crypt in CD, mice. Mice receiving chronic DMH treatment showed a dose‐dependent hyperplasia confined to the proliferative zone, with a parallel increase in mitotic and 3H‐TdR‐labelled cells and significant suppression of splenic NK activity. Complete ablation of splenic NK activity with anti‐asialo GM‐1 antibody (αAGM‐1) treatment slightly enhanced hyperplasia. Halving of the DMH dose for 2 weeks led to regression of hyperplasia, which was totally prevented by αAGM‐1 treatment. The αAGM‐1 treatment alone did not influence crypt size in normal mice. Finally, a stimulation of NK activity with Poly I:C treatment in DMH‐treated mice caused regression of the DMH‐induced hyperplasia. Our results suggest that hyperplastic cells with possible genetic alterations induced by the carcinogen express target structures for NK cells, but that simultaneous carcinogen‐induced suppression of NK activity hampers their containment, allowing progression of hyperplasia to neoplasia, possibly owing to additional genetic changes.
Detection of ebv gene expression in reed‐sternberg cells of Hodgkin's disease
Authors: Wu Tzyy‐Choou , Mann Risa B. , Charache Patricia , Hayward S. Diane , Staal Steve , Lambe Beverly C. , Ambinder Richard F.
Published: February 2007

EBV DNA has been detected by Southern blot hybridization in 20‐25% of Hodgkin's disease tumor specimens and localized to the Reed‐Sternberg cells by in situ hybridization. In the present investigation we used a 3H‐labelled EBER I anti‐sense RNA for in situ hybridization of archival formalinfixed paraffin‐embedded Hodgkin's disease specimens previ ously shown by Southern Blot hybridization to be EBV‐positive. In 6 of 8 specimens neoplastic cells showed an intense signal in virtually all of the tumor cells. The background lym phocytes, eosinophils, plasma cells and histiocytes did not demonstrate significant hybridization. In each case hybridiza tion tended to spare the nucleoli. Hybridization was detected in specimens with histologies of mixed cellularity and nodular sclerosis. The intensity of signal relative to background is bet ter than that in previous studies utilizing 35S‐labelled large internal repeat probes for EBV in Reed‐Sternberg cells. The exposure time is one week in contrast to the 4‐5 weeks reported by others for detection of EBV in Hodgkin's disease. Both increased relative intensity and shorter exposure re quirements may be attributed to the very high number of EBER transcripts in the target cells. The demonstration that EBER I is expressed is consistent with a role for EBV in growth regulation of Reed‐Sternberg cells and suggests that the virus is not merely a silent passenger in Hodgkin's disease.
Chromosome aberrations induced by etoposide (VP‐16) are not random
Authors: Maraschin Joëlle , Dutrillaux Bernard , Aurias Alain
Published: February 2007

The clastogenic effect of etoposide, an anti‐cancer chemotherapeutic drug, was investigated in vitro on lymphocytes of 5 healthy donors. The analysis of the first division metaphases arising after mutagenesis in G1, phase shows that chromosome‐type aberrations are much more frequent than chromatid‐type lesions. The distribution in relation to chromosome lengths of the 439 breakpoints that were accurately identified is not random: chromosomes I, II and 17 are most frequently involved, while chromosomes 4, 5 and × are seldom affected. This non‐random distribution may be related to chromosome structure, since R‐band‐rich chromosomes are significantly more affected than G‐band‐rich chromosomes.