bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential in vitro sensitivity of human tumor and normal cells to chemotherapeutic agents and resistance modulators
Authors: Nygren Peter , Larsson Rolf
Published: February 2007

The intrinsically Vincristine(Ver)‐resistant human kidney adenocarcinoma cell line ACHN, the human acute lympho‐blastic leukemia cell line L0, Its more‐than‐100‐fold Ver‐resistant subline L100, normal human fibroblasts and lymphocytes, also tumor cells from patients with chronic lymphocytic leukemia (CLL), acute myeloblastic leukemia (AML) and solid tumors, were compared for sensitivity to cytotoxic drugs and resistance modulators (RMs). The L100 cells showed pronounced sensitivity to the RMs verapamil (Ver), cyclosporin A (CsA) and buthionine sulfoximine (BSO) alone as well as to clsplatinum, whereas the L0 and ACHN cells, also slowly growing fibroblasts and non‐proliferating lymphocytes, were considerably less sensitive. Compared with AML cells and lymphocytes, CLL cells were more sensitive to Ver and CsA alone. The cytotoxlcity of Vcr was significantly increased in the Vcr‐resistant ACHN and L100, but also in sensitive L0 cells by Ver and CsA, with smaller effects on Dox and Vp‐16 toxicity. Fibroblasts and lymphocytes were generally resistant to the cytotoxic agents and RM addition had only minor effects. CLL cells were more sensitive to Dox and Ver as compared with normal lymphocytes, with potentiation of the Ver effect by Ver and CsA. The Ver effect in non‐proliferating Vcr‐resistant cells from a malignant schwannoma was potentiated by Ver and CsA, which had no effect in cells from a kidney adenocarcinoma. We conclude that cytotoxlcity of RMs alone is not dependent on the proliferation rate of tumor cells and that potentiation of cytotoxic drugs by RMs may be selective for tumor cells irrespective of their initial level and mode of drug resistance.
Attenuating effect of the monoamine oxidase inhibitor furazolidone on the anti‐carcinogenetic effect of cysteamine on gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in Wistar rats
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Baba Miyako , Taniguchi Haruo
Published: February 2007

The effect of furazolidone on inhibition by cysteamine of gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nltrosoguanidine (MNNG) was investigated in inbred Wistar rats. After oral treatment with MNNG for 25 weeks, rats received cysteamine, furazolidone, or both compounds. In week 52, rats treated with cysteamine had a significantly decreased incidence of gastric cancers. Concomitant treatment with furazolidone significantly attenuated the inhibitory effect of cysteamine on gastric carcinogenesis. Administration of furazolidone alone significantly increased the number, but not the incidence, of gastric cancers. The norepinephrine concentration of the antral portion of the gastric wall and the labelling index of the antral mucosa were significantly reduced in rats treated with cysteamine, and significantly higher in rats treated with both compounds than in those treated with cysteamine alone. These findings indicate that the cysteamine‐induced inhibition of gastric carcinogenesis is mediated by catecholamlnes.
Production of a recombinant human T‐cell leukemia virus type‐I trans‐activator (tax1) antigen and its utilization for generation of monoclonal antibodies against various epitopes on the tax1 antigen
Authors: Tanaka Yuetsu , Yoshida Atsushi , Tozawa Hideki , Shida Hisatoshi , Nyunoya Hiroshi , Shimotohno Kunitada
Published: February 2007

A 42‐kDa recombinant protein, PX141, consisting of the trans‐activator protein encoded by human T‐cell leukemia virus (HTLV‐I) (tax, antigen) and the amino‐terminal fusion peptide of 12 amino acid residues of the a‐peptide encoded by the plasmid pUC19 was produced. In order to investigate the immunogenicity of the tax, antigen, mice were immunized with the purified PX141 and 4 anti‐tax, monoclonal antibodies (MAbs) designated TAXY‐I, TAXY‐6, TAXY‐7 and TAXY‐8 were generated, and their reactivity was characterized along with another anti‐tax, MAb, Lt‐4. Immunoblot assays showed that all the MAbs reacted with the PX141, the native tax, antigen expressed in various HTLV‐I‐infected cell lines and the gp68 of MT‐2 cells expressing the tax, amino acids 94–353. Immunoblot assays using recombinant, truncated tax, antigens, XD59 (expressing amino acids 180–338) and XD128 (expressing amino acids 1–47 and 286–353) showed that: (I) TAXY‐I and Lt‐4 did not react with either antigen; (2) TAXY‐6 and TAXY‐8 reacted with only XD128; and (3) TAXY‐7 reacted with both. In addition, TAXY‐I, but not the other MAbs, reacted with a putative tax antigen of an STLV‐I‐infected cell line, designated RfM26‐I. Competitive binding assays showed that TAXY‐6 and TAXY‐8 did not compete against each other. Sera from HTLV‐I‐infected humans interfered with the binding of all of these anti‐tax, MAbs. These results indicate that the tax1 antigen and the PX141 express at least 5 distinct epitopes recognized by human and mouse antibodies.
Epidemiological and clinical correlations with genetic characteristics of Wilms' tumor: Results of the Brazilian Wilms' tumor study group
Authors: Franco Eduardo L. , de Camargo Beatriz , Saba Leda , Marques Lourdes A. ,   Brazilian Wilms' Tumor Study Group
Published: February 2007

The epidemiological and clinical features of Wllms' tumor (WT) were analyzed in 176 patients admitted to the Brazilian WT Study Group. The occurrence of congenital anomalies (9.1%) and the M:F ratio (0.83) were comparable to those observed by the US National WT Study and the International Society of Pediatric Oncology trials. Bilateral cases were younger on average than unilateral cases (37.2 vs. 45.0 months). Ethnic group and gender were also associated with age, with non‐white children being generally older (46.1 months) than whites (39.5 months), and boys being younger than girls (37.0 vs. 44.1 months). However, the most important factor in association with age at diagnosis was disease stage. No early disease patients were diagnosed after 8 years of age (mean: 37.S months), whereas 10% of those with advanced disease were diagnosed between the ages of 8 and 10 years (mean: 56.3 months). There were no clear distinctions in age distributions on the basis of the presence of tumor multicentrlcity, intra‐or perilobar nephroblastomatosis, and of a combination of putative genetic determinants. The mean age at diagnosis for cases with congenital defects was higher than that for the remaining patients. Some of the study results are in support of the recessive oncogene model for WT. However, the possible confounding effect of disease stage and the strong Interdependence of the remaining factors may be masking important relations in regard to mutational events occurring during embryogenesis.
Detection of anti‐epstein‐barr‐virus transactivator (ZEBRA) antibodies in sera from patients with nasopharyngeal carcinoma
Authors: Joab Irène , Nicolas Jean‐Claude , Schwaab Guy , de‐Thé Guy , Clausse Bernard , Perricaudet Michel , Zeng Yi
Published: February 2007

The Epstein‐Barr virus (EBV) is a ubiquitous Herpes virus which causes infectious mononucleosis and is associated with such different neoplasms as Burkitt's lymphoma and nasopharyngeal carcinoma. EBV latently infects its target cells; nevertheless, evidence of viral replication in NPC tumours has been uncovered. Among the EBV transactivators, the ZEBRA protein plays a crucial role in switching the virus from a latent to a productive mode. ZEBRA protein was produced using a eukaryotlc expression vector: the open reading frame containing the BZFLI cDNA has previously been inserted downstream from the adenovirus major late promoter leading to expression of a 38‐kDa nuclear protein. We performed serological studies by employing ZEBRA protein expressed in human cells for immunofluorescence and Western‐blot assays. We were able to detect IgG anti‐ZEBRA antibodies (IgG/ZEBRA) in 87% of NPC patients. These antibodies were absent in control sera; IgG/ZEBRA antibodies can be proposed as a useful marker for diagnosis of NPC tumors.
A cell line (LIM 2463) derived from a tubulovillous adenoma of the rectum
Authors: Whitehead Robert H. , van Eeden Pauline , Lukeis Robyn E.
Published: February 2007

We describe a new epithelial cell line (LIM 2463) derived from tubulovillous adenoma of the rectum. The cells grow as organoids and secrete large amounts of mucus. The cells are polarized, with a microvillar brush border, and express dipeptidyl peptidase IV in a polarized manner. No staining was seen with 3 other antibodies directed against other brush‐border hydrolases or disaccharidases. Focal polarized staining was obtained with 2 antibodies directed against other brush‐border‐associated peptides. The cells are aneuploid with a distinctive karyotype (48, XX, +9, +13). All attempts to clone the cells in semi‐solid agar or to grow them as xenografts in nude athymic mice have failed.
Establishment from a human chondrosarcoma of a new immortal cell line with high tumorigenicity in vivo, which is able to form proteoglycan‐rich cartilage‐like nodules and to respond to insulin in vitro
Authors: Takigawa Masaharu , Pan Hai‐Ou , Kinoshita Akihiro , Tajima Koji , Takano Yoshiro
Published: February 2007

The human chondrosarcoma cell line (HCS‐2/8) established by our group expresses cartilage phenotypes such as production of cartilage‐type proteoglycans and collagen type II, but its tumorigenicity is low. To develop an in vitro experimental system for studies of human chondrosarcomas, a new immortal cell line of human chondrosarcoma, named HCS‐2/A, was established from the same tumor. HCS‐2/A cells proliferated with a doubling time of 3° days in a medium containing 20% fetal bovine serum (FBS). This growth rate was comparable to that of HCS‐2/8 cells. However, HCS‐2/A cells proliferated more rapidly than HCS‐2/8 cells in the presence of 2–10% FBS. Like HCS‐2/8 cells, HCS‐2/A cells had a polygonal shape in sparse cultures and became spherical as they reached confluence, after which they formed nodules composed of multi‐layered cells and a large quantity of extracellular matrix showing strong metachromasia. The nodules formed by HCS‐2/A cells were thicker and also larger in diameter than those formed by HCS‐2/8 cells. Electron microscopically, the cells in the nodules resembled chondrocytes in vivo, but each cell had an irregular‐shaped nucleus which is a characteristic of tumor cells. The cells actively synthesized “cartilage‐specific” large proteoglycans and their level of proteoglycan synthesis was comparable to that of HCS‐2/8 cells. Insulin, which stimulates proteoglycan and DNA syntheses in cultured chondrocytes, markedly Increased proteoglycan synthesis in HCS‐2/A cells. On the other hand, the hormone only slightly increased proteoglycan synthesis in HCS‐2/8 cells. Insulin also stimulated DNA synthesis in cultured HCS‐2/A cells, but not in HCS‐2/8 cells. Immunostaining revealed that HCS‐2/A cells produced type‐11 collagen but not type‐1 collagen. However, the level of collagen synthesis of HCS‐2/A cells was lower than that of HCS‐2/8 cells. Inoculation of HCS‐2/A cells into athymic mice resulted in the formation of chondrosarcomas that grew faster than those arising from HCS‐2/8 cells.
Localization of monoclonal antibody G250 and bispecific monoclonal antibody CD3/G250 in human renal‐cell carcinoma xenografts: Relative effects of size and affinity
Authors: van Dijk J. , Zegveld S. Th. , Fleuren G. J. , Warnaar S. O.
Published: February 2007

A study was made of the relative effects of size and binding strength of various forms of the monoclonal antibody (MAb) G250, reacting with primary and metastatic human renal‐cell carcinoma (RCC), on the localization in human RCC xenografts in nude mice. Preferential tumor localization was demonstrated after injection of 1251‐labelled intact IgG, with increasing tumor/non‐tumor ratios in time. Approximately 27.4% of the injected dose/gram (%ID/g) was localized in the xenograft 24 hr post‐injection. A control MAb did not preferentially localize in xenografts. With F(ab′), fragments, higher tumor/blood ratios were obtained, although a lower percentage of injected dose per gram was bound to the tumor, 24 and 48 hr post‐injection. Using a bispecific MAb CD3/G250 F(ab′)2 fragment, which reacts with CD3 on human T lymphocytes and binds monovalently to RCC, an enhanced accumulation in tumor tissue was also observed. The %ID/g tumor obtained with bispecific CD3/G250 F(ab′)2 was comparable with %ID/g tumor found with G250 F(ab′)2. The 10‐fold lower binding affinity to RCC compared with intact IgG or F(ab′)2 had only marginal effects on %ID/g tumor. These results show that MAb G250 preferentially localizes to RCC xenografts. Because injection of F(ab′)2 fragments resulted in higher tumor/non‐tumor ratios, G250 F(ab′)2 may therefore be more suitable for diagnostic evaluation of RCC in patients. The tumor uptake is more dependent on size than on affinity. Furthermore, the data obtained with bispecific MAb CD3/G250 F(ab′)2 support the hypothesis that this bispecific MAb may be able to target cytotoxic T lymphocytes to RCC in humans to mediate destruction of RCC.
A novel recombinant tumor necrosis factor‐alpha mutant with increased anti‐tumor activity and lower toxicity
Authors: Nakamura Satoshi , Kato Arata , Masegi Tsukio , Fukuoka Masami , Kitai Kazuo , Ogawa Hiroko , Ichikawa Yataro , Maeda Masahiro , Watanabe Naoki , Kohgo Yutaka , Niitsu Yoshiro
Published: February 2007

We prepared a novel recombinant tumor necrosis factor‐α (TNF) mutant (mutant 471), in which 7 N‐terminal aminoacids were deleted and Pro8Ser9Asp10 was replaced by ArgLysArg, and compared its biological activity with that of wild‐type recombinant TNF. Mutant 471 had a 7‐fold higher anti‐tumor activity against murine L‐M cells in vitro, and a higher binding activity to TNF receptors on L‐M cells, than wild‐type TNF. Furthermore, mutant 471 showed a higher anti‐tumor effect on murine Meth A‐HM tumors transplanted Into BALB/c mice, with complete regression of the tumors being observed in the animals. The possible cachectin activity of mutant 471 was almost the same as that of wild‐type TNF. The acute lethal toxicity of mutant 471 in β‐D‐galactos‐amine‐sensitized C3H/HeJ mice was 18 times lower than that of wild‐type TNF. These results suggest that mutant 471 might be a more promising anti‐cancer agent than wild‐type TNF.
The effects of γ‐interferon combined with 5‐fluorouracil or 5‐fluoro‐2′‐deoxyuridine on proliferation and antigen expression in a panel of human colorectal cancer cell lines
Authors: Maas Ingrid W. H. M. , Boven Epie , Pinedo Herbert M. , Schlüper Hennie M. M. , Haisma Hidde J.
Published: February 2007

Gamma‐lnterferon (IFN‐γ) and the antimetabolites 5‐fluorouracil (5‐FU) and 5‐fluoro‐2′‐deoxyuridine (FUdR) were investigated as individual agents and in combination for their In vitro antiproliferative capacity and for their effect on the expression of HLA class‐1 antigen, carcinoembryonic antigen (CEA) and the intracellular tumor‐associated antigen CTA‐I In 7 human colorectal cancer cell lines: WiDr, HT29, Colo 205, SW1116, LS174T, SW1398, and LoVo. Growth inhibition by IFN‐γ at clinically relevant concentrations (50–100 U/ml) was found in 4/7 cell lines. The cell lines were equally sensitive to 5‐FU (IC50, in a range of 2–10 μM), while sensitivity to FUdR varied considerably (IC50 in a range of 0.01–90 μM). When 50 U/ml IFN‐γ were combined with 5‐FU or FUdR, the antiproliferative effects were synergistic in those cell lines with sensitivity to IFN‐γ as a single agent, but not in the IFN‐γ‐insensitive cell lines. IFN‐γ was able to enhance the expression of HLA Class I and CEA in 4/7 and 3/7 cell lines, respectively, as measured by flow cytometry. CTA‐1 expression could not be enhanced with IFN‐γ. The expression of the 3 antigens tested was also increased by 5‐FU and FUdR. This effect was concentration‐dependent in most instances and varied between the individual cell lines. The combination of 50 U/ml IFN‐γ with 25% growth‐inhibitory concentration of 5‐FU or FUdR for each cell line resulted in an additional increase in antigen expression in 4/7 cell lines. No relation was found between the enhancement of antigen expression and the sensitivity to IFN‐γ or the anti‐metabolites. The enhancement in antigen expression also did not show a relationship with changes in cell‐cycle distribution upon exposure to IFN‐γ or the anti‐metabolites. These results suggest independent mechanisms for the antiproliferative and antigen‐enhancing effects of IFN‐γ, 5‐FU and FUdR.
Comparison of serological expression of different epitopes on the CA50‐carrying antigen CanAg
Authors: Johansson Christina , Nilsson Olle , Lindholm Leif
Published: February 2007

C203 and C242 are mouse monoclonal antibodies (MAbs) generated using a human colon carcinoma cell line. They recognize novel tumour‐associated epitopes present in elevated levels in sera from patients with colon and pancreatic cancer. These epitopes were found to be co‐expressed with sialylated Lewis2 on the CanAg molecule. To study the association and distribution of the epitopes of CanAg in sera, these new antibodies, together with C50, were used in different combinations in time‐resolved fluoroimmunoassays. Relative serum concentrations were examined in patients with various types of carcinoma and in patients with ulcerative colitis and benign pancreatic, and hepatobiliary diseases. A double‐determinant assay using C50 and C242 was shown to distinguish carcinoma from benign biliary and hepatocellular diseases better than a single‐determinant assay based on C50 as both catching and tracing antibody. The number of sera with elevated CanAg levels from patients with benign obstructive biliary disease was 17 out of 29 using the single‐determinant CASO assay. This was reduced to 4 out of 29 in the double‐determinant assay. When sera from patients with liver cirrhosis were analyzed, 16 of 23 patients showed elevated CanAg levels with the C50‐C50 combination, but only 4 of 23 patients had elevated antigen values using the C50‐C242 assay. The increased specificity was obtained without loss of sensitivity. MAb C203 was evaluated both in a double‐determinant combination with C50 and in an homologous assay, but did not contribute either Increased sensitivity or specificity as compared with C50‐C50.
A human bronchial epithelial cell strain with unusual in vitro growth potential which undergoes neoplastic transformation after SV40 T antigen gene transfection
Authors: Reddel Roger R. , Hsu Ih‐Chang , Mass Marc J. , Hukku Bharati , Gerwin Brenda I. , Salghetti Simone E. , Somers Angela N. A. , Galati Anthony J. , Gunning William T. , Harris Curtis C. , Stoner Gary D.
Published: February 2007

Bronchial epithelial cells were cultured from an individual with no evidence of malignant disease. These cells, designated HB56B, had a greatly extended In vitro life‐span, being able to undergo 50 passages and 200 population doublings in contrast to the usual 3 to 4 passages and 20 to 30 population doublings characteristic of normal human bronchial epithelial cells. HB56B cells had karyotypic evidence of an amplified region on the short arm of chromosome 11. Unlike normal bronchial epithelial cells, which undergo terminal squamous differentiation In vitro in response to fetal bovine serum, HB56B cells were only minimally affected by serum. These cells were readily established as an immortalized cell line, HB56B/5T, following transfection with a plasmld containing SV40 early region DNA. HB56B cells were non‐tumorigenic in athymic nude mice, but HB56B/5T cells within a few passages of transfection with the SV40 plasmid formed tumors of which 28/37 regressed. HB56B cells may offer an experimental system for the study of proliferation, differentiation, and senescence control in human bronchial epithelial cells.
Nucleolar protein B23 translocation after deferoxamine treatment in a human leukemia cell line
Authors: Yung Benjamin Y‐M. , Yang Y. H. , Bor Amy M‐S.
Published: February 2007

Localization of nucleolar protein B23 in HL‐60 cells under the treatment by iron chelator deferoxamine (DSF) was studied using indirect immunofluorescence. Bright nucleolar fluorescence was observed in exponentially growing control cells. The addition of DSF in the culture system resulted in time‐and dose‐dependent Induction of protein B23 translocation from nucleoli to nucleoplasm, inhibition of cell growth, DNA and RNA synthesis. The addition of FeCI3 at culture Initiation completely reversed the effects of DSF. Furthermore, significant numbers of HL‐60 cells could be rescued from the effects of DSF when iron was added back as late as 24 hr after exposure to DSF. Cells resumed their abilities to grow and to synthesize DNA and RNA upon the iron rescue. Protein B23, accordingly, relocated from nucleoplasm to nucleoli. These results indicate the importance of iron for proliferation of leukemfc cells and localization of protein B23 in nucleoli. Preribosomal ribonucleoprotein particles (pre‐rRNPs) were extracted from isolated nucleoli of HL‐60 cells and fractionated on sucrose density gradients. Protein B23 was found to be co‐localized with the pre‐rRNPs as determined by ELISA assays. No such B23‐associated pre‐rRNPs or other pre‐rRNP fractions were obtained from nucleoli of DSF‐treated cells. These results suggest that one of the effects of the anti‐proliferative action of DSF is the Inhibition of rRNA synthesis in nucleoli. Due to the lack of new synthesis of rRNA in nucleoli, protein B23 loses its binding target and translocates into the nucleoplasm. B23 translocation, as observed by immunofluorescence, may be a simple and rapid method for assessing inhibition of cell growth in response to anti‐proliferative drugs such as deferoxamine in cancer chemotherapy.
Enhancement by tyrosine methyl ester of gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in wistar rats
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Baba Miyako , Taniguchi Haruo
Published: February 2007

The effect of tyrosine methyl ester (TME) on the incidence, number, and histological types of gastric cancers induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) was investigated in male Wistar rats, Rats were subcutaneously given TME, 512 mg/kg body weight, every other day after 20 weeks of oral treatment with MNNG. Prolonged alternate‐day administration of TME caused a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. However, it did not affect the histology of the cancers. TME also caused a significant increase in tissue norepinephrine concentrations in the antral portion of the gastric wall and in the labelling indices of the antral epithelial cells. However, TME had no influence on the serum gastrin level and antral pH. These findings indicate that TME enhances gastric carcinogenesis, and this may be related to its effects on increasing norepinephrine levels in the gastric wall and stimulating proliferation of the antral epithelial cells.
Differential expression of two lck transcripts directed from the distinct promoters in HTLV‐I+ and HTLV‐I− T‐cells
Authors: Nakamura Kazuhiko , Koga Yasuhiro , Yoshida Hiroki , Kimura Genki , Nomoto Kikuo
Published: February 2007

The lck gene encodes a lymphocyte‐specific tyrosine protein ktnase,p56lck, the expression of which is almost exclusive In T‐cells. The expression of lck in human T‐cell leukemia virus type I (HTLV‐1)‐transformed T‐cell lines is closely associated with interleukin‐2 (IL‐2) dependence for their growth. That is, IL‐2‐dependent HTLV‐1‐transformed cell lines contain the lck message abundantly as HTLV‐1‐negative T‐cell lines, whereas IL‐2‐Independent HTLV‐1‐transformed cell lines express either no or little lck mRNA, although they are derived from T‐cells. The lck gene contains 2 distinct promoters which direct 2 types of lck transcript with different S′ untranslated regions. In this study, we show that HTLV‐1‐transformed IL‐2‐dependent T‐cell lines contain the upstream promoter‐initiated lck transcript exclusively, in contrast to HTLV‐1‐negative transformed T‐cell lines which express the downstream promoter‐as well as the upstream promoter‐initiated lck transcript. In addition, lck mRNA disappears transiently in IL‐2‐dependent HTLV‐1‐transformed T‐cell lines after stimulation for T‐cell activation, which is also observed In peripheral blood T lymphocytes. These results indicate that the disappearance of lck mRNA in HTLV‐1‐transformed, IL‐2‐independent cell lines Is caused by a mechanism which down‐regulates the upstream promoter‐initiated lck transcript and this IL‐2‐independent state may represent a further “activated” condition of the IL‐2‐dependent state by the stimulation which mediates T‐cell activation.
The epstein‐barr‐virus‐encoded membrane protein LMP but not the nuclear antigen EBNA‐1 induces rejection of transfected murine mammary carcinoma cells
Authors: Trivedi Pankaj , Masucci Maria G. , Winberg Gösta , Klein George
Published: February 2007

The EBV‐encoded membrane protein (LMP) and the nuclear antigen EBNA‐I were compared for their capacity to induce rejection of transfected murine mammary carcinoma cells in syngenelc hosts. The tumorigenic potential of stable LMP and EBNA‐I expressing sublines of the ACA (H‐2f)‐derived mammary carcinoma line S6C was tested in pre‐immunized syngeneic and semi‐syngeneic animals. LMP expressing S6C cells elicited a strong rejection response as demonstrated by the lower tumor take and slower growth in immunized vs. control mice. In contrast, EBNA‐I‐expressing cells were non‐immunogenic in syngeneic hosts and in one semi‐syngeneic F1‐hybrid. Rejection in 2 additional F1‐hybrids did not appear to be due to EBNA‐I‐specific immune responses. Our findings support the hypothesis that the escape of EBV carrying tumor cells from EBV‐specific immune surveillance may be facilitated by the fact that viral gene expression is limited to EBNA‐I.
Early‐age body size, adult weight gain and endometrial cancer risk
Authors: Marchand Loïc Le , Wilkens Lynne R. , Mi Ming‐Pi
Published: February 2007

To further characterize the association of obesity and endometrial cancer, in particular with regard to the role of early‐age obesity and adult weight gain, the authors assembled by computer linkage a population‐based historical cohort of 30,266 women born between 1913 and 1932, for whom weight and height had been recorded in 1942‐43 and 1972. Linkage of this cohort to the Hawaii Tumor Registry resulted in the Identification of 214 (mainly post‐menopausal) Incident cases of endometrial cancer for 1972‐1986. An average of 3.7 cancer‐free controls were matched to each case on month and year of birth and ethnicity. A case‐control analysis, conducted In each 5‐year birth cohort, revealed no clear association of endometrial cancer with weight, height or body mass at ages 10 to 29 years. However, positive associations with adult body weight and gain in body mass since 1942 were observed for women diagnosed at age 60 or older. This association with obesity was strongest in women whose body mass was below the median in 1942 and equal to or above the median in 1972. No association with body size was detected in women diagnosed before age 60. Parity, age at first birth and socio‐economic indicators for 1942 and 1972 did not confound the analysis. These findings suggest that obesity affects the late stages of endometrial carcinogenesis, and the possibility that one or more determinants of weight gain may be independently associated with endometrial cancer risk.
Alcohol consumption and risk of breast cancer
Authors: Sneyd M. J. , Paul Charlotte , Spears G. F. S. , Skegg D. C. G.
Published: February 2007

In a national case‐control study, 891 New Zealand women aged 25 to 54 with newly diagnosed breast cancer were compared With 1,864 control subjects selected at random from the electoral rolls. The relative risk of breast cancer for current drinkers of alcohol, compared with women who had never drunk alcohol, was 1.0 (95% confidence Interval 0.64 to 1.7). For ex‐drinkers the relative risk was 1.3 (95% confidence interval 0.74 to 2.5). Women drinking up to 14 drinks per week had no increase in risk, while the relative risk in those consuming more than 14 drinks per week was 1.8 (95% confidence interval 0.87 to 3.8). There was no evidence of effect modification by age at diagnosis, menopausal status, body mass index, or any of the other variables examined. While these results provide little support for the hypothesis that moderate alcohol consumption increases the risk of breast cancer, they are not inconsistent with the weak associations that have been found in many other studies. Possible explanations for such a relationship are considered.
opisthorchis viverrini infestation and endogenous nitrosamines as risk factors for cholangiocarcinoma in thailand
Authors: Srivatanakul P. , Sukaryodhin S. , Ohshima H. , Khlat M. , Parkin M. , Brouet I. , Bartsch H.
Published: February 2007

Cholanglocarcinoma (CCA) is one of the most common cancers In north‐east Thailand and has been associated with infestation by the liver fluke Opisthorchis viverrini (OV). Two samples of 12‐hr overnight urine (after dosing with proline and ascorbic acid or proline alone) were collected from 20 Inhabitants from each of 5 contrasting incidence areas for CCA. The incidence of CCA was not correlated with either the amount of NPRO or other nitrosamino acids, endogenous nitrosation potential (difference in NPRO levels between proline dose and proline and ascorbic dose), or nitrate level. However, when urinary levels of nitrosamino acids were compared in subjects living in high‐risk areas, subjects who were positive for OV antibody excreted significantly more (P < 0.01) NPRO (12.3 ± 18.7 μg/12 hr) after proline ingestion than those who were negative (3.5 ± 3.2 μg/12 hr). After ingestion of ascorbic acid, the NPRO levels in the positive subjects were significantly reduced (p < 0.01) to 2.4 ± 2.0 μg/12 hr, suggesting that endogenous nitrosation of proline was inhibited. Thus, endogenous nitrosation potential estimated from the difference between NPRO and the sum of nitrosamino acids excreted in the 2 urine samples was significantly higher in subjects positive for the OV antibody. Small amounts of pre‐formed nitrosamines were found in fermented fish and pork food items, which are consumed frequently in the high‐risk area for CCA. These results suggest that the interaction between chemical carcinogens, especially nitrosamines, and OV infestation may play a role in the development of cholangiocarcinoma in Thailand.
Tumor IGF‐II content in a patient with a colon adenocarcinoma correlates with abnormal expression of the gene
Authors: Lambert Sylvie , Gol‐Winkler Rosita , Collette Julien , Gillis Jacqueline , Franchimont Paul , Desaive Claude
Published: February 2007

We have recently reported abnormal insulin‐like growth factor‐II (IGF‐II) mRNA levels in a number of human colorectal adenocarcinomas. Using an IGF‐II radioimmunoassay, we have now detected high levels of both 10‐kDa and 7.5‐kDa IGF‐II species (2,370 ng/g) in a right colon tumor showing a 800‐fold IGF‐II gene over‐expression in comparison to the normal adjacent tissue. The higher‐molecular‐mass form represents 74% of the total immunoreactive IGF‐II detected in the tumor. This form appears to be less reactive in the radioreceptor assay than in the radioimmunoassay. The insulin‐like growth factor‐I (IGF‐I) concentration in the tumor is low. The patient's pre‐operative serum IGF‐II level is not increased and the proportion of the 10‐kDa species Is normal. In addition, the IGF‐II/IGF‐I ratio is 3 in the serum and 308 in the tumor. Our results show that the very high IGF‐II level produced by the tumor does not Influence the seric concentration of the growth factor.
The eortc melanoma group exchange program: Evaluation of a multicenter monoclonal antibody study
Authors: Carrel Stefan , Doré Jean‐François , Ruiter Dirk J. , Prade Michel , Lejeune Ferdy J. , Kleeberg Ulrich R. , Rümke Philip , Bröcker Eva B.
Published: February 2007

In the framework of the European Organisation for Research and Treatment of Cancer (EORTC), the Immunology and Pathology Subgroups of the Malignant Melanoma Cooperative Group undertook a large multicenter monoclonal antibody (MAb) study. Fourteen laboratories from 7 European countries tested a panel of 23 MAbs for immunohistological staining reactivity for malignant and non‐malignant lesions involving the melanocytic lineage. A standardized im‐munoperoxidase procedure was used and the results were evaluated using a standard protocol and data evaluation form developed in collaboration with the EORTC Data Center. According to this analysis, the antibodies in the panel could be classified into 3 main groups. The first group of MAbs includes those antibodies which stained the majority (>80%) of all primary tumors, irrespective of their Breslow thickness and the majority of metastatic lesions. In addition, these MAbs stained a high percentage of cells within a given lesion. Several antibodies of Group I were likewise reactive with the majority of naevoblasts and with normal melanocytes. The second group of MAbs included antibodies reacting only with a limited number of primary melanomas and metastatic lesions. Antibodies of Group II reacted only weakly, if at all, with normal melanocytes or naevocytes. The percentage of cells within a malignant lesion stained by these MAbs was always rather tow. The MAb group III detected surface structures whose expression appeared to be related to tumor progression; they did not react or reacted only weakly with naevi, and they all reacted with a small number of early primary melanomas (<0.75 mm). The number of lesions stained increased with increasing Breslow thickness. Our study suggests that the application of a panel of well defined MAbs might be of diagnostic and prognostic value in evaluating malignant melanoma.
Modulation of cis‐diamminedichloroplatinum(II) accumulation and sensitivity by forskolin and 3‐isobutyl‐1‐methylxanthine in sensitive and resistant human ovarian carcinoma cells
Authors: Mann Stephen C. , Andrews Paul A. , Howell Stephen B.
Published: February 2007

We have determined the effect of forskolin, an adenyl cyclase agonist, and 3‐isobutyl‐1‐methylxanthine (IBMX), a phosphodiesterase inhibitor, on the accumulation and cyto‐toxicity of cisplatin (DDP) In 2008 human ovarian carcinoma cells. In DDP‐sensitive 2008 cells, forskolin and IBMX caused 2.1‐fold and 2.3‐fold Increases, respectively, in the short‐term accumulation of DDP relative to untreated cells. The inactive analogue, 1,9‐dideoxyforskolin, decreased DDP accumulation. Forskolin and IBMX also increased accumulation in A2780 cells. Neither forskolin nor IBMX had any effect on DDP accumulation in DDP‐resistant 2008 cells, the effects were detectable as early as I min and persisted at 60 min. The concentrations for half‐maximal stimulation of DDP accumulation were approximately 0.2 μM for forskolin and 0.2 mM for IBMX. Forskolin caused marked increases in cAMP levels in both sensitive and resistant 2008 cells within I min, although there were differences in the subsequent time‐courses of the response. Both 2008 cell types had identical cAMP‐dependent protein kinase (PKA) activity. These results suggest that there is a target downstream of PKA that is an Important participant in DDP accumulation, and that this target is defective of missing in DDP‐resistant cells. Following a 1‐hr exposure to drugs, forskolin and IBMX at concentrations that were by themselves completely non‐toxic increased the slopes of the clonogenic survival vs. DDP concentration curves in 2008 cells 1.9‐fold and 3.3‐fold, respectively. In DDP‐resistant 2008 cells, however, forskolin and IBMX increased the slopes only 1.2 and 2.6‐fold, respectively. These effects of forskolin and IBMX on DDP cytotoxicity did not directly correlate with the effects on the 1‐hr DDP accumulation which suggested that, in addition to modulating DDP accumulation, these agents increase the cytotoxicity of the intracellular platinum. The results indicate that modulation of cAMP levels can have important effects on DDP accumulation and cytotoxicity in 2008 cells and that these effects are significantly diminished in DDP‐resistant cells.
Induction of mouse mammary tumours in a transplantation system by the sequential introduction of the myc and ras oncogenes
Authors: Bradbury Jane M. , Sykes Helen , Edwards Paul A. W.
Published: February 2007

A novel helper‐free defective retrovirus containing the v‐Ha‐ras oncogene has been constructed and used to introduce the gene into primary mouse mammary epithelial cells already containing the v‐myc oncogene. Transplantation of such doubly altered cells into cleared mammary fat pads led to the formation of mammary tumors within 6 to 8 weeks of transplantation. In a separate experiment, both oncogenes were simultaneously introduced to normal epithelium and once again tumours were formed. Neither oncogene alone gave a significant rate of tumour formation, although myc alone gave a reproducible hyperplasia as previously reported and ras alone gave occasional dysplastic or alveolar lesions. The results presented here demonstrate the progression of a normal cell through a hyperplastic intermediate to a tumour‐forming cell in a versatile in vivo transplantation model.
Establishment of a human leukemia subline resistant to the growth‐inhibitory effect of 12‐o‐tetradecanoylphorbol 13‐acetate (TPA) and showing non‐P‐glycoprotein‐mediated multi‐drug resistance
Authors: Takeda Yuichiro , Nishio Kazuto , Sugimoto Yoshikazu , Kasahara Kazuo , Kubo Sachiyo , Fujiwara Yasuhiro , Saijo Nagahiro , Niitani Hisanobu
Published: February 2007

We have previously reported that K562/ADM, a typical P‐glycoprotein‐mediated multi‐drug‐resistant cell line, is cross‐resistant to the growth‐inhibitory effect of 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) and non‐TPA type tumor promoters. To elucidate the mechanism of cross‐resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA‐induced growth inhibition by exposing K562 cells to N‐methyl‐N'‐nitro‐N‐nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA‐induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500‐fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross‐resistance to etoposide, tenlposide, adriamycin (ADM), vincristine, vindesine and 3‐[(4‐amino‐2‐methyl‐5‐pyrimidinyl)] methyl‐1‐(2‐chloroethyl)‐l‐nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross‐resistant to 3′‐deamino‐3′‐morpholino‐13‐deoxo‐10‐hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross‐resistant to MX2. By Northern blot analysis, K562/TPA did not express MDR‐1. Accumulation of ADM by K562/TPA was no lower than that of K562 although that of K562/ADM was 5‐fold lower than K562. We examined the subcellular distribution of ADM by fluorescence microscopy. The fluorescence of ADM was located in the nucleus of K562 and mainly in the cytoplasm of K562/TPA and K562/ADM. The distribution of ADM in K562/TPA, however, was different from that in K562/ADM. These results suggested that K562/TPA had a non‐P‐glycoprotein‐mediated multi‐drug‐resistance phenotype and that the mechanism of drug‐resistance in this cell line might be explained by an alteration in the intracellular drug distribution.
Induction of autologous tumor‐specific cytotoxic T cells in patients with liver cancer. Characterizations and clinical utilization
Authors: Aruga Atsushi , Yamauchi Katsumi , Takasaki Ken , Furukawa Takaji , Hanyu Fujio
Published: February 2007

To generate autologous‐tumor‐specific cytotoxic T cells (CTL), peripheral blood mononuclear cells (PBMC) obtained from cancer patients were cultivated with autologous tumor cells for 5 days, and restimulated with interleukin‐2 for another 5 days. Subsequently, their cytotoxic activity was examined by an in vitro cytotoxic test as well as by Winn's assay utilizing nude mouse transplanted autologous tumors. The present results demonstrated that these in vitro‐stimulated cells were able to kill autologous tumor cells but not allogeneic tumors, and that they also inhibited the growth of transplanted autologous tumors in the nude mouse. Their cytotoxic activity was completely abrogated by pre‐treatment with either anti‐CD3 or anti‐CD8, but not with anti‐CD4, plus complement. Based on these studies, we injected these CTL via the hepatic artery into patients having either non‐resected tumors or recurrent tumors in the liver. Among 15 treated patients (13 with hepatocellular carcinoma and 2 with metastatic liver cancer) 2 complete responses, 3 partial responses and 4 minor responses were observed. During the 6 to 25 months following injection of CTL, no definite signs of tumor recurrence or regrowth were demonstrated in these 5 responding patients (complete plus partial).
Prognostic significance of her‐2/neu expression in breast cancer and its relationship to other prognostic factors
Authors: Rilke Franco , Colnaghi Maria Ines , Cascinelli Natale , Andreola Salvatore , Baldini Maria Teresa , Bufalino Rosaria , Porta Giuseppe Della , Ménard Sylvie , Pierotti Marco A. , Testori Alessandro
Published: February 2007

Archival surgical specimens from 1,210 female breast cancer patients treated between 1968 and 1971 and with a 19‐year follow‐up were reanalyzed with special reference to several parameters, such as size of the primary tumor, axillary nodal involvement, histologic grade, degree of inflammatory infiltrate (LPI) of the tumor and expression of the neu onco‐protein (p185) as detected by immunohistochemistry. In a multifactorial analysis the 4 former factors were found to be independent prognostic parameters. Over‐expression of p 185 was found to be related to tumor size and grade and to LPI but not to pathologic nodal status. Over‐expression of p185 showed a negative impact upon survival in node‐positive but not in node‐negative patients. However, in the subset of node‐negative patients without LPI, p185 over‐expression showed the same correlation with a poor prognosis as in node‐positive patients. In contrast, in node‐negative and LPI‐positive patients, p185 over‐expression correlated with a good prognosis. Also, the prognosis of patients with positive nodes, presence of LPI and no p185 over‐expression was similar to that of patients with negative nodes, absence of LPI and p185 over‐expression.
Pooled analysis of 3 european case‐control studies of epithelial ovarian cancer: III. Oral contraceptive use
Authors: Franceschi Silvia , Parazzini Fabio , Negri Eva , Booth Margaret , La Vecchia Carlo , Beral Valerie , Tzonou Anastasia , Trichopoulos Dimitrios
Published: February 2007

The relationship between use of oral contraceptives (OCs) and other contraceptive methods and the risk of ovarian cancer was examined in a combined analysis of 3 hospital‐based case‐control studies conducted in Italy, the United Kingdom, and Greece, for a total of 971 ovarian cancer cases and 2,258 controls under age 65. Compared with never‐users, the combined multivariate relative risk (RR) for ever‐users was 0.6 (95% confidence interval, CI = 0.4‐0.8) and the estimates were consistent in the 3 datasets. The protection was also similar across strata of age and parity. Considering various measures of OC use, available in the Italian and British data‐sets only, the protection conveyed on ovarian cancer risk increased with the duration of use and persisted in the medium‐long period: the RR in women reporting their last OC use ≧15 years prior to diagnosis was 0.5 (95% CI = 0.2‐1.0). The risks in ever‐users were appreciably lower in those women who reported their first OC use before 25 years of age (RR = 0.3 for first use before age 25. 0.8 for first use at age 25‐34 and 0.7 at 35 years or after). Such findings emerged similarly from Italian and British data. This combined analysis, besides offering further quantitative estimates of the protective effects of OCs on ovarian cancer risk in European populations, provides useful insights into the time pattern of the relationship between OC use and ovarian carcinogenesis, suggesting that the protection persists for 15 years or more after cessation of use and may be larger for use at younger age.
Severe cachexia in mice inoculated with interferon‐γ‐producing tumor cells
Authors: Matthys Patrick , Dukmans Roger , Proost Paul , Van Damme Jo , Heremans Hubertine , Sobis Halina , Billiau Alfons
Published: February 2007

Nude mice were inoculated with CHO/IFN‐γ cells, a line of Chinese hamster ovary tumor cells, that had been genetically engineered to produce murine IFN‐γ. Severe cachexia, as evident from body weight loss and reduced food intake, occurred in these mice, but not in those injected with CHO/ control cells, i.e. the original, non‐IFN‐γ‐producing line. The essential role of IFN‐γ in the pathogenesis of cachexia was confirmed by the demonstration that monoclonal antibodies (MAbs) against IFN‐γ, given prior to injection of the tumor cells, prevented cachexia. In addition to IFN‐γ, the presence of the tumor cells was also required for cachexia to develop. As evident from pair‐feeding experiments, reduced food intake could only partially account for the rapid and extensive body‐weight loss. Cachexia was characterized by a marked reduction in the amount of interscapular fat tissue. Injected tumor cells exclusively invaded intraperitoneal adipose tissue and elicited an inflammatory cell infiltrate, indicating that interscapular fat loss was due to humoral factors. Our data suggest that, among the humoral factors responsible for cancer‐associated cachexia, IFN‐γ plays a prominent role.
c‐myc Gene in a murine plasmocytoma without visible chromosomal translocations moves to chromosome 12f1 with pvt‐1 and rearranges with IgH enhancer‐Sμ sequences
Authors: Ohno Shinsuke , Migita Shunsuke , Murakami Seishi
Published: February 2007

The DCPC 21 plasmocytoma lacks any of the MPC‐associated chromosomal translocations. However, the c‐myc gene has been transposed to the IgH locus on chromorome 12 by an Ig switch‐region‐mediated recombination mechanism. DNA sequencing analysis, further, revealed that this recombination is consistent with an insertion of the IgH enhancer (Eμ)‐Sμ sequences, 2341 bp in length, into the c‐myc 5′‐flanking region, resulting in 5′: c‐myc 5′‐flanking‐Eμ‐Sμ‐c‐myc 5′‐flanking‐c‐myc exon‐1 : 3′ segment. In situ molecular hybridization of DCPC 2I metaphase chromosome spreads using a Pvt‐1 probe demonstrated that Pvt‐1 has also moved to the FI sub‐band region of chromosome I2 where the IgH genes are located. These results indicate that the c‐myc gene has been inserted into the IgH locus together with the Pvt‐I, regardless of whether plasmocytoma has cytogenetically identifiable translocations. The possible interaction between c‐myc activation and Pvt‐I in the development of MPCs is discussed.