bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemoprevention by indomethacin of tumor promotion in a rat urinary bladder carcinogenesis model
Authors: Shibata Masa‐Aki , Hasegawa Ryohei , Shirai Tomoyuki , Takesada Yasuko , Fukushima Shoji
Published: February 2007

The chemopreventive effects of indomethacin (IM) on the enhancement of bladder carcinogenesis and transitional‐epithelial‐cell proliferation by butylated hydroxyanisole (BHA) or sodium L‐ascorbate (Na‐AsA) were investigated. All animals were given 0.05% N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. They then received 2% BHA or 5% Na‐AsA for 20 weeks, followed by 20 ppm IM in the drinking water or normal tap water without supplement for a further 20 weeks, or BHA or Na‐AsA alone or concomitantly with IM for 40 weeks. No differences in bladder‐tumor development were found when IM was administered after cessation of BHA or Na‐AsA exposure. However, IM in combination with either BHA or Na‐AsA significantly reduced both the incidence and the multiplicity of papillomas and carcinomas as compared with the values of groups receiving BHA or Na‐AsA alone. This was associated with decreased DNA synthesis and prostaglandin (PG) E2 levels in the existing bladder tumors. Combined treatment with IM did not exert any effects on BHA forestom‐ach carcinogenesis. A separate 8‐week combination study demonstrated that IM diminished the increase in expression of proliferation nuclear‐cell antigen (PCNA) induced by BHA or Na‐AsA alone. The present results suggest that PGE2 may be involved in promotion of rat bladder carcinogenesis and that the PG synthesis blocker IM might exert preventive effects on the development of bladder cancer in humans.
Tamoxifen modulation of cisplatin cytotoxicity in human malignancies
Authors: McClay Edward F. , Albright Kathleen D. , Jones Jeffrey A. , Christen Randolph D. , Howell Stephen B.
Published: February 2007

Recent clinical trials have indicated that addition of tamoxifen (TAM) to a combination of cisplatin (DDP), carmustine and dacarbazine markedly increases the overall objective response rate of patients with metastatic malignant melanoma. Previous studies have determined that there is remarkable synergy between TAM and DDP in a human melanoma cell line T‐289. Using the technique of median effect analysis, in clonogenic assay, we observed a highly synergistic interaction between TAM and DDP. To determine whether or not this synergistic interaction was unique to human melanomas, or is generally observed in other types of malignancy, we examined the nature of this interaction using a human ovarian carcinoma and small cell lung cancer cell line. Synergy was observed in both cell lines. In the case of all 3 types of malignancy, synergy was observed at concentrations of both TAM and DDP that can be achieved in patients. Our results demonstrate that cytotoxic synergy between the DDP and TAM is observed in cell lines established from multiple types of human malignancies. It is important to note that the synergy between TAM and DDP is not dependent on the presence of estrogen or progesterone receptors. Since TAM is well tolerated by patients, it is particularly attractive as a potential agent with which to sensitize human tumors to DDP.
Inhibition of metastatic cell colonization in murine lungs and tumor‐induced morbidity by non‐peptidic Arg‐Gly‐Asp mimetics
Authors: Hardan I. , Weiss L. , Hershkoviz R. , Greenspoon N. , Alon R. , Cahalon L. , Reich S. , Slavin S. , Lider O.
Published: February 2007

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood‐vessel walls, cells, including malignant ones, must recognize and associate with the sub‐endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM‐glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg‐Gly‐Asp (RGD)‐containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non‐peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the α11b ‐β3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD‐containing peptides and the RGD mimetic, compound SF‐6,5, but not the Arg‐Gly‐Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16‐F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF‐6,5 to mice inhibited the formation of B16‐F10 colonies in experimental and spontaneous models of metastases. Moreover, SF‐6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD‐containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non‐peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrindependent cell‐cell and cell‐ECM interactions.
Differences in cell surface carbohydrates, and in laminin and fibronectin synthesis, between adherent and non‐adherent ehrlich ascites tumor cells
Authors: Song Zhiwei , Varani James , Goldstein Irwin J.
Published: February 2007

Differences in cell surface carbohydrates and in laminin and fibronectin synthesis between 2 Ehrlich ascites tumor (EAT) cell lines, the adherent and non‐adherent EAT cells, have been studied. The adherent EAT (a‐EAT) cells grow in monolayer in vitro in the presence of fetal bovine serum. The classical, or non‐adherent EAT (na‐EAT), cells grow in suspension in ascites form in the peritoneal cavity of mice, and they do not adhere when cultured in vitro. Both EAT cell lines express surface glycoproteins reactive with Maackia amurensis lectin (MAL) and Griffonia simplicifolia isolectin GS I‐B4. However, only a‐EAT cells react with elderberry (Sambucus nigra) bark lectin (SNA), suggesting that there are some differences in the sialylation of cell surface carbohydrate moieties between these 2 EAT cell lines. Removal of cell surface sialic acid by treating a‐EAT cells with Vibrio cholerae neuraminidase did not abolish the ability of these cells to adhere to laminin‐or fibronectin‐coated plates, indicating that the sialic acid of the cell surface glycoproteins is not essential for their adhesion to these extracellular matrices. Therefore, the difference in sialylation of cell surface glycoproteins is not responsible for the difference in cell adhesion between these 2 lines of EAT cells. Both EAT cell lines express detectable amounts of laminin but not fibronectin on their surfaces; they both secrete fibronectin and entactin into the medium. The na‐EAT cells (but not the a‐EAT cells) also secrete laminin A chain into the culture medium; however, no B chain was detected in the culture medium of either cell line. The laminin isolated from the cell surface of na‐EAT cells reacts with GS 1 and MAL lectins, but not with SNA, whereas the laminin isolated from a‐EAT cells reacts with SNA, as well as GS 1 and MAL.
Prognostic significance of cell DNA content in early‐stage ovarian cancer (figo stages I and II/A) by means of automatic image cytometry
Authors: Wagner T. M. U. , Adler A. , Sevelda P. , Assmann I. , Knepflé C. F. , Czerwenka K. , Heinzl H. , Ploem‐Zaaijer J. J.
Published: February 2007

Paraffin‐embedded material from 69 patients with epithelial ovarian cancer FIGO stages I and II/A (including 21 patients with borderline carcinoma) was studied with automatic DNA image cytometry. Univariate analysis indicated a significant difference in survival based on the presence of nuclei with high DNA content (higher than 5 C). A group of patients with less than 0.2% cells with high DNA content had a 6‐year survival of 87%, whereas in a group of patients with more than 0.2% of such cells, 6‐year survival was 49%. This parameter remained significant when used in a group of stage I/a and I/b patients. Statistical analysis of diploid vs. non‐diploid tumors also showed significant difference in survival. Separate analysis of 48 invasive ovarian cancers indicated that ploidy, the percentage of cells with high DNA content and tumor stage (stage I/a + b vs. stages I/c + II/a) reached significance for survival, whereas grading did not. In addition, comparison of clinical stage, grading, ploidy and the percentage of cells exceeding 5 C with a threshold at 0.2% by means of a murtivariate analysis (Cox regression model) showed that only the percentage of cells exceeding 5 C remained statistically significant.
The effect of ethnic differences on the pattern of HTLV‐I‐associated T‐cell leukemia/lymphoma (HATL) in the United States
Authors: Levine Paul H. , Manns Angela , Jaffe Elaine S. , Colclough Ginga , Cavallaro Ann , Reddy Gautham , Blattner William A.
Published: February 2007

Human T‐cell lymphotropic virus Type I (HTLV‐I) is the primary etiologic factor for adult T‐cell leukemia/lymphoma (ATL). Although HTLV‐I is endemic in japan and the Caribbean islands, the reported clinical and epidemiologic features of ATL in these 2 parts of the world are quite different. ATL has been diagnosed at a younger age and is reported more frequently as the lymphomatous type rather than the acute type with leukemia in the Caribbean basin as compared with the presentation in Japan. In order to characterize ATL in the United States, a registry has been established at the National Cancer Institute for the purpose of recording all cases originally diagnosed in the United States. This registry was utilized to examine the effect of ethnic differences on age of onset and clinical features of ATL, using the same data base. Clinical and laboratory information was obtained from 177 patients suspected of having ATL, who were treated at the National Institutes of Health, or had biological samples sent for evaluation, or were reported in the literature. Histopathologic review and virologic studies were performed by standardized methods. Of 177 patients registered, 127 were considered as having ATL, according to an algorithm combining clinical, pathologic and laboratory features. Presenting features in the confirmed cases consisted primarily of lymphadenopathy (76.6%), hypercalcemia (72.5%), leukemia (82%), skin involvement (48.2%) and hepatomegaly (53.6%). Patients of Japanese ancestry were generally older (median age 63, range 51 to 73 years) than patients of African‐American descent (median age 39, range 7 to 75 years) and presented more often with leukemia (90 vs. 69%). Of the 103 cases where country of birth was confirmed, 45 (43.7%) were born in the United States. The prognosis was generally poor (median survival 3.24 months), but rare longterm remissions were documented.
Human papillomavirus type 18 E6* MRNA in primary tumors and pelvic lymph nodes of hungarian patients with squamous cervical cancer
Authors: Czégledy J. , Evander M. , Hernádi Z. , Gergely L. , Wadell G.
Published: February 2007

Seven biopsy specimens from squamous‐cell carcinomas of the uterine cervix were examined by RT‐PCR for human papilloma‐virus(HPV)‐specific transcripts. With our HPV18 transcription‐specific primer pair (5′ nts 127–149; 3′ nts 587–607), all 7 were shown to contain one strong viral mRNA signal from the early 6/early 7 open reading frames (E6/E7 ORFs). Sequence analysis of the cloned PCR product proved that the transcript was generated by splicing out an intron in E6 from nucleotides 233 to 416, thereby corresponding to the HPV18 E6* spliced mRNA. Nine out of 9 metastatic and 5 of 7 histologically negative lymph nodes from the same patients were also found to be positive for the same mRNA transcript. However, 4 HPV18 unrelated primary tumors and the connected regional pelvic lymph nodes (3 metastatic, 7 histologically negative) were negative for the HPV18 E6* mRNA. Cytokeratin signals indicating tumor cells of epithelial origin were detected in 7 out of the 9 transcript‐positive lymph nodes with histological signs of metastasis and in 2 out of the 5 transcript‐positive histologically negative lymph nodes. This suggests that the dispersion of the epithelial monoclonal tumor cells was lymphogenic in origin.
Risk excess of soft‐tissue sarcoma and thyroid cancer in a community exposed to airborne organochlorinated compound mixtures with a high hexachlorobenzene content
Authors: Grimalt Joan O. , Sunyer Jordi , Moreno Victor , Amaral Osvaldo C. , Sala María , Rosell Antoni , Anto Josep M. , Albaiges Joan
Published: February 2007

Unusually high levels of hexachlorobenzene (HCB) were detected in the air and in sera of volunteers of a village located in the vicinity of an organochlorinated‐compounds factory (Flix, Catalonia, Spain). A significant increase for specific causes of death was obtained only for neoplasms of unknown origin. However, an excess of incident cases was observed for thyroid neoplasms, soft‐tissue sarcoma and brain neoplasms in men. These descriptive findings are in agreement with previously reported associations between soft‐tissue sarcoma and human exposure to organochlorinated compounds, as well as with animal experiments relating HCB and thyroid cancer, and add new information on the possible relation between organochlorinated compounds, and particularly HCB, and cancer.
Myeloproliferation in long‐term plasmacytoma‐regressor mice
Authors: Sagi‐Assif Orit , Douer Dan , Shaked Nili , Russell Stephen W. , Witz Isaac P.
Published: February 2007

MOPC‐315 plasmacytoma‐bearing BALB/c mice were treated with high doses of melphalan, causing a permanent and complete regression of the tumor. In the present study we analyzed plasmacytoma‐regressor mice (PRM) 3–6 months after plasma‐cytoma regression. A second group of otherwise untreated normal mice was treated with melphalan (M—control group). A third group of mice remained untreated and served as an age‐and sex‐matched control group. PRM were cachectic and had an increased mortality rate compared to the M and the C control groups. Histopathological examination indicated that the spleen of PRM showed pronounced abnormalities, primarily in the red pulp. These abnormalities consisted of extramedullary hematopoiesis and myeloid‐granulocytic hyperplasia. Spleens of M mice showed similar abnormalities but to a much lesser extent. Flow cytometric analysis of cellular surface markers of PRM splenocytes indicated a high number of large MAC‐1‐and GR‐1‐positive cells compared to splenocytes of M or C controls. These large cells also expressed For receptors (FcτRII), stained positively with non‐specific esterase and adhered to plastic dishes; a certain percentage expressed MAC‐2 and MAC‐3 antigens. A quantitative suppression of CD4+ T cells and of B cells was also shown. Circulating levels of TNF were higher in PRM than in M or C mice. The capacity of splenocytes from PRM to secrete factors that stimulated CFU‐GM colony formation in soft agar by bone‐marrow cells from normal mice was significantly up‐regulated compared to that of splenocytes from M or C mice. PRM‐derived splenocytes also reacted significantly better to rIL‐3 and rGM‐CSF than splenocytes from M or C controls. We conclude that the splenic myeloproliferation in PRM was not caused by melphalan chemotherapy alone and is an abnormality related to the primary tumor, possibly in conjunction with chemotherapy. No evidence of a secondary overt malignancy was obtained.
Increased expression of the matrix metalloproteinase 2 in differentiating tera 2 human embryonal carcinoma cells
Authors: Tienari Jukka , Pertovaara Liisa , Saksela Olli , Lehtonen Eero , Vartio Tapio
Published: February 2007

Secretion of proteolytic enzymes by cells has been implicated in tissue remodeling during embryonic development as well as in invasive neoplastic diseases. We studied the regulation of type‐IV‐collagenase activity in Tera 2 human embryonal carcinoma cells, which in the undifferentiated state proliferate rapidly and are tumorigenic. The undifferentiated cells produced relatively low levels of matrix‐metalloproteinase‐2 (MMP‐2) activity. This activity was not markedly affected by exogenous basic fibroblast growth factor (bFGF) or 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), even though the plasminogen activator activity of the cells was increased by these agents. Tera 2 cells can be induced by retinoic acid to differentiate into quiescent cells, of which many express neuronal characteristics. The type‐IV‐collagenase activity of the cells increased markedly during the differentiation. This increase was mainly due to increased expression of MMP‐2. Expression of tissue inhibitors of metalloproteinases (TIMP‐1 and TIMP‐2) was not markedly affected by the differentiation of Tera 2 cells. The results show that in the Tera 2 cell system, increased expression of MMP‐2 is characteristic of the differentiated derivatives. This is in contrast with many other model systems, where increased type‐IV‐collagenase activity is associated with the malignant phenotype. This pattern of regulation may reflect the facts that Tera 2 cells resemble early embryonic cells and that their differentiation mimics related cell‐differentiation processes in the developing embryo.
Changes in perfusion of mouse tumours after photodynamic therapy
Authors: van Geel I. P. J. , Oppelaar H. , Oussoren Y. G. , Stewart F. A.
Published: February 2007

The influence of photodynamic therapy (PDT) on vascular perfusion was investigated in 2 s.c. mouse tumours, a radiation‐induced fibrosarcoma (RIFI) and a squamous‐cell carcinoma (SCCVII). The 86Rb extraction technique was used to measure changes in perfusion relative to cardiac output at various intervals after interstitial PDT. Control groups showed that vascular perfusion in the RIFI tumours decreased with increasing tumour size. For both tumours, of constant size, vascular perfusion decreased to less than 10% of control values within 5 min after high PDT doses. Significant decreases in vascular perfusion were also seen after lower, sub‐curative doses. Thereafter there was slow recovery towards control levels. Photofrin given at shorter intervals before illumination generally resulted in even larger decreases in tumour perfusion, and slower recovery. Comparison of tumour perfusion measurements after PDT with tumour response revealed an inverse correlation with tumour growth delay both for the RIFI and for the SCCVII tumours. PDT with sub‐curative light doses appears to decrease vascular perfusion in the RIFI and SCCVII for a period of at least 24 hr. The most severe reductions in tumour blood flow were associated with the longest regrowth delays, indicating a major role of vascular damage in tumour response to PDT.
Peptide‐antibody conjugates for tumour therapy: A MHC‐class‐II‐restricted tetanus toxin peptide coupled to an anti‐IG light chain antibody can induce cytotoxic lysis of a human B‐cell lymphoma by specific CD4 T cells
Authors: Yu Zhiwei , Healy Frank , Valmori Danila , Escobar Patricia , Corradin Giampietro , Mach Jean‐Pierre
Published: February 2007

Anti‐idiotype antibody therapy of B‐cell lymphomas, despite numerous promising experimental and clinical studies, has so far met with limited success. Tailor‐made monoclonal anti‐idiotype antibodies have been injected into a large series of lymphoma patients, with a few impressive complete tumour remissions but a large majority of negative responses. The results presented here suggest that, by coupling to anti‐lymphoma idiotype antibodies a few molecules of the tetanus toxin universal epitope peptide P2 (830–843), one could markedly increase the efficiency of this therapy. We show that after 2‐hr incubation with conjugates consisting of the tetanus toxin peptide P2 coupled by an S‐S bridge to monoclonal antibodies directed to the X light chain of human immunoglobulin, human B‐lymphoma cells can be specifically lysed by a CD4 T‐lymphocyte clone specific for the P2 peptide. Antibody without peptide did not induce B‐cell killing by the CD4 T‐lymphocyte clone. The free cystein‐peptide was also able to induce lysis of the B‐lymphoma target by the T‐lymphocyte clone, but at a molar concentration 500 to 1000 times higher than that of the coupled peptide. Proliferation assays confirmed that the antibody‐peptide conjugate was antigenically active at a much lower concentration than the free peptide. They also showed that antibody‐peptide conjugates required an intact processing function of the B cell for peptide presentation, which could be selectively inhibited by leupeptin and chloroquine. It is reasonable to expect that, in vivo, the anti‐idiotype antibodies will selectively transport the tetanus toxin peptides to the B‐lymphoma cells, which will process the conjugates and present the peptides to the patients' CD4 T‐cell repertoire. Our tetanus‐toxoid‐vaccinated population has T cells specific for the immunogenic peptide and these, in principle, could be further expanded prior to injection of the conjugate.
Effects of nIFN β and rifn γ on growth and morphology of two human melanoma cell lines: Comparison between two‐and three‐dimensional culture
Authors: Görlach A. , Herter P. , Hentschel H. , Frosch P. J. , Acker H.
Published: February 2007

We compared the anti‐proliferative effects of natural inter‐feron β (nIFN β) and recombinant interferon γ (HFN γ) on 2 human melanoma cell lines, IGRI and SK‐Me128, grown in 2‐dimensional monolayer and in 3‐dimensional spheroid culture. In monolayer culture, growth of both lines was inhibited in a dose‐dependent manner by 5‐day treatments with IFN in concentrations ranging between I and 5,000 IU/ml. Incubations with 120 IU/ml nIFN βor 25 IU/ml rIFN γ led to a 50% growth inhibition of IGRI cells. A 50% growth inhibition of SK‐Me128 cells was obtained with 60 IU/ml nIFN β, whereas even 5,000 IU/ml rIFN γ inhibited the growth of this line by only 30%. Growing these melanoma cell lines in 3‐dimensional spheroid culture for 5 days reduced their sensitivity to interferon. Growth inhibition values of 50% were achieved with 3,000 IU/ml rIFN γ or 9,000 IU/ml nIFN β for IGRI spheroids and 10,000 IU/ml nIFN β for SK‐Me128 spheroids, while 10,000 IU/ml rIFN γ reduced the growth of SK‐Me128 spheroids by only 25%. Outgrowth tests showed that the proliferative capacity after 5‐day incubations with IFN was only reduced in IGRI spheroids treated with high doses of nIFN β. The macroscopically observed increased density of interferon‐treated spheroids could be confirmed by light microscopy as corresponding to reduced intercellular space in these spheroids. Scanning electron microscopy furthermore showed variations on the surface of IFN‐treated spheroids as well as in cellular organization and structures between cells, hinting at a possible involvement of extracellular matrix substances in the reaction to interferons. These findings show that the high anti‐proliferative sensitivity of the melanoma cell lines in monolayer culture could not be achieved in spheroid culture. The volume decreases seen in the presence of interferon might be, at least in part, due to an increased packing density in combination with changes in the cellular organization of interferon‐treated spheroids, rather than to direct antiproliferative effects.
Immunoselection of GRP94/endoplasmin from a KNRK cell‐specific λGTLL library using antibodies directed against a putative heparanase amino‐terminal peptide
Authors: de Vouoe Michael W. , Yamazaki Amy , Bennett Steffany A. L. , Chen Jia‐Hua , Shwed Philip S. , Couture Chantal , Birnboim H. Chaim
Published: February 2007

Induction of an invasive phenotype by metastatic tumour cells results in part from inappropriate expression of extracellular matrix‐degrading enzymes normally involved in embryonic morphogenesis, tissue remodelling, angiogenesis and wound healing. Such enzymes include endoglycosidases that degrade heparan sulfate (HS) in endothelial basement membrane, as well as better characterized proteases. Heparanase, an endo‐β‐D‐glucuronidase initially detected in B16 melanoma cells, has been described as a Mr 96 000 glycoprotein with pl of 5.2, and has been immunolocalized to the cell surface and cytoplasm. We have utilized a polyacrylamide‐gel‐based HS degradation assay to demonstrate that KNRK, a rat kidney fibroblast cell line transformed by v‐K‐ras, exhibits HS‐degrading activity similar to that of B16F10 mouse melanoma cells. To immuno‐select heparanase‐expressing clones from a KNRK‐cell‐specific λgtII cDNA library, we have also prepared a rabbit anti‐serum directed against a putative amino‐terminal peptide of B16F10 cellular heparanase. Lysogens from one clone expressed a β‐galactosidase fusion protein whose staining with peptide anti‐serum was inhibited by competition with excess peptide. Dideoxy‐mediated sequencing of the insert termini of this reco.mbinant revealed that it represents a rat homologue of Mr94,000 glucose‐regulated protein (GRP94/endoplasmin), a molecular chaperone that contains the exact amino‐terminal sequence previously attributed to heparanase. Our results call into question the specificity of this peptide sequence, as well as previous immunolocalization studies of heparanase carried out using such anti‐sera.
Establishment of human oral‐cancer cell lines (KOSC‐2 and ‐3) carrying p53 and c‐myc abnormalities by geneticin treatment
Authors: Inagaki Toshiro , Matsuwari Satoshi , Takahashi Rei , Shimada Kei‐Kichi , Fujie Kimiko , Maeda Sakan
Published: February 2007

Two cultured cell lines derived from human squamous‐cell carcinomas were established through xenografted tumors in nude mice by „Geneticin”︁ treatment, which allows to eliminate contaminated mouse fibroblasts and obtain enriched tumor cells at the early stage of cultivation. Line KOSC‐2 and KOSC‐3 were each derived from a squamous‐cell carcinoma of the oral floor and of the lower gingiva, respectively. Both lines grew in a cobblestone pattern, demonstrating their epithelial heritage. Ciemsa‐banding patterns by chromosome analysis confirmed that both lines are of human origin. Molecular analysis of cancer‐related genes, including the Ha‐ras, c‐myc and p53 genes, was performed. KOSC‐3 cells showed co‐over‐expression of p53 and c‐myc mRNA, in addition to p53 point mutation at codon 248 with transition from CGG to TGG. However, loss of heterozygosfty (LOH) on chromosome 17 was detected in both lines by Southern blotting. These cell lines provide a model for elucidating the mechanism involving p53 inactivation and c‐myc‐gene over‐expression.
Decreased reactivity to PPD among htlv‐i carriers in relation to virus and hematologic status
Authors: Welles Seth L. , Tachibana Nobuyoshi , Okayama Akihiko , Shioiri Shigemasa , Ishihara Shiro , Murai Koichi , Mueller Nancy E.
Published: February 2007

Data on human T‐cell lymphotropic‐virus‐type‐1 (HTLV‐I) status and hematology from 528 individuals were analyzed for associations with low reactivity to the purified protein derivative (PPD) of Mycobacterium tuberculosis recall antigen. Subjects were classified as HTLV‐I carriers with abnormal lymphocytes (Ably), carriers without Ably, and seronegatives. All carriers had a significant 2.6‐fold risk of being low responders to PPD compared with the seronegatives, carriers with Ably having the highest relative risk. Carriers with HTLV‐I‐antibody titer 1:256, or with other detectable markers of virus status such as antibody to tax and proviral DNA, had increased risk for low response to PPD similar to the estimate for HTLV‐I seropositivity alone, compared with the seronegatives. Subjects with a low lymphocyte count had 3.5 times the risk for being low responders to PPD, compared with subjects with high counts. Similarly, subjects with a low monocyte count had 2.0 times the risk for low reactivity of those with a moderate to high count. Results were not confounded by age, sex, smoking or alcohol drinking. Using multiple logistic regression, only HTLV‐I seropositivity and low lymphocyte and monocyte counts were predictive of low reactivity to PPD. Analysis indicates that suppression of delayed‐type hypersensitivity is associated with HTLV‐I infection per se, and not with viral replication or load. Furthermore, this effect may occur in part via changes in the number and function of lymphocytes and monocytes. Such a mechanism may involve altered cytokine production in carriers and concomitant changes in cell populations involved in delayed‐type hypersensitivity.
Expression of gp 185HER‐2 in human cutaneous melanoma: Implications for experimental immunotherapeutics
Authors: Natali Pier Giorgio , Nicotra Maria Rita , Digiesi Giovanna , Cavaliere Renato , Bigotti Aldo , Trizio Domenico , Segatto Oreste
Published: February 2007

Over‐expression of the HER‐2 oncogene correlates with poor prognosis in breast and ovarian carcinomas. Using a sensitive immunohistochemical assay, we have detected low levels of gp 185 HER‐2 in intradermal nevi (78%) and in primary (75%) and metastatic melanomas (58%). The HER‐2 gene product expressed by cultured melanoma cells had the expected molecular weight, but no levels of tyrosine phosphorylation could be detected. Consistently, we were unable to inhibit in vitro growth of melanoma cells with an anti‐gp 185HER‐2 MAb, in conditions in which the growth of SKBr‐3 breast‐carcinoma cells was severely impaired. However, immunotoxins to gp 185HER‐2 were able to kill gp 185Her‐2‐positive melanoma cells. These data indicate that low levels of gp 185HER‐2 are expressed by the melanocyte lineage, with no correlation with transformation or tumor progression. Nevertheless, gp 185HBR‐2 appears a suitable target for immunotherapy of cutaneous melanoma.
Risk factors for non‐melanomatous skin cancer in Alexandria, Egypt
Authors: El Khwsky Fayek , Bedwani Ramez , D'Avanzo Barbara , Assaad Sameir , Ali Adel El Shafei , Mokhtar Samiha , La Vecchia Carlo
Published: February 2007

The role of constitutional and environmental factors on the risk of non‐melanomatous skin cancer was evaluated in a case‐control study conducted in 1992 in Alexandria, Egypt, on 136 incident historically confirmed (99 basal‐cell and 37 squamous‐cell) cases of non‐melanomatous skin cancer (NMSC) and 145 controls in hospital for a broad spectrum of acute non‐sun‐related dermatological conditions. In relation to skin colour, compared with brown‐skinned subjects, the multivariate relative risks (RR) were 2.3 for olive‐skinned subjects and 3.8 for fair/medium‐skinned subjects. Three cases and 29 controls were black (RR = 0.2). The trend in risk with skin colour was significant. Likewise, compared with subjects with brown or hazel eyes, those with green or blue eyes had a RR of 3.1. In relation to acute sun reaction, compared with subjects reporting easy tanning, the RRs were 2.5 for subjects reporting moderate tanning and 4.7 for those reporting easy burning. The risk of NMSC was higher for subjects reporting an outdoor occupation than for those reporting an indoor occupation (RR = 7.7). A significant trend in risk was observed with degree of sun exposure: compared with subjects reporting light sun exposure, the RR was 3.0 for those reporting moderate exposure, and 6.1 for those reporting heavy sun exposure. There was an indication of a relationship between clothing pattern and skin‐cancer risk: compared with subjects reporting frequent use of traditional Egyptian clothes, the RR for dressing in short clothes was 1.8. The presence of signs of photo damage was also associated with NMSC (RR = 3.7). Exposure to arsenic was reported by 10 cases and 1 control (RR = 9.5). A positive interaction between sun exposure and skin colour was observed, and the RR rose to 14.2 for medium‐or fair‐skinned subjects with heavy exposure compared with brown‐or black‐skinned subjects with light or moderate sun exposure. In this Egyptian population, over 60% of NMSC could be attributed to sun exposure and approximately 45% to skin colour.
Body iron stores and risk of cancer
Authors: Knekt Paul , Reunanen Antti , Takkunen Heikki , Aromaa Arpo , Heliövaara Markku , Hakuunen Timo
Published: February 2007

A high level of available tissue iron may increase the risk of cancer through its contribution to the production of free oxygen radicals. Serum iron, total iron‐binding capacity (TIBC) and transfer‐fin saturation levels were studied for their prediction of different cancers in a cohort of 41,276 men and women aged 20–74 years and initially free from cancer. During a mean follow‐up of 14 years, 2,469 primary cancer cases were diagnosed. Excess risks of colorectal and lung cancers were found in subjects with transferrin saturation level exceeding 60%. The relative risks, adjusted for age, sex and smoking, were 3.04 for colorectal cancer and 1.51 for lung cancer, in comparison with subjects having lower levels. The risk of lung cancer was inversely related to serum TIBC, with a relative risk between the highest and lowest quartiles of 0.69 for men and 0.19 for women. For the risk of stomach cancer, we detected inverse relationships with serum iron and with transferring saturation and a positive relationship with TIBC, but these associations weakened when the cancer cases occurring during the 5 first years of follow‐up were excluded. High iron stores may increase th risk of colorectal cancer, whereas low iron stores may be an early sign of occult stomach cancer.
Detection of increased amounts of the extracellular domain of the c‐erbB‐2 oncoprotein in serum during pulmonary carcinogenesis in humans
Authors: Brandt‐Rauf Paul W. , Luo Jiin‐Chyuan , Carney Walter P. , Smith Steven , Devivo Immaculata , Milling Cassandra , Hemminki Kari , Koskinen Heikki , Vainio Harri , Neugut Alfred I.
Published: February 2007

Over‐expression of the c‐erbB‐2 oncogene‐encoded p185 protein product has been implicated in the pathogenesis of a wide variety of human malignancies, including lung cancer. Over‐expression of p185 can be detected immunologically by quantification of the extracellular domain of p185 (c‐erbB‐2 oncopeptide) in extracellular fluid in vitro and in serum in vivo. An enzyme‐linked immunosorbent assay (ELISA) for the c‐erbB‐2 oncopeptide was used to examine banked serum samples of 11 pneumoconiosis patients who subsequently developed lung cancer and serum samples from 11 hospital controls matched for age, sex, ethnic group and smoking as well as 55 unmatched general population controls. The mean serum level for the c‐erbB‐2 oncopeptide in human neu units/ml in the lung cancer cases (1,756 ± 549 HNU/ml) was statistically significantly elevated (p < 0.001) in comparison to the mean level in the matched controls (976 ± 488 HNU/ml) or the general population controls (888 ± 655 HNU/ml). Defining a positive elevation of the serum c‐erbB‐2 oncopeptide as any value more than 2 standard deviations above the mean of the matched controls, 64% (7 of 11) of the lung cancer cases were positive compared to 0% (0 of 11) matched controls and 5% (3 of 55) of the unmatched controls. In addition, 4 of the 7 c‐erbB‐2 oncopeptide‐positive cancer cases had positive serum samples prior to the time of disease diagnosis (average = 35 months). These results suggest that serum c‐erbB‐2 oncopeptide may be elevated at an early stage of pulmonary carcinogenesis and that further prospective study of the utility of this biomarker is warranted.
Angiostatic activities of medroxyprogesterone acetate and its analogues
Authors: Yamamoto Takashi , Terada Nobuyuki , Nishizawa Yasuko , Petrow Vladimir
Published: February 2007

The effects of medroxyprogesterone acetate (MPA) (1) and related compounds (II‐VI) upon angiogenesis induced by basic fibroblast growth factor (bFGF) or transforming growth factor‐α (TGF‐α) were investigated using a rabbit cornea system for assay of angiogenesis. Dexamethasone (Dex) was used as a positive control. The MPA analogues tested were 6,6′‐dehydro MPA (II), megestrol acetate (III), l‐dehydromegestrol acetate (IV), melengestrol acetate (V), and l‐dehydromelengestrol acetate (VI). The inhibitory activities of these steroids using bFGF were in the order: Dex = MPA = (VI) = (V) > (IV) > (III). Steroid (II) was inactive. 5α‐dihydrotestosterone was weakly active, while estradiol‐17β and progesterone were inactive. The angiostatic activity of MPA was completely abolished by mefipristone (RU 486) which showed no anti‐angiogenic activity in this assay. With TGF‐α, the order of angiostatic activities was Dex = (VI) > (IV) > (III) > (V). Steroid (II) was again inactive. Dex, MPA, and all the MPA analogues except steroid (II) markedly inhibited the activity of plasminogen activator secreted by cultured calf pulmonary artery endothelial cells, but did not inhibit growth of these cells. The binding affinities of MPA and its analogues to glucocorticoid, progesterone and androgen receptors were determined, but were found not to be correlated with their angiostatic activities.
Susceptibility of lactating rat mammary glands to gamma‐ray‐irradiation‐induced tumorigenesis
Authors: Suzuki Keiko , Ishi‐Ohba Hiroko , Yamanouchi Hiroshi , Wakabayashi Katsumi , Takahashi Masakazu , Inano Hiroshi
Published: February 2007

Lactating rats of the Wistar‐MS strain were irradiated with 260 cGy of gamma rays 21 days after parturition (day 21). Diethylstilbestrol (DES) pellets were implanted one month after termination of nursing and were allowed to remain for one year. A significantly higher incidence (96.4%) of mammary tumors was observed in these rats irradiated during late lactation than in virgin irradiated animals (30.4%). A control group of lactating animals irradiated during late lactation but not treated with DES was also observed for one year; the final incidence of mammary tumors in this group was 35.3%. The latency period was shortest in the DES‐treated group irradiated during late lactation. Histological examination showed that the mammary glands of lactating rats were highly developed, with alveoli filled with milk. Five days after weaning, there was degeneration of alveolar tissue, concomitant with a marked decrease in the concentration of estrogen and prolactin receptors. A considerable amount of epithelial tissue remained in the mammary glands during the process of atrophy. When the rats were irradiated 5 days after weaning, and then were treated with DES for one year, the incidence of mammary tumors was 73.3%, significantly higher than that in virgin irradiated rats. However, this incidence was not significantly different from that in animals irradiated during late lactation. These results suggested that the induction of mammary tumors by gamma irradiation before or after weaning was more dependent upon the stage of differentiation in mammary glands than upon the proliferative activity of epithelial cells, and that DES is essential as a promoter for radiation‐induced mammary tumorigenesis.
Karyotypic characterization of human T‐cell lines immortalized by Herpesvirus saimiri
Authors: Troidl B. , Simmer B. , Fickenscher H. , Müjller‐Fleckenstein I. , Emmrich F. , Fleckenstein B. , Gebhart E.
Published: February 2007

Merpesvirus saimiri subgroup‐C strains transform non‐neoplastic human T lymphocytes in vrtro to antigen‐independent continuous growth. The karyotypes of 8 of these T‐cell lines, derived from peripheral blood or bone marrow, are analyzed here, In general, these lines showed a normal diploid karyotype, although one of them had acquired a clonal chromosomal rearrangement after 21 months in culture. Chromosomally aberrant cell clones were found more frequently in cell lines derived from blood lymphocytes of leukemia patients than in cultures from healthy donors: However, the observed aberrations, some of which were defined in detail using chromosome in situ suppression hybridization (CISS) with chromosome‐specific recombinant ONA libraries, did not show any relation between the various cell lines nor to the respective types of leukemia.
Inhibition of human B‐cell chronic lymphocytic leukemia by a monoclonal antibody in xenograft models
Authors: Zhu Zhenping , Ghose Tarunendu , Hoskin David , Lee Christine L. Y. , Fernandez Louis A. , Rowden Geoffrey , Lee Spencer H. S.
Published: February 2007

To establish xenograft models of human B‐cell chronic lymphocytic leukemia (CLL), we inoculated S × 106 D10‐1 cells, a subline of Epstein‐Barr virus (EBV)‐transformed human B‐cell CLL with a marker chromosomal anomaly, into SCID or irradiated nude mice by the intravenous (i.v.) or intraperitoneal (i.p.) route. All i.p. tumor‐inoculated mice developed rapidly progressive, lethal ascites tumor, and 100% of i.v. tumor‐inoculated mice developed disseminated CLL. All mice died of tumor within 8 weeks of tumor inoculation. Tumor‐inoculated SCID mice died earlier with wider tumor dissemination than the tumor‐inoculated nude mice. All the tumor‐inoculated mice had histologically confirmed metastases in lymph nodes, and most of them also had metastases in one or more internal organs. Cytogenetic analysis confirmed the origin of these tumors from the xenografted D10‐1 cells. The D10‐1 cells harvested from the xenografts did not differ from the parent D10‐1 cells as regards (i) reactivity with 2 monoclonal antibodies (MAbs) directed against CLL‐associated cell‐surface antigens; (ii) rate of proliferation in vitro; and (Hi) sensitivity to the 2 chemotherapeutic agents, methotrexate and adriamycin. Administration of 50 μg/mouse of Dal B02, an IgG1 (K) MAb directed against surface‐associated antigens of human B‐cell CLL, significantly prolonged the survival of D10‐1‐inoculated nude and SCID mice. The MAb was more effective in D10‐1‐inoculated nude mice than in SCID mice. In all the D10‐1 xenograft models, the effectiveness of Dal B02 decreased with higher tumor load but increased with the amount of MAb injected. Dal B02 F(ab)'2 fragment failed to demonstrate any anti‐tumor activity in D10‐1‐inoculated nude mice. In vttro assays revealed that Dal B02 had no direct inhibitory effect on D10‐1 cells, but could be cytotoxic towards D10‐1 cells in the presence of splenic cells or peritoneal macrophages from nude and SCID mice, or together with rabbit complement.
p53 genetic abnormalities and myc activation in human lung carcinoma
Authors: Gazzeri Sylvie , Brambilla Elisabeth , De Fromentel Claude Caron , Gouyer Valérie , Moro Denis , Perron Pascal , Berger François , Brambilla Christian
Published: February 2007

p53 mutations and myc gene amplification and expression were studied in 119 lung carcinomas of all histological types. A mutant p53 immunophenotype was previously found in 47% of these tumors by immunohistochemical analysis. Seven cases exhibited p53 genomic rearrangements on Southern blots. Elevated levels of p53 transcript were found in 12 carcinomas (10%) and decreased levels in 27 carcinomas (23%) on Northern blots. In most of the cases, low levels of transcript were associated with negative immunostaining, whereas elevated levels of mRNA were related to positive immunostaining (mutant immunophenotype). p53 RT/PCR analysis in 10 tumors with absence of transcript on Northern blots revealed only weak or absent expression of normal and/or altered size transcripts. These abnormal transcripts showed deletions, insertions or splicing abnormalities. Taken together, p53 abnormalities were found in 66% of lung carcinomas [52% of neuroendo‐crine (NE) carcinomas and 75% of NSCLC]. c‐myc was found to be activated in 24% (10/42) of these NE and in 48% (33/69) of these NSCLC carcinomas using Southern‐ and Northern‐blot techniques. In addition, L‐ and N‐myc genes were also activated in 26% (10/42) of NE carcinomas. No correlation was found between p53 mutations and myc activation in SCLC or in NSCLC, but their association was significantly more frequent in NSCLC than in SCLC. These results indicate that the p53‐positive immunophenotype uncovers the occurrence of p53 point mutations in lung cancer and that p53 and c‐myc gene alterations are important but represent independent occurrences in the development of lung tumors.
Epstein‐barr virus (EBV)‐related lymphoproliferative disorder with subsequent EBV‐negative T‐cell lymphoma
Authors: Tao Qian , Srivastava Gopesh , Loke Shee Loong , Liang Raymond H. S. , Liu Yan Tat , Ho Faith C. S.
Published: February 2007

A 58‐year‐old Chinese man presented initially with generalized lymphadenopathy, and lymph‐node biopsy showed disturbed architecture with preponderance of large B‐blasts mixed with numerous CD8+ T lymphocytes, consistent with an acute Epstein‐Barr virus(EBV) infection. Immunohistological and gene rearrangement studies confirmed the absence of clonal T or B cells. Polyclonal EBV with lytic infection was detected by Southern blot hybridization (SoBH). Expression of EBV proteins (EBNA2, LMP and ZEBRA) was detected in a proportion of cells by immunostaining. EBV‐lytic proteins EA‐D, VCA, MA were also detected in rare scattered cells. Double immunostaining showed that the LMP‐positive cells were of B and of T phenotype: 73% CD19+, 26% CD2+ 23% CD3+ 8% CD4+ 17% CD8+. After biopsy, there was spontaneous regression of lymph‐node enlargement, but lymphadenopathy recurred 8 months later, and the second lymph‐node biopsy showed T‐cell lymphoma, confirmed by detection of clonally rearranged T‐cell‐receptor beta‐chain gene. However, EBV genome could not be detected in the second biopsy by SoBH, in situ hybridization for EBV‐encoded EBER RNA, and immunostaining for EBNA2, LMP and ZEBRA was also negative. This case is of special interest because an EBV‐negative T‐cell lymphoma developed shortly after an acute episode of EBV‐related lymphoproliferation, even though many EBV‐positive T cells were detected during the acute episode. EBV was apparently not a direct cause of the lymphoma, but the close temporal association of the 2 lesions supports the hypothesis that EBV can act as a co‐factor in lymphomagenesis. © 1994 Wiley‐Liss, Inc.
Time trends in the incidence of renal carcinoma: Analysis of connecticut tumor registry data, 1935‐1989
Authors: Katz David L. , Zheng Tongzhang , Holford Theodore R. , Flannery John
Published: February 2007

Recent trends in the incidence of renal cancer, stratified by histology, have not been reported. This study utilized data from the Connecticut Tumor Registry (CTR), the oldest population‐based cancer registry in the United States, to establish time trends in the incidence of adenocarcinoma and transitional cell carcinoma of the kidney and urinary tract. All 10, 209 incident cases of renal cancer reported to the CTR between 1935 and 1989 were analyzed. Regression modelling was employed to determine the effects of age, period, and birth cohort on incidence rates, and to project future trends. The incidence rate of adenocarcinoma increased in females from 0.7/100,000 in 1935‐39, to 4.2/100.000 in 1905‐89; and in males, from 1.6 J. 100,000 in 1935‐39, to 9.6/100,000 in 1985‐89. The reported incidence of transitional cell carcinoma increased in males from 0.5/100,000 in 1950‐54 to 2.8/100,000 in 1985‐89, and in females from 0.2/100,000 to 1.1/100,000 over the same period. Regression modelling revealed that both net and recent drift, the sum of period and cohort slopes, were positive for adenocarcinoma in both sexes, largely due to a positive cohort effect. While the net drift for transitional cell carcinoma was positive, recent drift was negative in both sexes due primarily to a negative cohort effect. Incidence rates of adenocarcinoma are likely to rise in the immediate future, with the rate of rise in females possibly exceeding that in males. Incidence rates of transitional cell carcinoma will stabilize. © 1994 Wiley‐Liss, Inc.