bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of interleukin‐2‐receptor‐targeted cytotoxins on a unique model of murine interleukin‐2‐receptor‐expressing malignancy
Authors: Bacha Patricia A. , Forte Serene E. , McCarthy Donna M. , Estis Leonard , Yamada Gen , Nichols Jean C.
Published: February 2007

DAB486IL‐2 is a genetically engineered fusion protein consisting of a portion of diphtheria toxin fused to human IL‐2. It is specifically cytotoxic for tumor cells which bear high‐affinity IL‐2 receptors (IL‐2R). DAB389IL‐2 is a similarly constructed hybrid protein which is smaller than DAB486IL‐2 and is slightly more potent in vitro. We have developed a murine model of IL‐2R‐expressing malignancy to study the in vivo efficacy of these genetically engineered cytotoxins. Following intravenous administration of CP3 cells, C57BL/6 mice develop tumors which are lymphatic in distribution. When mice are injected i.v. with 106 CP3 cells, 90% of the animals show signs of observable tumor by day 10 to 20; death occurs in 50% of untreated animals by day 30. Intravenous treatment of mice with DAB486IL‐2 (10 μg daily for 10 days), beginning 24 hr after administration of CP3 cells, increases mean survival time by approximately 50%. In comparative studies, DAB389IL‐2 is more potent in vivo than DAB486IL‐2, with approximately 90% of treated animals with no evidence of tumor at 60 days. The mechanism of action of tumor inhibition by DAB486IL‐2 is specific, since treatment of animals which have 1L‐2R‐negative EL4 tumors has not resulted in increased survival time. In addition, treatment of such tumors with DAglu53B486IL‐2, a fusion protein which can bind to the IL‐2R but is incapable of inhibiting protein synthesis, is ineffective.
Regulation of protein kinase a activation and prostaglandin E2‐stimulated migration of lewis lung carcinoma clones
Authors: Young M. Rita , Young Melvin E. , Lozano Yvonne , Coogan Michael , Bagash Jamila M.
Published: February 2007

Lewis lung carcinoma (LLC) clones were used in in vitro models for dissemination to identify mechanisms regulating the stimulation of metastatic LLC‐LN7 migration by prostaglandin E2 (PGE2) or forskolin plus 3‐isobutyl‐I‐methyl‐xanthine (IBMX), and the lack of responsiveness to generated cAMP in non‐metastatic LLC‐C8 cells. The regulatory subunits of protein kinase A (PKA) from LLC‐LN7 cells bound more 8‐N3‐32P‐cAMP, even though production of regulatory subunits was equal to that in LLC‐C8 cells. Protein kinase C (PKC) differentially regulated PKA activation in the LLC variants. PKC activation inhibited PGE2‐stimulated migration by LLC‐LN7 cells. Inhibition of PKC with staurosporine stimulated LLC‐LN7 cell migration to a level comparable with that induced by PGE2. However, PGE2 did not further stimulate the migration of staurosporine‐treated cells. The PGE2 or staurosporine stimulation of LLC‐LN7 cell migration was dependent on PKA activation. The effects that modulation of PKA and PKC had on LLC‐LN7 cell migration paralleled the effects on endogenous protein phosphorylation. LLC‐LN7 cell autophosphorylation was stimulated to a similar degree by PGE2, forskolin plus IBMX, staurosporine, or the combination of staurosporine and forskolin plus IBMX. In contrast, neither migration nor autophosphorylation was stimulated in nonmetastatic LLC‐C8 cells by cAMP elevation or by PKC inhibition. Autophosphorylation, although not migration, of LLC‐C8 cells was stimulated by forskolin plus IBMX when PKC activity was inhibited. These results suggest that the increased PKA response of metastatic LLC‐LN7 cells is contributed by an increased binding of cAMP by the PKA regulatory subunits and a reduced level of regulation by PKC.
Tumor progression in human malignant melanoma is associated with changes in α6/β1 laminin receptor
Authors: Natali Pier Giorgio , Nicotra Maria Rita , Cavaliere Renato , Giannarelli Diana , Bigotti Aldo
Published: February 2007

Cells of the melanocytic lineage have been shown to be capable of producing laminin and to lose this property during transformation. In the present study, we have evaluated immunohistochemically whether these changes are paralleled by an altered expression of the α6/β1 laminin receptor. Results of this analysis have shown that while nevic cells display high levels of the receptor, this heterodimer undergoes a progressive decrease in expression in cutaneous melanomas of increasing invasiveness. A loss or unco‐ordinated expression of the α1/β complex is present in the majority of the metastatic foci at different body sites. The present results show that during transformation the α6/β1 laminin receptor undergoes quantitative alterations and deregulated expression of the 2 subunits. Although the functional relevance of these changes remains unknown, their occurrence in association with modifications of other cellular and extracellular macro‐molecules associated with tumor progression, strongly suggests a role in human melanoma progression.
Serological discrimination between HTLV‐I and HTLV‐II antibodies by elisa using synthetic peptides as antigens
Authors: Washitani Yukiko , Kuroda Naotaka , Shiraki Hiroshi , Nishimura Youko , Yamaguchi Kazunari , Takatsuki Kiyoshi , Fernando Leonor P. , Fang Chyang T. , Kiyokawa Hiroyuki , Maeda Yoshiaki
Published: February 2007

Using the peptides from amino acids 100‐130 of the HTLV‐I gag protein, 175‐199 of the HTLV‐I env protein and the corresponding peptides of HTLV‐II (amino acids 106 to 135 of the gag protein and 171 to 196 of the env protein), we tested for reactivity against antibodies by enzyme immunoassay in sera from HTLV‐I and HTLV‐II carriers. The peptides derived from the env proteins have high specificity for antibody binding. The peptide based on amino acids 175‐199 of HTLV‐I reacted with antibodies in sera from all HTLV‐I carriers, and the peptide composed of amino acids 171‐196 of HTLV‐II reacted with antibodies in sera from all HTLV‐II carriers. For the peptides derived from the gag proteins, we observed some cross‐reactivity in sera from persons with anti‐HTLV‐I and anti‐HTLV‐II, due to antibody binding to the peptide corresponding to 12 amino acids from the C‐terminal end of the gag protein. Separate enzyme immunoassays that used the four synthetic peptides as antigens clearly distinguished between serum with antibodies to HTLV‐I or HTLV‐II in various individuals and excluded false positive results using the particle agglutination assay that used a whole‐virus lysate of HTLV‐I as antigen.
Depot‐medroxyprogesterone acetate (DMPA) and risk of liver cancer
Authors:   THE WHO COLLABORATIVE STUDY OF NEOPLASIA AND STEROID CONTRACEPTIVES, Mati J. G. , Kenya P. , Kungu A. , Gatei D. , Silpisoronkosol Suporn , Pardthaisong Tieng , Sahapong Virote , Theetranont Choti , Boosiri Banpot , Chutivongse Supawat , Virutmasen Pramuan , Wongsrchanalai Chansuda , Sindhvananda Sermsri , Koetsawang Suporn , Rachawat Daungdao , Koetsawang Amom , Anthony P. P. , Thomas David B. , Noonan Elizabeth A. , Ray Roberta M. , Rosenblatt Karin A. , Stanford Janet L. , Holck Susan , Farley Timothy M. M. , Rosenblatt Karin A. , Thomas David B.
Published: February 2007

A hospital‐based case‐control study was conducted to assess the possible relationship between use of depot‐medroxy‐progesterone acetate (DMPA), an injectable progestational contraceptive, and the development of liver cancer in 2 developing countries where hepatitis B is endemic. Information about prior DMPA use and potential confounders was ascertained during personal interviews with 71 cases and 530 controls from 3 hospitals in Thailand and 1 hospital in Kenya. No significant association between liver cancer and DMPA use was observed in Kenya (RR = 1.64, 95% CI = 0.4‐0.6) or Thailand (RR = 0.33, 95% CI = 0.1‐1.O). No consistent changes in risk were observed with duration of use, time since last use, or time since first use. No significant associations were observed between DMPA use and risks of either hepatocellular carcinoma or cholangiocarcinoma. These findings suggest that risk of liver cancer in areas where hepatitis B is endemic is not appreciably altered by the use of DMPA.
p53 Protein alterations in human testicular cancer including pre‐invasive intratubular germ‐cell neoplasia
Authors: Bártkov´ Jir̂ina , Bártek Jir̂í , Lukáŝ Jir̂ina , Vojtêŝek Bor̂ivoj , Staŝková Zdenka , Rejthar Aleŝ , Kovar̂ík Jan , Midgley Carol A. , Lane David P.
Published: February 2007

Expression of the p53 oncoprotein was examined in a wide range of primary human testicular germ‐cell tumours using a new mouse monoclonal antibody (MAb) BP53‐11 raised and characterized in this study, in parallel with a polyclonal rabbit antiserum CM‐1. Immunohistochemistry on paraffin sections showed positive nuclear reaction in at least a fraction of malignant cells in 90 (84%) out of 107 cases studied. Aberrant accumulation of the p53 protein was found among testicular tumours of all major histological types, although generally a higher percentage of positive cases and a higher proportion of p53 over‐expressing nuclei within individual lesions was observed in embryonal carcinomas when compared with seminomas. The typical heterogeneous staining pattern characteristic of histological specimens was also found in a cultured cell line derived from a human embryonal carcinoma. In contrast to immunohistochemically undetectable levels in normal tes‐tes and morphologically normal tissue areas in the tumour‐bearing testes, the accumulation of the p53 protein was clearly identified in a high proportion (59% of cases) of the pre‐invasive lesions with positive atypical intratubular germ cells often found in the tissue adjacent to invasive tumours. Altered expression of the p53 protein is therefore a unifying feature of the majority of invasive male germ‐cell tumours and the change resulting in high levels of p53 appears to be a relatively early step in the human testicular cancer pathogenesis.
Diet and bladder cancer in Spain: A multi‐centre case‐control study
Authors: Riboli Elio , González Carlos A. , López‐Abente Gonzalo , Errezola Manuel , Izarzugaza Isabel , Escolar Antonio , Nebot Manuel , Hémon Bertrand , Agudo Antonio
Published: February 2007

A multi‐centre case‐control study on bladder cancer and diet was carried out in 5 regions of Spain. We report results on 432 male cases and 792 matched controls. Usual dietary habits were investigated by means of an interview‐based dietary history questionnaire. Bladder‐cancer cases were selected from the registers of 12 hospitals located in the study areas. Each case was matched by sex, age and area of residence to 2 controls, one identified in the same hospital and one drawn from population lists. Descriptive analyses indicated that the average dietary pattern was typical of Mediterranean populations: a high P/S ratio, high intake of fish, fruits and vegetables and moderate or low intake of meat and dairy products. Relative risks for specific foods and nutrients were adjusted for tobacco smoking and energy intake. Subjects in the highest quarter of intake of saturated fat had a significantly increased risk of bladder cancer (RR for highest quarter = 2.25; 95% CI = 1.42 to 3.55). Moderate increases in risk for high intake of mono‐unsaturated fats and calcium, and a slight decrease for iron were also found, but these disappeared after adjustment for saturated fat. Intake of vitamin E was related to slightly reduced risk (RR for highest quarter = 0.72; 95% CI = 0.48 to 1.09) which was not modified by adjustment for fat. No association was found with intake of retinol or carotene. These results, along with those of previous studies, suggest that saturated fat intake may influence the occurrence of bladder cancer.
Prediction of antifolate efficacy in a rat sarcoma model
Authors: Li Wei Wei , Lin James T. , Chang Y. M. , Schweitzer Barry , Bertino Joseph R.
Published: February 2007

A methylcholanthrene‐induced rat sarcoma propagated both in vitro and in vivo was used to examine the usefulness of a rapid biochemical in situ assay that measures thymidylate synthase (TS) activity in whole cells to predict sensitivity and resistance to the folate antagonists methotrexate (MTX), 10‐ethyl‐10‐deazaaminopterin (10‐EDAM) and trimetrexate (TMTX). There was an excellent correlation between the effects of these drugs on inhibiting TS and cytotoxicity as measured by a clonogenic assay, when the exposure time was 4 hr, and those when the rat sarcoma cell line was employed (p < 0.001). When tumor‐cell suspensions were prepared from the rat sarcoma propagated in vivo, they were less sensitive to these antifolates, but the relative effectiveness of the 3 antifolates was similar: TMTX ≫ 10‐EDAM > MTX. As expected, continuous exposure (10 to 12 days) produced cytotoxicity at a much lower dose of these drugs. When the 3 drugs were tested for anti‐tumor effectiveness in rats bearing this tumor, the tumor regression measured was best with TMTX; 10‐EDAM was intermediate in effectiveness as compared with MTX. These results indicate that the in situ TS assay and clonogenic assay may be used to predict anti‐tumor efficacy of antifolates in vivo in this rat sarcoma.
Selective induction of endothelial cell tissue factor in the presence of a tumour‐derived mediator: A potential mechanism of flavone acetic acid action in tumour vasculature
Authors: Clifford Murray J. , Clauss Matthias , Denekamp Juliana , Stern David
Published: February 2007

Flavone acetic acid (FAA) is a potentially useful anti‐tumour agent which has been reported to induce changes in tumour vasculature, in particular loss of bloodflow. This led us to examine whether endothelium could be a cellular target of FAA action, with resultant modulation of cell‐surface coagulant properties leading to activation of coagulation and blockade of tumour blood flow. Incubation of endothelium with FAA led to the expression of functional tissue factor on the cell surface, in a time‐dependent and dose‐dependent (half‐maximal at 0.6‐0.7 mg/ml) manner. Induction of tissue‐factor activity resulted from de novo translation of the tissue factor message. To explain the selectivity of FAA's action on tumour vasculature in vivo, we considered its interaction with tumour‐derived factors. Starting with serum‐free FO‐I‐melanoma cell‐conditioned medium, a co‐factor enhancing FAA‐mediated induction of endothelial tissue factor (FO‐I factor) was partially purified by sequential ion exchange and reverse phase chromatography, followed by preparative SDS‐PAGE. The FO‐I factor migrates with an apparent Mr of approx. 20 to 25,000 on non‐reduced SDS‐PAGE, is sensitive to protease K, and augments the effect of FAA on endothelial‐cell‐tissue factor. This activity is not found in supernatants from non‐neoplastically transformed cell lines. These data lead us to hypothesize that FAA exerts its action, at least in part, by promoting activation of coagulation on the endothelial surface, and this effect is selective for the tumour bed by virtue of its interaction with a tumour‐derived factor. The interaction of FAA with host factors may be important for optimizing its therapeutic efficacy for a particular tumour.
Synergistic anti‐tumor effects of combined IL‐1/IFN‐α/β therapy in mice injected with met astatic friend erythroleukemia cells
Authors: Belardelli F. , Gabriele L. , Proietti E. , Sestili P. , Peretti M. , Rozera C. , Gresser I.
Published: February 2007

Peritumoral injection of relatively low doses of either mouse interferon (IFN)‐α/β (10,000‐20,000 unit/injection) or of recombinant human interleukin‐I (IL‐1) β (125‐250 ng/ injection) in mice transplanted S.C. with Friend erythroleukemia cells (FLC) resulted in some inhibition of primary tumor growth, inhibition of liver and splenic metastases and increased survival time. A synergistic anti‐tumor effect was observed in mice injected with both IL‐l and IFN‐α/β. Highly purified mouse IFN‐β also exerted a synergistic anti‐tumor effect when combined with IL‐I‐β in mice injected with FLC. The anti‐tumor action of IL‐I/IFN was markedly reduced in mice treated with antibodies to CD4 antigens. Antibodies to asialo‐GM1 also diminished the anti‐tumor effect by the combined cytokine treatment. The combined IL‐I/IFN therapy was effective in NK‐deficient bg/bg mice, although the extent of the anti‐tumor response in these mice was less than that observed in bg/+ mice.
Subcellular localization, redistribution and photobleaching of sulfonated aluminum phthalocyanines in a human melanoma cell line
Authors: Peng Q. , Farrants G. W. , Madslien K. , Bommer J. C. , Moan J. , Danielsen H. E. , Nesland J. M.
Published: February 2007

Intracellular localization, intracellular translocation and photobleaching following non‐lethal laser microirradiation of the fluorescing derivatives of sulfonated aluminum phthalocyanines (A1‐PcSn, n = 1‐4) in a human melanoma cell line (LOX) were studied by means of confocal laser scanning microxopy (LSM) and image processing. Use of confocal microscopy allowed 3‐dimensional information to be obtained. Both A1‐PcS1, and A1‐PcS2, localized diffusely in the cytoplasm of the cells, while A1‐PcS3, and A1‐PcS4, exhibited a granular pattern in the extranuclear fraction of the cells. None of the A1‐PcSn, family was observed in the nuclei of the cells except that a small fraction of fluorescence was occasionally detected in nuclei of some cells treated with A1‐PcS1, and A1‐PcS2. Furthermore, exactly the same granular localization patterns and positions in the same cells were found after incubation initially with A1‐PcS3, (or A1‐PcS4,) followed by acridine orange (AO) which emits red fluorescence from lysosomes of cells. Thus, the granular fluorescence of A1‐PcS3, and A1‐PcS4, is confined to the lysosomes of the LOX cells. Non‐lethal laser exposure of cells incubated with high concentrations of the 2 dyes resulted in a translocation of the dyes from the lysosomes to the whole cytoplasm and an increase in total intracellular fluorescence intensity. Finally, a small fraction of the dyes localized into the nuclei of the cells. The laser exposure of cells incubated with low concentrations of the lysosomally localized dyes resulted in an increase in the intracellular fluorescence intensity with no translocation of the dyes. Under all conditions, high laser exposure resulted in a decrease in the total intracellular fluorescence intensity.
Tumoricidal alveolar macrophage and tumor infiltrating macrophage cell lines
Authors: Palleroni Alicia V. , Varesio Luigi , Wright Rosemary B. , Brunda Michael J.
Published: February 2007

Continuous alveolar macrophage (AM) and tumorinfiltrated (TIM) cell lines have been generated from C57B16J mice by in vitro infection with the J2 retrovirus carrying the v‐raf and v‐myc oncogens. Four cloned AM cell lines (AMJ2‐C8, AMJ2‐C10, AMJ2‐C11, AMJ2‐C20) and 3 cloned TIM cell lines (TIMJ2‐C4, TIMJ2‐C7 and TIMJ2‐C15) were expanded for further characterization. Flow cytometry detected the product of the raf gene in the cytoplasm of all these cell lines. Studies on the tumoricidal properties of these AM and TIM cell lines demonstrated differences in their response to a panel of known macrophage activators. Four of these cell lines (AMJ2‐C8, AMJ2‐C10, TIMJ2‐C7 and TIMJ2‐C15) were activated following exposure to recombinant murine interferon gamma (rMuIFN‐γ) but not lipopolysaccharide (LPS) or muramyl dipeptide (MDP). AMJ2‐C20 was only activated by incubation with rMuIFN‐γ plus LPS. AMJ2‐C11 and TIMJ2‐C4 are the cell lines that most closely resembled the response pattern of the parental AM and TIM, since they could be activated by either the combination of rMuIFN‐γ plus LPS or rMuIFN‐γ plus MDP. Constitutive expression of MHC‐class‐II antigens was low on AMJ2‐C11 or TIMJ2‐C4 but was increased following exposure to rMuIFN‐γ. Neither cell line secreted substantial amounts of IL‐1 or TNF but both secreted large amounts of IL‐6. Thus these cell lines could be powerful tools to study AM and TIM activation and cytotoxicity.
Survival of leukemic cells in a dormant state following cyclophosphamide‐induced cure of strongly immunogenic mouse leukemia (DL811)
Authors: Matsuzawa Akio , Takeda Yasutaka , Narita Mutsumi , Ozawa Hideki
Published: February 2007

The B‐cell leukemia line, DL811, established in DDD mice, has been characterized by strong immunogenicity leading to occasional spontaneous cure with tumor dormancy. Cyclophosphamide (CY) is an available chemo‐immunotherapeutic agent. The effects of CY on the cure and dormancy of DL811 leukemias were investigated. Simultaneous injection of DL811 cells and CY into athymic nude mice revealed that DL811 cells were sensitive to CY doses of 0.5 mg and more per mouse in a dose‐related manner. A single dose of 1 mg CY on day 7 after DL811 cell inoculation was most curative of disseminated leukemias (cure rate: 50‐80%) as compared with other single CY doses at different times. Cured mice were strongly immune to DL811 leukemias. This therapeutic modality had no curative effect in athymic nude mice. Relapses occurred occasionally in CY‐cured mice and most relapsed tumors had the same surface phenotype as that of the DL811 leukemia. In comparison with DL811 leukemias, however, relapsed tumors were less sensitive to rejection by cured mice and less frequently cured by a single dose of 1 mg CY on day 7 of inoculation, implying that they changed in antigenicity and drug sensitivity. Whole‐body irradiation of 400 rad γ‐rays to cured mice raised the incidence of relapses from 22.9 to 44.7% and that of deaths from relapses from 8.6 to 26.3%. Thus, leukemic cells may survive against host immune surveillance in a dormant state and relapse after changing their immunologic and chemotherapeutic natures. Lyt‐2+, L3T4‐ T cells appeared to mediate host anti‐tumor immunity to eradicate leukemic cells and maintain dormant state.
Production and characterization of two immunotoxins specific for M5b ANLL leukaemia
Authors: Tecce R. , Fraioli R. , De Fabritiis P. , Sandrelli A. , Savarese A. , Santoro L. , Cuomo M. , Natali P. G.
Published: February 2007

We describe the production and functional characterization of 2 monocytic‐cell‐lineage‐specific immunotoxins constructed with saporin emitoxin (SAP) from Saponaria officinalis. Interest in the production of these immunotoxins, of possible clinical relevance, has been raised by the availability of 2 MAbs of high specificity for circulating monocytes and M5b ANLL, thus envisaging their potential use in bone‐marrow purging. SAP emitoxin was selected on the basis of the low cytotoxicity in unconjugated form, as opposed to highly specific cytotoxicity and favourable pharmacokinetical properties in the conjugated form. SPDP conjugation produced immunotoxins which retained serological specificity and protein‐synthesis‐inhibitory activity. The 2 immunotoxins did not interfere with bone‐marrow progenitor‐cell growth in a CFU‐GM colony assay. On the contrary, they were capable of killing monocytic cells selectively, as demonstrated in phenotypical and functional assays. Thus these 2 novel immunotoxins appear to be promising reagents in purging autologous bone marrow prior to transplantation in patients suffering from monocytic leukaemia.
Changes in glycolipids in human renal‐cell carcinoma and their clinical significance
Authors: Sito Seiichi , Orikasa Seiichi , Ohyama Chikara , Satoh Makoto , Fukushi Yasuo
Published: February 2007

The expression patterns of glycolipids of human renal‐cell carcinoma were studied in primary tumors from 23 cases and 5 metastatic lesions from 4 cases using HPTLC (high‐performance thin‐layer chromatography). The expression pattern of glycolipids in primary tumors was characteristic of the histological cell type. In granular‐cell carcinoma, lactosylceramide (CDH), GM3 and the longer‐chain gangliosides (gangliosides migrating more slowly than GM3) increased, although in clear‐cell carcinoma, CDH and other glycolipids tended to decrease. Globoside decreased in all cases but one, irrespective of cell type. In metastatic lesions of the clear‐cell type, the prominent increase in longer‐chain gangliosides was characteristic. Furthermore, the same expression pattern as that of metastastatic lesions was shown in 3 of 14 patients with primary clear‐cell carcinoma, all of whom developed metastases soon after radical nephrectomy. These studies indicate that the increased expression of the longer‐chain gangliosides in primary tumor is one of the factors associated with high metastatic potential, and also predict early post‐operative development of metastasis.
Effects of HC antibody in autologous tumor‐specific cytotoxicity by human melanoma tumor‐infiltrating lymphocytes
Authors: Mansfield Paul F. , Salmeron Marie A. , Rosenblum Michael G. , Itoh Kyogo
Published: February 2007

Heteroconjugate (HC) antibody has a potential use in cancer biotherapy because of its ability to mimic antigenic specificity and induce cytotoxicity in the activated lymphocytes against various tumor cells. This study investigated the effects of HC antibody (anti‐CD3 MAb x anti‐p97 melanoma cell MAb) in autologous tumor‐specific cytotoxicity by interleukin‐2 (IL‐2)‐activated melanoma tumor‐infiltrating lymphocytes (TILs). HC antibody significantly augmented p97pos uncultured autologous tumor cell lysis mediated by effector TILs or cytotoxic T lymphocyte (CTL) clones derived from TIL. It did not significantly increase p97mix autologous tumor‐cell lysis and slightly inhibited the lysis only at higher E:T ratios and higher concentrations (≥ 100 ng/ml). It inhibited p97neg autologous tumor‐cell lysis. HC antibody respectively induced potent lysis of p97pos or modest lysis of p97mix tumor cells by allogeneic effector TILs as well as PBMC. In contrast, parental anti‐CD3 MAb primarily suppressed the autologous tumor‐specific cytotoxicity, and did not induce lysis of uncultured melanoma cells, regardless of differences in expression of p97 antigens on tumor cells. Although parental anti‐p97 MAb did not augment or suppress the autologous tumor‐specific cytotoxicity, it completely abrogated HC antibody‐mediated augmentation of p97pos autologous tumor cell lysis by effector TILs. Anti‐class‐IMAb, but not anti‐DR MAb, suppressed the autologous tumor‐specific cytotoxicity, but failed to block HC antibody‐mediated augmentation of p97pos autologous tumor‐cell lysis. These results suggest that the levels of p97 antigen expression largely influenced HC antibody‐mediated modulation of TIL cytotoxicity against uncultured autologous tumor cells.
Tra‐1‐60: A new serum marker in patients with germ‐cell tumors
Authors: Marrink J. , Andrews P. W. , Van Brummen P. J. , De Jong H. J. , Sleijfer D. T. H. , Schraffordt Koops H. , Oosterhuis J. W.
Published: February 2007

TRA‐1‐60 is a monoclonal antibody (MAb) that recognizes a mucin‐like antigenic determinant expressed on the surface of embryonal carcinoma (EC) progenitor cells. In order to determine whether this antigen is released into the serum of patients with a non‐seminomatous germ‐cell tumor (NSGCT), we developed a sensitive 2‐step immunoenzymometric assay. Of 42 EC‐positive NSGCT patients tested, 32 (76%) were found to release TRA‐1‐60‐reactive antigen into their serum, in contrast to 1 positive finding in 10 EC‐negative NSGCT patients. The marker was found in 67% (10/15) of the EC‐positive patients who were negative for both AFP and HCG. Sera from seminoma patients did not contain elevated levels of the TRA‐1‐60 antigen. Therefore, we propose that the TRA‐1‐60 antigen is a useful additional serum marker for following the progress of NSGCT(EC+) patients.
Prevalence of HTLV‐I and HTLV‐II infection in gabon, africa: Comparison of the serological and pcr results
Authors: Delaporte Eric , Monplaisir Nicole , Louwagie Joost , Peeters Martine , Martin‐Prével Yves , Louis Jean‐Paul , Trebucq Arnaud , Bedjabaga Léonard , Ossari Simon , Honoré Cécile , Larouzé Bernard , d'Auriol Luc , Van DerGroen Guido , Piot Peter
Published: February 2007

A cluster sampling survey was performed in 1989 in Libreville, Gabon, to determine HTLV‐1 and HTLV‐11 prevalence and to compare the efficacy of polymerase chain reaction (PCR) and serology in detecting HTLV‐1 and HTLV‐11 infections. A total 322 sera from adults were tested by ELISA and by Western blot (WB). The WB patterns were interpreted according to WHO criteria and those of the manufacturer. PCR analysis using primer pairs in the gag and pol region, with a specific probe for HTLV‐1 and HTLV‐11, was performed on the lymphocytes of the 322 adults. In addition, 134/322 samples were re‐tested with tax primers, in a second laboratory. Using WHO criteria, 8/322 (2.5%) samples were positive on WB and 25 were indeterminate; with the criteria of the kit, 26/322 (8.1%) were positive and 7 were indeterminate by WB. By PCR, 13 (4%) samples were positive, including 12 for HTLV‐1 (3.7%) and one for HTLV‐11 (0.3%). All 8 seropositive samples (by the WHO criteria) were positive by PCR, as were 4 out of 25 indeterminate samples. Only one out of 289 seronegative samples was positive by PCR. In contrast, only 12/26 positive samples by the kit criteria were confirmed by PCR. These results confirm the relatively high HTLV‐1/11 seroprevalence observed in Gabon. HTLV‐1 infection is preponderant, but HTLV‐11 is also present. The WHO criteria for WB give a better fit with PCR results than the kit criteria for WB. In the absence of a specific confirmatory test and based on the uncommon „seronegative”︁ HTLV‐1/11 infection, the indication for PCR appears limited to the positive WB samples (to differentiate HTLV‐1 and 11 infection) and to the indeterminate WB samples.
Effect of cigarette smoking and alcohol consumption in the etiology of cancers of the digestive tract
Authors: Choi Soo Yong , Kahyo Hiroaki
Published: February 2007

This study presents the comparative patterns of risk of selected digestive tract cancers (esophagus, stomach, colon, rectum and liver) for males in relation to cigarette smoking and alcohol drinking, based on the data from case‐control studies conducted in the Korea Cancer Center Hospital (KCCH). There was strong positive association between cigarette smoking and esophageal cancer, but none of the other sites was significantly related to cigarette smoking. In esophageal cancer, a dose‐ dependent effect for cigarette smoking was observed, with the odds ratio ranging from 1.29 for ever smoking up to 1 pack daily to 3.17 for smokers of more than 2 packs per day. The risk declined markedly following cessation of smoking. Cancers of the esophagus, rectum and liver were strongly related to alcohol consumption. Compared with non‐drinkers, the OR for heavy drinkers was 9.14 in esophageal cancer, 4.75 in rectal cancer and 2.46 in liver cancer. In cancer of the stomach and colon, however, there was no association with alcohol drinking.
Autocrine control of human meningioma proliferation: Secretion of platelet‐derived growth‐factor‐like molecules
Authors: Adams Eric F. , Todo T. , Schrell U. M. H. , Thierauf P. , White M. C. , Fahlbusch R.
Published: February 2007

We have used cell‐culture techniques to investigate growth‐ factor production by human meningioma cells. Meningioma tissue was dispersed with collagenase and the cells grown to high density in tissue‐culture flasks. The cultures were used to generate conditioned medium (MEN‐CM), which was used to cultivate IMR32 cells (a human neuroblastoma line) and freshly dispersed primary meningioma cells. MEN‐CM profoundly stimulated the in vitro growth of both IMR32 and meningioma cells. In addition, H3‐thymidine uptake by cultured meningioma cells was increased in a dose‐dependent manner by varying concentrations of MEN‐CM. A neutralizing anti‐body against platelet‐derived growth factor (PDGF) completely abolished the stimulatory effects of MEN‐CM, whereas an antibody against TGF‐α was without effect. The mitogenic activity of MEN‐CM, as assayed by promotion of H3‐thymidine uptake by cultured meningioma cells, eluted from a Sephadex G‐100 column in 3 peaks corresponding to molecular weights of ≥ 150, 56 and 28 kDa. Our results show that proliferation of human meningiomas may be under autocrine control via secretion of PDGF‐like molecules.
Increased ether lipid cytotoxicity by reducing membrane cholesterol content
Authors: Diomede Luisa , Piovani Bianca , Modest Edward J. , Noseda Alessandro , Salmona Mario
Published: February 2007

Ether‐linked glycerophospholipids (ether lipids, EL) are selectively toxic and anti‐proliferative agents against cancer cells in vitro. The reason for such selectivity is not completely clear. Their mechanism of action is mediated through an interaction with the plasma membrane and the membrane lipid composition may modulate it. As a continuation of previous reports, we now present data showing that cholesterol concentration modulates EL toxicity in the K562, U937 and MOLT4 leukemic cell lines in vitro. Cells become sensitive to otherwise ineffective doses of EL when their cholesterol content is lowered. Cell cholesterol levels were reduced by exposure to an egg lipid mixture (neutral glycerides, phosphatidylcholine and phosphatidylethanolamine, AL721). The data contribute to an understanding of the EL mechanism of action on membranes and suggest that the cellular cholesterol concentration must be considered a major factor in modulating the cytotoxic effects of EL.
Activation of an alpha‐fetoprotein (AFP)/receptor autocrine loop in HT‐29 human colon carcinoma cells
Authors: Esteban Cristina , Geuskens Maurice , Uriel José
Published: February 2007

Immunological and morphological approaches have been used to demonstrate, respectively, alpha‐fetoprotein (AFP) synthesis and receptor expression in the HT‐29 human colon carcinoma parental cell line. HT‐29 cells cultivated in the presence of glucose synthesized and secreted AFP in the medium from 48 to 96 hr after seeding, as revealed by monoclonal antibodies (MAbs) to human AFP. Light microscopic observations of cells incubated with fluoresceinated AFP showed that the protein was specifically bound to the cell surface at 4°C, and was internalized in the cytoplasm at 37°C. At the ultrastructural level, horseradish peroxidase (HRP)‐conjugated AFP, as well as HRP‐transferrin (Tf) (used as control), appeared to be internalized via coated pits and vesicles before being delivered to endosomes, from which they were apparently recycled back to the cell surface via small vesicles. Our results suggest that a AFP/receptor autocrine pathway might operate in these cells, be preferentially active at the beginning of the exponential phase of cell culture growth, and contribute to cell proliferation.
Immunotoxins constructed with anti‐CD25 monoclonal antibodies and deglycosylated ricin a‐chain have potent anti‐tumour effects against human hodgkin cells in vitro and solid hodgkin tumours in mice
Authors: Engert Andreas , Martin Gary , Amlot Peter , Wijdenes John , Diehl Volker , Thorpe Philip
Published: February 2007

Twenty‐three monoclonal antibodies (MAbs) against the IL‐2 receptor α‐chain (CD25) were evaluated as ricin A‐chain immunotoxins for the treatment of Hodgkin's disease. Primary screening used an indirect assay in which the cells were treated with the test antibody followed by a Fab immunotoxin against mouse immunoglobulin. This screening identified 5 MAbs which inhibited protein synthesis in L540 Hodgkin cells by 50% at a concentration (IC50) of 6 × 10−11 M or less: RFT5γ1, RFT5γ2a, B‐B10, B‐F2 and B‐G3. These MAbs were then linked directly to deglycosylated ricin A‐chain (dgA) and were confirmed to have potent and specific toxicity for L540 cells. The immunotoxins had the following potency order: RFT5γ1 > RFT5γ2a > B‐B10 > B‐F2 > B‐G3. The most effective immunotoxin, RFT5γ1.dgA, had an IC50 value of 7 × 10−12 M, which is the same as that of whole ricin. In vivo, a single intravenous injection of 48 μg of RFT5γ1.dgA, RFT5γ2a.dgA, B‐B10.dgA or B‐F2 induced lasting complete remissions in 78, 66, 50 and 44%. respectively, of nude mice bearing subcutaneous solid L540 tumours of 0.7 cm diameter. Two tumours which regrew after B‐B10.dgA treatment were re‐established in tissue culture. Both had reduced sensitivity to B‐B10.dgA in vitro but not to immunotoxins recognizing different antigens on Hodgkin cells. The MAbs that produced the most potent immunotoxins, RFT5γ1, RFT5γ2a and B‐B10, had no significant cross‐reactivity with normal human tissues outside the lymphoid system as judged from indirect immunoperoxidase staining of frozen sections. By contrast, B‐F2 strongly stained normal human renal tubules.
Characterization of gangliosides in human uveal melanoma cells
Authors: Soulieres Denis , Rousseau Alain , Deschenes Jean , Tremblay Michel , Tardif Manon , Pelletier Guy
Published: February 2007

We have evaluated the ganglioside composition of 20 primary uveal melanomas, of 2 cell lines derived from 2 uveal melanomas, of a liver metastasis from an uveal melanoma, and 8 of normal choroids. The results show that normal choroid tissue has a ganglioside content similar to the primary tumors of uveal melanoma except for GD1a, GD1b, and GT1b, which are present only on normal choroid tissues. On the other hand, the uveal melanomas have similarities with cutaneous melanomas, since GM3 (74%) and GD3 (25%) are found in both tissues and are present in about the same amounts. However, GM1 was found in 50%, GM2 in 20% and GD2 in none of the uveal melanomas. According to data published by others, cutaneous melanoma biopsies have no GM1, whereas GM2 is present in 100% and GD2 in 71% of tumor tissues. Transplantation of the 2 cell lines subcutaneously into nude mice resulted in the growth of tumors which had a ganglioside profile larger than that of the primary tumors. GM3 was significantly diminished and GD3 significantly increased in the primary uveal melanoma from patients who had received radiotherapy before enucleation compared with those who did not have radiotherapy. These results show that uveal melanomas contain gangliosides that could be used as targets for monoclonal antibody therapy.
Meat, cooking methods and colorectal cancer: A case‐referent study in Stockholm
Authors: de Verdier Maria Gerhardsson , Hagman Ulla , Peters Ruth K. , Steineck Gunnar , Övervik Eva
Published: February 2007

The associations between methods of cooking meats and colorectal cancer were examined in a population‐based case‐ referent study performed in Stockholm in 1986‐1988. The study included 559 cases and 505 referents. Total meat intake, frequent consumption of brown gravy, and a preference for heavily browned meat surface each independently increased the risk for colorectal cancer. The relative risks (RR) were higher for rectal than for colon cancer, and for boiled meat (RR colon = 1.7, RR rectum = 2.7) than for meat fried with medium or lightly browned surface (RR colon = 0.8, RR rectum = 1.1), but the highest risks were for meat fried with heavily browned surface (RR colon = 2.8, RR rectum = 6.0). The analyses were adjusted for year of birth, gender and fat intake. Further adjustments for total energy, dietary fiber intake, body mass and physical activity had little or no influence on the results. The findings suggest that, in addition to frequent meat intake, a heavily browned meat surface formed when frying meat at high temperatures is important in the etiology colorectal cancer.
The impact of a breast cancer screening programme on quality‐adjusted life‐years
Authors: de Haes J. C. J. M. , de Koning Harry J. , van Oortmarssen Gerrit J. , van Agt Heleen M. E. , de Bruyn Arry E. , van der Maas Paul J.
Published: February 2007

Trials have shown that breast cancer screening is effective in reducing breast cancer mortality and gaining life‐years. The question is whether taking into account the impact of a screening programme on quality of life would lead to a less positive view. Screening may have effects on quality of life in the short run for women participating and effects in the long run as a result of the expected shift in the number of women experiencing early and advanced phases of the disease, after the initiation of the programme. In this study 4 steps have been taken: (1) published studies on quality of life and breast cancer (screening) up to 1989 have been reviewed and summarized and, based on these data, the consequences of breast cancer and treatment have been described: (2) values have been assigned to the disease and treatment phases by experts in breast cancer and public health (N = 31, response 87%); (3) these values have been inserted in the MISCAN model predicting the prevalence of disease/treatment phases with and without a 2‐yearly screening programme for women aged 50‐70 and multiplied by the duration of these phases; (4) analyses have been done to establish the sensitivity of the results for the values inserted. The programme of 2‐yearly mammographic screening for women aged 50‐70 is predicted to be 8% „less effective”︁ (range − 19.7 to +3.2%) when computing quality‐adjusted life‐years. We conclude that this adjustment is too small to attribute a major role to quality of life in the decision to undertake a large‐scale breast cancer screening programme.
Concentrations of oestrone and 4‐hydroxyandrostenedione in malignant and normal breast tissues
Authors: Reed M. J. , Aherne G. W. , Ghilchik M. W. , Patel S. , Chakraborty J.
Published: February 2007

4‐Hydroxyandrostenedione (4‐OHA) is a specific inhibitor of aromatase activity used for the treatment of breast cancer in post‐menopausal women. Treatment with 4‐OHA has been shown to inhibit the peripheral conversion of androstenedione to oestrone and reduce plasma oestrogen concentrations, but the effect of treatment on breast‐tissue oestrone concentrations is not known. We have therefore examined the effect of treatment with 4‐OHA on oestrone concentrations in normal and malignant breast tissues and also measured plasma and tissue 4‐OHA concentrations. Changes in tumour oestrone concentrations were related to DNA polymerase α activity, a marker of cellular proliferation. Blood and breast‐tissue samples were obtained before and 36 hr after treatment with 4‐OHA. The mean plasma concentration of 4‐OHA was 27.9 ± 19.3 ng/ml, compared with levels of 33.7 ± 25.6 ng/g for breast tumour and 13.5 ± 11.5 ng/g for normal breast tissue. There was a significant correlation between 4‐OHA concentrations in plasma and normal breast tissue (r = 0.91, p < 0.001). Treatment with 4‐OHA resulted in a significant (p < 0.02) decrease in breast‐tissue oestrone concentrations. For 3/4 tumour samples, a marked decrease in the concentration of oestrone (78 ± 4%) was associated with a similar decrease (64 ± 16%) in DNA polymerase α activity. It is concluded that treatment with 4‐OHA effectively reduces breast‐tissue exposure to oestrogen.
Enhancement of anti‐neoplastic activity of cytosine arabinoside against human HL‐60 myeloid leukemic cells by 3‐deazauridine
Authors: Momparler Richard L. , Bouffard David Y. , Momparler Louise F. , Marquet Jeanine , Zittoun Jacqueline , Marie Jean‐Pierre , Zittoun Robert
Published: February 2007

Drug resistance is one of the major reasons for failure of chemotherapy of acute leukemia with cytosine arabinoside (ARA‐C). In order to overcome this problem we have investigated the interaction of ARA‐C with 3‐deazauridine (3‐DU) against HL‐60 myeloid leukemic cells. 3‐DU is an interesting agent to use in combination with ARA‐C, since drug‐resistant cells that are deficient in deoxycytidine kinase are very sensitive to this uridine analogue. We have observed that for both short and long drug exposure there was a potent synergistic interaction between ARA‐C and 3‐DU with respect to their cytotoxic effects on HL‐60 leukemic cells. This synergy could be explained by an increased cellular uptake of ARA‐C to ARA‐CTP by the leukemic cells in the presence of 3‐DU, due to the reduction in the pool of dCTP produced by this latter analogue. Since dCTP is a potent feedback inhibitor of the phosphorylation of ARA‐C by deoxycytidine kinase, the reduction in the dCTP produced by 3‐DU results in an increased rate of phosphorylation of the arabinosyl analogue. Our results suggest that ARA‐C and 3‐DU may be an interesting drug combination to circumvent drug resistance in the chemotherapy of acute leukemia.
Putrescine and spermidine uptake is regulated by proliferation and dexamethasone treatment in AR4‐2J cells
Authors: Nicolet Thierry , Scemama Jean‐Luc , Pradayrol Lucien , Berthélémy Philippe , Seva Catherine , Vaysse Nicole
Published: February 2007

Polyamines are essential for cell growth and differentiation. Their specific uptake contributes to the regulation of intracellular polyamine levels. In this study, we describe the modulation of this transport mechanism in a rat tumoral pancreatic acinar cell line (AR4‐2J) and analyze the transport system characteristics of the normal rat pancreatic acini. Normal acini had a common carrier for spermidine and spermine, like AR4‐2J cells, but not a specific putrescine carrier. Intracellular polyamine deprivation enhanced putrescine and spermidine uptake of AR4‐2J cells with no modification of polyamine carrier affinity. Uptake was modulated during growth and decreased for both polyamines at confluence. AR4‐2J cell differentiation with dexamethasone prevented cell proliferation and diminished uptake of both putrescine and spermidine without affecting their respective carrier affinities. Our data show, first, that the polyamine transport system could be modulated by polyamine metabolism with no change in its affinity characteristics. Second, in rat pancreatic acinar cells, neoplastic transformation was partly characterized by induction of a high‐affinity putrescine carrier. This phenotype was not reversed by dexamethasone‐induced cell differentiation.
Tumorigenicity of EBV‐carrying lymphoblastoid cell lines (LCLS): Distinctive grading in scid mice
Authors: Ramqvist Torbjörn , Norén Lennart , Iwarsson Krister , Klein George
Published: February 2007

The in vitro and in vivo growth of lymphoblastoid cell lines (LCLs), Burkitt lymphomas (BLs) and PBL‐derived immunoblastomas in SCID mice was studied in parallel. Most, but not all, of the LCLs tested were tumorigenic in SCID mice. Long‐term culturing in vitro was not a necessary prerequisite for tumorigenicity. There was a good correlation between in vivo and in vitro growth. Three major classes of cells could be distinguished on the basis of their growth properties.
Dipyridamole enhancement of doxorubicin‐induced translocation of nucleophosmin and inhibition of cell growth in HL‐60 cells
Authors: Yung Benjamin Yat‐Ming , Chang Fu‐Jung , Luo Kang‐Jiun
Published: February 2007

Dipyridamole (DPM) enhanced sensitivity to doxorubicin (DOX) in a human leukemia cell line that was already relatively sensitive to this agent. Using an immunofluorescence technique, we determined the localization of nucleophosmin (protein B23) in HL‐60 cells after incubation with DOX in the absence and presence of DPM. Bright nucleolar fluorescence was observed in control HL‐60 cells. The addition of DOX (0.1‐0.25 μg/ml) the culture system resulted in time‐ and dose‐dependent induction of nucleophosmin translocation from the nucleolus nucleoplasm and inhibition of cell growth. DPM (5 μM) alone had no effect on nucleophosmin translocation and inhibition cell growth. However, the addition of DPM to the cells enhanced DOX‐stimulated translocation of nucleophosmin. There was a good correlation between the DPM enhancement DOX‐induced nucleophosmin translocation and the increased inhibition of cell growth. The cell number decreased to greater extent within a shorter time period under treatment with DOX in the presence of DPM. Short exposure (0.5 hr) HL‐60 cells to DOX induced dose‐response nucleophosmin translocation and cell growth inhibition. Such effects of a short exposure to DOX were also enhanced by DPM (5 μM) included in the fresh medium after removal of DOX. This was agreement with the observation that DPM could increase the cellular DOX by inhibiting the drug efflux from the cells. These results demonstrate that DPM, being able to increase and retain the intracellular levels of DOX, can markedly enhance the cytotoxicity of DOX, and suggest possible clinical application. „Nucleophosmin translocation”︁, as observed by immunofluorescence, could be useful in determining the efficacy combinations of DOX and DPM in cancer chemotherapy.