bluuebunny/crossref_metadata_2025 huggingface dataset:
The immunoscintigraphic use of Tc‐99m‐labelled monoclonal anti‐CEA antibodies (BW 431/26) in patients with suspected primary, recurrent and metastatic breast cancer
Authors: Lind Peter , Smola Michael G. , Lechner Peter , Ratschek Manfred , Klima Gert , Költringer Peter , Steindorfer Peter , Eber Otto
Published: February 2007

The discrepancy between serum CEA levels and CEA tissue expression in patients with breast cancer is well known. Whereas immunohistochemistry shows positive CEA expression in 70‐90%, the serum CEA levels are often within the normal range. We performed immunoscintigraphy and SPECT with a Tc‐99m labelled anti‐CEA monoclonal antibody (MAb BW 431/26) in 46 women with suspected breast cancer or recurrence. The results of anti‐CEA immunoscintigraphy, mammography, serum CEA levels and immunohistochemistry were evaluated according to the histology of the tumor. Histology verified breast cancer or recurrence (pT1 [n = 7], pT2 [n = 17], pT3 [n = 3], pT4 [n = 3]) in 30 out of 46 patients; benign breast disease such as fibrocystic disease, fibroadenoma, fatty necrosis or chronic mastitis was responsible for suspicious mammographic findings in 16 patients. Immuno‐SPECT showed 25 true‐positive, 5 false‐negative, 11 true‐negative and 5 false‐positive findings (sensitivity 83%, specificity 69%). Anti‐CEA immuno‐SPECT of 2 patients with bone metastasis showed all lesions previously detected by bone scintigraphy to be CEA‐expressing metastases. In contrast, serum CEA levels were slightly elevated in only 5 out of 30 patients with histologically verified breast cancer (sensitivity 17%). The results of immuno‐histochemistry were surprising; tissue CEA expression could be demonstrated in only 5 patients with breast cancer. According to our experiences with this Tc‐99m labelled anti‐CEA MAb, immuno‐SPECT is a suitable additional method for the diagnosis of breast cancer and especially of recurrence. Pre‐operative serum CEA levels give no support for the differentiation between benign and malignant breast tumors.
Tumor‐promoting activity of epstein‐barr‐ virus‐inducing factor transforming growth factor type beta (EIF/TGF‐β) is due to the induction of irreversible transformation
Authors: Bauer Georg , Götschl Michaela , Höfler Petra
Published: February 2007

EBV‐inducing factor/transforming growth factor type beta (EIF/TGF‐β) exhibits tumor‐promoting activity for C3H‐10T1/2 mouse fibroblasts in vitro. Treatment of C3H 10 T 1/2 fibroblasts seeded at low density with initiating doses of UV light, followed by culture in the presence of EIF/TGF‐β leads to the appearance of foci of stably transformed cells that have the potential to grow in soft agar. The promoting effect depends both on the dose of EIF/TGF‐β applied and its continuous presence for 2 to 3 weeks. In addition to its pro‐carcinogenic effect in tumor promotion, EIF/TGF‐β exhibits a strong negative effect on transformed cells surrounded by normal cells, indicating a dual role of EIF/TGF‐β in carcinogenesis. The lack of completely transformed individual cells in the initiated cell population and the negative effect of EIF/TGF‐β on transformed cells in contact with normal cells exclude any possible explanation of the tumor‐promoting effect of EIF/TGF‐β as being the result of a selection process due to the establishment of growth advantages for cells transformed by the initiator. The data, in fact, indicate that tumor promotion by EIF/TGF‐β implies the stable acquisition of distinct qualitative changes by the cells.
Anti‐drug monoclonal antibodies antagonize toxic effect more than anti‐tumor activity of doxorubicin
Authors: Balsari A. , Ménard S. , Colnaghi M. I. , Ghione M.
Published: February 2007

Monoclonal antibodies (MAbs) able to bind epitope(s) of drug molecule can interfere with the biologic action of the drug. This is known and already exploited in some instances of practical relevance, as in the reversal of the digoxin effect. Similar antidotal action is exhibited by MAbs reacting with a cytotoxic antibiotic, doxorubicin (DXR), and in such a way as to induce differential neutralization of drug action. Indeed, within certain limits, the cytotoxic action of DXR in vitro as well as in vivo is more effectively neutralized on normal than on tumor cells, with consequent increase in therapeutic index.
Therapeutic efficacy of two‐route chemotherapy using cis‐diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, combined with the angiotensin‐II‐induced hypertension method in a rat uterine tumor
Authors: Kobayashi Hiroaki , Hasuda Keitaro , Taniguchi Shun'Ichiro , Baba Tsuneo
Published: February 2007

To enhance the therapeutic effect of conventional TRC using intra‐arterial (i.a.) DDP plus simultaneous i.v. STS, we combined the AT‐II‐induced hypertension method with TRC and evaluated its efficacy for a rat uterine tumor, using the simulation of intra‐arterial chemotherapy for human uterine tumors. During interruption of arterial blood flow by vascular manipulations, DDP plus AT‐II were injected for 10 min through the abdominal aorta in the direction of the uterus. Then STS was administered i.v. for a further 5 min and all the arterial restrictions were released. This modified TRC using AT‐II showed a much higher anti‐tumor effect than that seen in conventional TRC without AT‐II and was free from DDP‐induced renal damage. On the other hand, severe nephrotoxicity was unavoidable in the rats given the delayed i.v. administration of STS to i.a. DDP alone. The feasibility of post‐administration of STS without obvious nephrotoxicity in modified TRC was explained by transient inhibition of DDP delivery to the kidney during the AT‐II‐induced hypertension. The loss of body weight and the decrease in the number of leukocytes after this therapy were tolerable. Modified TRC showed a higher anti‐tumor effect and a lower nephrotoxicity compared with other treatments, as follows: DDP i.a. with or without AT‐II; i.v. infusion of DDP alone. Such a superior anti‐tumor effect of modified TRC consists of the following 2 factors: (i) the post‐administration of STS leading to the delayed neutralization of DDP at the tumor site; (ii) the selective enhancement of DDP delivery to the tumor tissue during AT‐II‐induced hypertension.
Intra‐thecal treatment of leptomeningeal lymphoma with immunotoxin
Authors: Urch Catherine E. , George Andrew J. T. , Stevenson George T. , Bolognesi Andrea , Stirpe Fiorenzo , Weller Roy , Glennie Martin J.
Published: February 2007

An animal model has been established to investigate the effect of intra‐thecal (i.t.) immunotoxins in the treatment of leptomeningeal metastases of acute lymphoblastic leukaemia (ALL). Direct inoculation of L2C lymphoma cells into the cisterna magna of guinea‐pigs gives rise to a leptomeningeal pattern of growth, similar to that of human ALL, and to a systemic leukaemia which develops in approximately 14 days. In our model the systemic disease could be controlled with cyclophosphamide while the meningeal disease progressed and provided a target for i.t. immunotoxin. The immunotoxin used consisted of an anti‐idiotypic antibody disulphide‐bonded to the ribosome‐inactivating protein saporin. It was highly cytotoxic to L2C cells in vitro, being around 30,000 times more potent than a control immunotoxin at inhibiting protein synthesis. In vivo, the maximum tolerated dose of i.t. immunotoxin was 10 μg. From the rate at which radiolabeled immunotoxins appeared in the plasma following i.t. injection, we were able to estimate that its half‐life in the cerebrospinal fluid (CSF) was between 1° and 2 hr. Intrathecal treatment of guinea‐pigs with immunotoxin I day after inoculation of L,C cells into the cisterna magna had a remarkable therapeutic effect. All guinea‐pigs treated with 0.5 or 5 μg of immunotoxin survived, and remained tumour‐free for more than 100 days after treatment, while control animals given cyclophosphamide alone or an irrelevant immunotoxin had a mean survival time of 28 days. Provided concerns over toxicity can be overcome, these results indicate that i.t. immunotoxins offer an alternative, highly specific form of treatment in leptomeningeal neoplasia.
Expression of dipeptidyl aminopeptidase IV during enterocytic differentiation of human colon cancer (Caco‐2) cells
Authors: Yoshioka Masahiro , Erickson Roger H. , Matsumoto Hisashi , And Elizabeth Gum , Kim Young S.
Published: February 2007

The human colon cancer cell line Caco‐2 spontaneously differentiates to an enterocyte‐like cell after confluence under standard culture conditions. This is characterized by polarization of the cell monolayer with the appearance of tight junctions, a brush border membrane and expression of brush‐border‐membrane‐associated hydrolases. Studies have shown that differentiated Caco‐2 cells express relatively high levels of dipeptidyl aminopeptidase IV (DPP IV) when compared with other enzymes. However, the biochemical mechanisms involved in the expression of DPP IV in differentiated cells are currently unknown. Therefore, the biosynthesis and expression of membrane‐associated DPP IV in undifferentiated (0 day confluent) and differentiated (14 day confluent) Caco‐2 cells were examined. Though levels of DPP IV activity in differentiated cells was 5‐ to 6‐fold higher than undifferentiated cells, there was only a 1.6‐fold difference in the synthetic rate. Post‐translational processing of newly synthesized DPP IV occurred at a slower rate in differentiated cells, though there were no major differences in the type or degree of glycosylation. A comparison of the degradation rates revealed that they were similar with a half‐life of approximately 8 to 10 days. We conclude that the high levels of DPP IV expressed in differentiated Caco‐2 cells is primarily due to an increase in enzyme synthesis. In addition, accumulation of the enzyme is aided by its slow turnover rate.
Selection of monoclonal antibodies which induce internalization and phosphorylation of P185HER2 and growth inhibition of cells with HER2/neu gene amplification
Authors: Tagliabue Elda , Centis Filippo , Campiglio Manuela , Mastroianni Antonio , Martignone Stefania , Pellegrini Rita , Casalini Patrizia , Lanzi Cinzia , Ménard Sylvie , Colnaghi Maria I.
Published: February 2007

In order to obtain further information on the biological role of the HER2/neu oncoprotein monoclonal antibodies (MAbs) were produced against the p185 extracellular domain. To immunize the mice and screen the hybridoma supernatants we selected a lung adenocarcinoma cell line (Calu‐3), which demonstrated an over‐expression of p185HER2 measured as the reactivity with polyclonal rabbit serum to the 14‐amino‐acid carboxy‐terminal‐HER2/neu. Two MAbs, designated MGR2 (IgG,) and MGR3 (IgG2), selected for reactivity on Calu‐3 and negativity on A431 live cells, the reference target cell for EGF receptor expression, were found to immunoprecipitate a 185‐kDa molecule. Immunodepletion experiments with the polyclonal antiserum and cross‐competition experiments indicated that the 2 reagents recognized 2 different epitopes located on the pl85HES2 molecule. One of the 2 MAbs, MGR3, was found to internalize, induce p185HER2 phosphorylation and inhibit tumor cell growth in vitro. These results indicate that MGR3 is directed against a determinant located in the p185HER2 ligand binding site and may compete with the p185HER2 ligand, but is incapable of inducing a complete mitotic signal.
Effects of tyrosine kinase inhibitor, erbstatin, on cell growth and growth‐factor/receptor gene expression in human gastric carcinoma cells
Authors: Takekura Naoki , Yasui Wataru , Kyo Eikai , Yoshida Kazuhiro , Kameda Takashi , Kitadai Yasuhiko , Abe Kaoru , Umezawa Kazuo , Tahara Eiichi
Published: February 2007

The effect of tyrosine kinase inhibitor, erbstatin, on cell growth and mRNA expression of growth‐factor/receptor system was examined in 6 human gastric‐carcinoma cell lines. Erbstatin inhibited both EGF‐induced and serum‐stimulated cell growth of all 6 cell lines (TMK‐1, MKN‐1, −7, −28, −45, −74) in a dose‐dependent manner. 3H‐thymidine incorporation by TMK‐I cells was also suppressed by erbstatin. Erbstatin inhibited protein kinase activity of EGF receptor, p185ERBB2 and pp60c‐src in TMK‐I cells. The expression of mRNA of EGF receptor gene and ERBB‐2 by TMK‐1 cells was not changed by erbstatin treatment, whereas that of c‐src was slightly decreased. Interestingly, erbstatin decreased membrane‐bound TGF‐α precursor as measured by anti‐TGF‐α antibody‐binding assay, although mRNA expression for TGF‐α was not altered by erbstatin. Our findings suggest that erbstatin may act as a growth inhibitor for human gastric‐carcinoma cells and may not only inhibit tyrosine kinase activities but also negatively modulate the post‐transcriptional step of TGF‐α expression.
Indirect immunotargeting of CIS‐PT to human epidermoid carcinoma KB using the avidin‐biotin system
Authors: Schechter B. , Arnon R. , Wilchek M. , Schlessinger J. , Hurwitz E. , Aboud‐Pirak E. , Sela M.
Published: February 2007

Cis‐diamminedichloroplatinum (II) (cis‐Pt) complexed to a carboxymethyl dextran‐avidin conjugate was targeted to biotin‐monoclonal antibody 108 (b‐MAb108). This MAb recognizes the extracellular domain of the epidermal growth factor receptor (EGF‐R) on human epidermoid carcinoma (KB) cells over‐expressing EGF‐R. Cis‐Pt‐carboxymethyl‐dextran‐avidin (Pt‐dex‐Av) containing 60–90 M cis‐Pt/M avidin was administered 24 hr following b‐MAb108 containing 3–5 M biotin/ M MAb. This treatment was potentially more effective in suppressing the growth of established KB tumor xenografts, or in inhibiting the development of lung metastases in nude mice, than free MAb 108, free drug or MAb 108 followed by drug. Replacing b‐MAb108 by unbiotinylated antibody or by b‐MAb of a different specificity also yielded lower suppressive effects. The sequential administration of Pt‐dex‐Av following b‐MAb was more effective than Introduction, of the Pt‐dex‐Av when already complexed to b‐MAb 108. The results presented in this preliminary investigation suggest that Pt‐dex‐Av is specifically removed from the circulation by b‐MAb 108 concentrated at the tumor site.
Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast
Authors: Williams Gerard , Anderson Elizabeth , Howell Anthony , Watson Robert , Covne John , Roberts Stephen A. , Potten Christopher S.
Published: February 2007

The effect of ingestion of oral contraceptives (OCP) on cell proliferation and oestrogen (ER) and progesterone receptor (PR) expression of the epithelial cells of the normal human breast was compared with findings in controls not taking OCPs. Histologically normal breast tissue was removed during operation for fibroadenoma or reduction mammoplasty in 216 women whose mean age was 28.1 ± 8.5 years (±SD range 14–53 years). During natural cycles the mean proportion of cells expressing ER was 3.94 ± 3.71 (% mean ±SD, range 0–20.8, n = 51), while of those expressing PR it was 12.1 ± 7.1% (range 3.0–36.1, n = 47). There was a significant decline in ER during the menstrual cycle [p = <0.001 by multiple linear regression (MLR)], but there was no significant change in the proportion which expressed PR. The mean proportion of proliferating cells (LI) was 2.50 ± 2.42 (range 0–11.5, n = 147). There was a significant increase of LI during the cycle (p = <0.001, MLR) and a significant inverse relationship between LI and ER (r = −0.29, p < 0.01). Use of the OCP significantly reduced the number of cells which expressed ER and increased the LI earlier in the cycle. No effect of OCP use on the number of PR+ cells was detectable. We conclude that significant changes in the proportions of ER+ and proliferating cells occur during natural menstrual cycles. These changes are perturbed by ingestion of OCPs, so that there is greater suppression of ER and a longer period of high proliferation during the menstrual cycle. These results may explain the relationship between OCP use and the possible risk of breast cancer.
Differential expression of isopeptide bonds Nϵ(γ‐glutamyl) lysine in benign and malignant human breast lesions: An immunohistochemical study
Authors: Roch Anne‐Marie , Noel Patrick , Alaoui Said El , Charlot Carole , Quash Gérard
Published: February 2007

Nϵ(γ‐glutamyl) lysine isopeptide bonds were detected situ in histological sections from benign and malignant human breast tissue using the monoclonal antibody (MAb) 8 ID Ic2. On cryostat sections of fresh‐frozen mammary tissue post‐fixed in acetone, or on paraffin sections also from mammary tissue fixed in Bouin's solution, the MAb reacted preferentially with glandular epithelial cells and staining was restricted to the nuclei. In 41 out of 44 benign lesions examined, staining was strong or moderate, while in 25 out of 33 malignant lesions no staining was observed. In the 8 remaining lesions of this group, staining was positive but weak. The difference in reactivity of this MAb with the 2 types of lesions highly significant (p < 0.0005) according to the χ2 test.
Bispecific monoclonal antibodies directed to CD16 and to a tumor‐associated antigen induce target‐cell lysis by resting NK cells and by a subset of NK clones
Authors: Ferrini Silvano , Prigione Ignazia , Miotti Silvia , Ciccone Ermanno , Cantoni Claudia , Chen Qi , Colnaghi Maria Ines , Moretta Lorenzo
Published: February 2007

CD 16 surface antigens represent activatory molecules in CD3–16+ NK cells. In order to target NK cells against relatively NK‐resistant ovarian carcinomas, we used an anti‐CD 16 monoclonal antibody (MAb) (VD4), together with an anti‐ovarian carcinoma‐associated antigen (MOV19), to construct biMAbs. To this end, hybrid hybridomas were generated by fusing a TK‐deficient VD4 hybridoma mutant with a HGPRT‐deficient MOV19 hybrid. Supernatants from hybrid hybridomas that had been selected in HAT medium were screened for their ability to induce a CD3–16+ NK clone to lyse an MOV19+ ovarian carcinoma cell line in a 4‐hr 31Cr‐release assay. The NMB.45 hybrid hybridoma secreted a biMAb which triggered lysis of MOV19+ but not of MOV19‐target cells. Some degree of target cell lysis was also observed with MOV19 MAb (due to ADCC mechanisms), while the VD4 MAb was ineffective. HPLC fractionation of MAbs secreted by the hybrid hybridoma made it possible to identify 4 different peaks, one of which appeared to contain functional biMAb molecules. HPLC‐purified biMAb (100 ng/ml) induced resting PBL to lyse the “NK‐resistant” IGROVI ovarian carcinoma cell line. Fresh MOV19+ tumor cells were also lysed, although with lower efficiency. When IL‐2‐activated lymphocytes were used as a source of effectors, biMAb caused only minor increases in the IL‐2‐induced cytolytic activity. Further analyses of the effect of biMAb were performed at the clonal level. Among CD3–16+ NK cell clones, a clear enhancing effect could be observed only in GL183+ but not in GL183‐clones. In CD3+ cytotoxic clones a triggering effect could be detected in one out of 4 TCR γ/δ+ clones but not in TCR α/β+ clones.
Isolation and partial characterization of a soluble oncofetal antigen from murine and human amniotic fluids
Authors: Barsoum Adel L. , Coggin Joseph H.
Published: February 2007

A soluble (cell‐free) oncofetal antigen (OFA) was detected in murine and human amniotic fluids by immunostaining with the murine monoclonal antibody (MAb 115) produced by syngeneic immunization with mid‐gestational mouse fetal cells. OFA was purified from the amniotic fluids by ammonium sulfate precipitation at 30–70% saturation, followed by successive gel chromatography of the OFA‐containing fraction on Sephacryl‐S300 HR, Q‐and S‐Sepharoses and lentil lectin agarose. The fraction eluted from the lentil lectin column gave a single band on SDS‐PAGE of the same molecular weight as the membrane‐bound OFA found on both fetal and tumor tissues of humans and several rodents. Both soluble and membrane‐bound OFAs share several chemical characteristics, including binding to lentil lectin and wheat‐germ agglutlnin, molecular weight (44 kDa) and pI (6.8). Mild Periodate oxidation of OFA did not affect its binding to MAb 115 in an enzyme‐linked immunosorbent assay, indicating that the reactive epitope is a peptide.
Spontaneous outgrowth of epstein‐barr virus‐positive B‐cell lines from circulating human B cells of different buoyant densities
Authors: Yao Q. Y. , Czarnecka H. , Rickinson A. B.
Published: February 2007

Epstein‐Barr virus (EBV) has potent cell‐growth‐transforming activity for human B lymphocytes in vitro, yet appears to persist in the circulating B‐cell pool of virus carriers in vivo as a largely asymptomatic (i.e., non‐growth‐transforming) infection. The true nature of this infection, and the identity of the cells involved, remain to be determined. Studies of Lewin et al. (1987) have suggested (i) that the frequency of virus‐infected cells in the circulating B‐cell pool differs in different buoyant density fractions, being most abundant in the low‐density population, and (ii) that rare virus‐infected cells with the capacity for direct in vitro outgrowth to EBV‐transformed cell lines are segregated within the high‐density population. We have repeated this work using B‐cell fractions from a much larger panel of asymptomatic virus carriers and find (i) that the incidence of virus‐infected B cells Is not significantly different between high‐and low‐density fractions, and (ii) that virus‐infected cells from both fractions give rise to EBV‐transformed cell lines in culture predominantly through a 2‐step mechanism of virus replication and secondary infection rather than by direct outgrowth.
Sensitizer for photodynamic therapy of cancer: A comparison of the tissue distribution of photofrin ii and aluminum phthalocyanine tetrasulfonate in nude mice bearing a human malignant tumor
Authors: Peng Q. , Moan J. , Kongshaug M. , Evensen Jan F. , Anholt H. , Rimington C.
Published: February 2007

The distribution of Photofrin II (P‐II) and aluminum phthalocyanine tetrasulfonate (AIPCS4) in tissues of BALB/c nu/nu nude mice bearing the LOX human melanoma was measured fluorimetrically at different times after intraperitoneal injection of the drugs, 20 mg/kg body weight. The plasma levels of the drugs as well as the excretion in feces and urine were also determined. The plasma concentrations of both drugs were found to build up In a similar manner during the first 30 min after injection. Thereafter, the plasma level of AIPCS4 decreased exponentially with an elimination half‐life of 1.5 hr. The kinetics of elimination of P‐ll from the plasma were consistent with a 2‐compartment model, with 90% of sensitizer lost with a half‐life of about 5 hr, and the remaining fraction with a half‐life of 30 hr. About 80% of the injected dose of P‐II was excreted in the feces during the 7‐days following injection, while 77% of AlPCS4 was excreted in the urine during the same period. After injection of a dose of 20 mg/kg, the concentrations of P‐II in the LOX tumor as well as in the skin, muscle, brain, heart, lung, kidney and liver increased for about 24 hr, then remained constant or decreased slowly for the next 48 hr, after which they decreased slightly faster. On the other hand, the concentrations of AIPCS4 in most tissues as well as in the tumor peaked at about 30 min, then decreased with a half‐life of between 1.5 and 3 hr. The tumor/skin concentration ratio was about I for both drugs (1–24 hr after injection). The tumor/muscle concentration ratio was about 2 for P‐II at all sampling times, and maximally 10 (at 18 hr after injection) for AIPCS4. In the present tumor model, the tumor/tissue concentration ratio for all tissues at I hr and at 24 hr after the injection was equal for the 2 drugs or higher for AIPCS4.
Tumour‐growth suppression in nude mice by a murine monoclonal antibody: Factors hampering successful therapy
Authors: Johansson Christina , Segrén Sverker , Lindholm Leif
Published: February 2007

The murlne MAb C215 has been shown to mediate ADMMC In vitro and to have a tumour‐growth‐suppressive effect on xenografted COLO 205 human colocarcinoma cells in nude mice. To overcome the limitations of MAb therapy, it is necessary to understand the underlying mechanisms of tumour‐ growth suppression. In the present work, we have used C215 to define the Importance of different parameters involved in tumour therapy with murine IgG2a antibodies. The results show that there exists a period of roughly 2 days after inoculation into animals during which the tumour cells are sensitive to an inhibitory antibody‐mediated effect. After this initial period, the In‐vlvo sensitivity of tumour cells to antibody‐ mediated Inhibition Is much reduced. Tumour cells can remain “dormant” and, despite ongoing antibody treatment, develop Into tumours with a reduced growth rate, which is not caused by outgrowth of antigen‐deficient tumour cells. Finally, a pronounced dependence of antibody‐mediated tumour suppression on antibody dose was observed.
Human small‐cell lung‐cancer cells are cytokine‐resistant but NK/LAK‐sensitive
Authors: Lagadec Patricia F. , Saraya Khaled A. , Balkwill Frances R.
Published: February 2007

We have studied the effects of 8 cytokines and their combinations on the in vitro growth of 10 human small‐cell cancer lines (SCLC). Interferon‐α and γ (IFN‐α and γ) caused significant but slight growth inhibition over a 7‐day incubation period. However, none of the other 6 cytokines, tumor necrosis factor (TNF), lymphotoxin (LT), interleukin‐1β (IL‐1β), interleukin‐2 (IL‐2), transforming growth factor‐β1 (TGF‐β1), or granulocyte colony‐stimulating factor (G‐CSF), modified SCLC cell proliferation. In contrast, all 10 lines were sensitive to lysis by natural killer (NK) and lymphokine‐activated killer (LAK) cells. Sensitivity to LAK cells could be Increased by pretreatment of SCLC cells with IFN‐γ. As resistance to the cytostatic/cytotoxic activity of some cytokines has been associated with autocrine production of cytokines, we screened the SCLC lines for cytokine mRNAs. Within the limits of detection of the assay we found no expression of TNF, TGF‐β1, IL‐1β or IL‐6 mRNA in the 10 SCLC lines.
The risk of cancer at all sites following gastric operation for benign disease. A cohort study of 4,224 patients
Authors: Eide Tor J. , Viste Asgaut , Andersen Aage , Søreide Odd
Published: February 2007

This report represents the results of a historical cohort analysis of 3,360 males and 864 females who had a gastric resection or gastroenterostomy for benign disease between 1900 and 1969. Within the period 1970 to 1988 the cohort was cross‐checked with the data files at the Cancer Registry of Norway to identify the patients in whom cancer had been diagnosed. When analyzed according to cancer sites, increased risk was recorded for the oropharynx, stomach, colon, pancreas, liver, biliary tract, larynx, lungs, urinary bladder and non‐melanomatous cancers of the skin In males. In females, increased risk was only observed for the oropharynx, but was close to a statistically significant level also for cancer of the stomach. A lower number of tumors of the central nervous system than expected was observed in both males and females. The increased risk of cancer of the lungs, larynx and urinary bladder in males can be regarded as evidence of the high prevalence of smokers in the cohort. We suggest that die increased risk of cancer of digestive organs Is mainly related to life‐style factors, particularly tobacco‐specific nitrosamlnes whose effect Is enhanced by surgical sequelae.
Patients treated with a monoclonal antibody (ab1) to the colorectal carcinoma antigen 17–1A develop a cellular response (DTH) to the “internal image of the antigen” (ab2)
Authors: Mellstedt Håkan , Frodin Jan‐Erik , Biberfeld Peter , Fagerberg Jan , Gisombe Ricardo , Hernandez Aleida , Masucci Giuseppe , Li Su‐Ling , Steinitz Michael
Published: February 2007

The anti‐tumor effector functions of unconjugated MAb in cancer therapy are not fully understood. Direct cytotoxic mechanisms have been demonstrated as well as induction of anti‐idiotypic (ab2) and anti‐anti‐idiotypic (ab3) antibodies. If such a humoral response is induced, then an idiotypic cellular response would also be anticipated. Human monoclonal ab2s which mimic a tumor‐associated antigen (TAA) (CO17–1A) of colorectal carcinoma (CRC) cells (“the internal image of the antigen”) were produced. These ab2s were injected intradermally to patients with metastatic CRC who had been treated with the anti‐colon carcinoma MAb 17–1A (ab1). Five out of 12 patients had a specific DTH (delayed‐type hypersensitivity) reaction of the tuberculin type, which was proven by immunohistochemical analysis of skin biopsies. Serum ab, was demonstrated In 4/4 tested DTH+ patients and also in 4 DTH patients. Control patients did not show any skin reactivity. Generation of an idiotypic response induced by the infused antibody (ab1) might be regarded as an active anti‐tumor “vaccination”. Induction of an idiotypic cellular and humoral cascade might be an important anti‐tumor effector function of MAb and should be considered in future strategies for such therapy in cancer patients.
Oncofetal expression of the human intestinal mucin glycoprotein antigens in gastrointestinal epithelium defined by monoclonal antibodies
Authors: Hertzog Paul J. , Robinson H. Clem. , Ma Jeng , Mackay Ian R. , Linnane Anthony W.
Published: February 2007

A mucin preparation from a colonic adenocarcinoma was used to prepare monoclonal antibodies (MAbs) that reacted specifically either with normal adult small‐intestine mucin antigen(s) (SIMA), or normal adult large‐intestine mucin antigen(s) (LIMA). Both SIMA and LIMA show a unique oncofetal pattern of expression. Thus SIMA was expressed in early fetal stomach, large and small Intestines but thereafter only in the normal small intestine. SIMA expression was detected immunohistochemically in cancers of the colorectum (82/112) and stomach (48/86). LIMA was detected in the stomach of the early fetus but thereafter only in the normal large intestine. LIMA expression was detected in 61/86 cancers of the stomach. Moreover, both SIMA and LIMA were expressed inappropriately in mucosa adjacent to tumors, indicative of the detection of possible pre‐malignant epithelium. We used a sandwich ELISA and biochemical procedures to show that the SIMA and LIMA molecules were large extensively glycosylated multi‐unit mucin glycoproteins that differed markedly from each other. SIMA, whether extracted from normal small‐intestine or colonic cancers, had a molecular weight above 1.000 kDa, a mean buoyant density 1.33 g/ml and s value of 4.8. LIMA had a molecular weight above 10.000 kDa, a mean buoyant density 1.45 g/ml and an s value 9.5. The SIMA and LIMA epitopes were judged to be carbohydrate in nature by reason of their resistance to harsh physical chemical treatments or protease digestion, and sensitivity to periodate oxidation, neuraminidase or β elimination. Only the SIMA epitope was sensitive to neuraminidase. In conclusion, MAbs to carbohydrate‐dependent epitopes on SIMA and LIMA identify the oncofetal pattern of expression of these distinct intestinal mucin glycoproteins in colonic and gastric carcinoma. These MAbs will be useful in further studies of the significance of oncofetal mucin expression during carcinogenesis.
Barrett's esophagus: Epidemiological and clinical results of a multicentric survey
Authors:   Gruppo operativo per lo studio delle precancerosi dell'esofago (GOSPE)
Published: February 2007

In 1987 we established an kalian multicenter study involving 16 gastroenterologic institutions. The main aims of the study were to assess the prevalence of Barrett's esophagus in a cohort of patients undergoing upper gastrointestinal endoscopy, and the relationship between endoscopic and histologic features. We enrolled 14,898 consecutive patients, and found 251 (1.7%) had endoscopic findings consistent with Barrett's esophagus and/or esophagitis (grade 2 to 4 according to Savary). On histological examination, Barrett's esophagus was confirmed in III of 251 patients (44.2%). The crude prevalence rate of BE, based on histology, was 7.4/1000, and was 2.6‐fold higher In males than In females (c.i. 1.7–4.0). Barrett's esophagus proved to be 25‐fold more frequent among patients who complained of heartburn (80.1/1000) than among the others (3.2/1000). Specialized columnar epithelium was identified In 69 of 111 cases (62.2%) and the proportionate distribution of the histological subtypes was similar in males and in females (chi‐square Idf = 0.20, p = n.s.). Dysplasia was detected in 7 patients, all of whom had specialized columnar epithelium (6 low grade and 1 high grade). In conclusion, we believe that our rate of 7.4/1000 approaches the true prevalence rate of Barrett's esophagus, as it is based on our study of unselected patients presenting for initial evaluation of a variety of UGI symptoms. The occurrence of dysplasia in specialized columnar epithelium suggests that patients with this subtype of Barrett's esophagus may be at increased risk for developing cancer and might, therefore, benefit most from surveillance.
Evaluation of circulating tumor necrosis factor‐α in patients with gynecological malignancies
Authors: De Jaco Pierandrea , Asselain Bernard , Orlandi Camillo , Fridman Wolf Herman , Teillaud Jean‐Luc
Published: February 2007

TNF‐α levels in sera from patients with gynecological cancers were evaluated by ELISA and compared with those of patients with benign ovarian cysts or of anonymous healthy donors. Patients with cervical and endometrial carcinoma and with benign ovarian cysts showed levels of TNF‐α similar to those of healthy donors. In contrast, significantly increased levels of TNF‐α were found in patients with ovarian carcinoma, regardless of the stage of disease.
Antibody response to immunization with ganglioside GD3 and GD3 congeners (lactones, amide and gangliosidol) in patients with malignant melanoma
Authors: Ritter Gerd , Boosfeld Erika , Adluri Rita , Calves Michele , Oettgen Herbert F. , Old Lloyd J. , Livingston Philip
Published: February 2007

GD3 is the ganglioside most abundantly expressed on the cell surface of human melanoma, and treatment with a murine MAb recognizing GD3 has induced major responses in a small proportion of patients with melanoma. We have therefore attempted to induce production of GD3 antibodies in melanoma patients by active immunization. We found, however, that vaccination with GD3‐expressing melanoma cells or purified GD3 does not result in antibody production. We describe here attempts to overcome the poor immunogenicity of GD3 in patients with melanoma by chemical modification. GD3 lactones, GD3 amide and GD3 gangliosidol were synthesized, and the humoral immune response to these derivatives was analyzed. Immunization of melanoma patients with these GD3 derivatives resulted in production of IgM antibodies and, in the case of GD3 amide, also of IgG antibodies. The antibodies to the GD3 derivatives did not cross‐react with GD3. This is in contrast to observations In the mouse, where GD3 lactone I induced antibodies that showed cross‐reactivity with GD3. Thus, the human immune response was specifically directed toward the modified epitope, rather than to the native structure.
Variations in centromeric heterochromatin among patients with pre‐malignant and malignant oral diseases
Authors: Dave Bhavana J. , Trivedi Amit H. , Adhvaryu Siddharth G.
Published: February 2007

Polymorphism of heterochromatic regions of chromosomes 1, 9 and 16 was studied in 60 oral cancer patients, in 40 patients with oral submucous fibrosis (OSMF) and in 60 normal healthy subjects. The size heteromorphism was significantly greater (p < 0.001) in chromosome 1 of the patients. Localization variants were also significantly more frequent among the patients (p < 0.05 for OSMF and < 0.001 for oral cancer patients). The C‐band heteromorphism patterns remained comparable in OSMF and in oral cancer patients, with chromosome 1 being the most frequently involved. On correlating the tobacco/areca‐nut chewing habit with the presence of C‐band heteromorphism, we observed that C‐band heteromorphism was present in 89% of the habit‐free oral cancer patients and 80% of the OSMF patients with relatively shorter exposure to this habit, i.e. < 5 years. This signifies that genetic factors are important in the causation of oral precancerous and cancerous conditions and that polymorphism of the heterochromatic regions does appear to play a role in these conditions.
Diet and thyroid cancer: A pooled analysis of four european case‐control studies
Authors: Franceschi Silvia , Levi Fabio , Negri Eva , Fassina Ambrogio , La Vecchia Carlo
Published: February 2007

The relationship between frequencies of consumption of selected indicator foods and the risk of thyroid cancer was Investigated in a pooled analysis of 4 case‐control studies conducted in 3 areas of northern Italy and the Swiss Canton of Vaud, on a total of 385 historically confirmed cases of thyroid cancer and 798 controls in hospital for acute, non‐neoplastic, non‐hormone‐related diseases. Cases tended to consume significantly more frequently a number of starchy foods: the odds ratio (OR) for the highest vs. lowest tertile was 1.8 for pasta or rice, 2.1 for bread, 1.6 for pastry and 2.0 for potatoes. ORs also tended to be above unity for several types of meat and significantly so for chicken and poultry, cooked ham, salami and sausages. Raw ham and fish were significantly protective (OR = 0.7 in the highest tertile for both). Significant direct associations were observed with cheese (OR = 1.4 for the highest tertile), butter (OR = 2.1) and oils other than olive (OR = 1.6). The risk estimates were below unity for most types of vegetables and fruits, and the Inverse trends were significant for carrots (OR = 0.6 for the highest tertile), green salad (OR = 0.6) and citrus fruits (OR = 0.7). No association was observed with alcohol intake. These results were consistent and reproducible across various study centers.
Induction of in vitro and in vivo anti‐tumor responses by sensitization of mice with liposomes containing a crude butanol extract of leukemia cells and transferred inter‐membranously with cell‐surface proteins
Authors: Shibata Ryujiro , Noguchi Tetsuro , Sato Toshinori , Akiyoshi Kazunari , Sunamoto Junzo , Shiku Hiroshi , Nakayama Eiichi
Published: February 2007

Generation of cytotoxic T lymphocytes (CTL) in vitro and tumor‐rejection responses by sensitization of semi‐syngeneic mice with tumor‐antigen‐reconstituted liposomes were investigated. Liposomes were prepared from a crude' butanol extract (CBE) of BALBRVD leukemia cells and egg phosphatidylcholine (PC): 1,2‐dimyristoylamido‐1,2‐deoxyphosphatidylcholine (DDPC) (3:2) or dimyristoylphosphatidylcholine (DMPC) : DDPC (1:4). Inter‐membrane protein transfer (IMPT) liposomes were prepared by incubating BALBRVD cells with DMPC : DDPC (1:4) liposomes. Sensitization of male CB6F, mice with CBE or IMPT liposomes induced a level of cytotoxicity similar to that on sensitization with mitomycin‐C(MMC)‐treated BALBRVD against BALBRVD target cells after In vitro sensitization with the tumor cells. Sensitization with CBE alone resulted in only marginal cytotoxicity. The cytotoxic effector cells induced by either mode of sensitization were CD8+ T‐cells whose recognition was Kd‐restricted. No difference in specificity was observed with the different modes of sensitization. Two in vivo immunizations with CBE or with CBE liposomes at a dose of 25 μg of protein (equivalent to 2.5 × 107 cells) cause moderate inhibition of BALBRVD tumor growth in male CB6F1 mice and immunization with IMPT liposomes at a dose of 1 μg of protein result in efficient protection.
Biodistribution of a monoclonal antibody (RNL‐1) against the neural cell adhesion molecule (NCAM) in athymic mice bearing human small‐cell lung‐cancer xenografts
Authors: Boerman O. C. , Mijnheere E. P. , Broers J. L. V. , Vooijs G. P. , Ramaekers F. C. S.
Published: February 2007

The purpose of this investigation was to determine the targeting potential of the murine monoclonal antibody (MAb) RNL‐1 for human small‐cell lung cancer (SCLC) in a nude mouse model. RNL‐1 is preferentially reactive with SCLC and lung carcinoids, and was classified as a cluster‐1 MAb as defined by the International Workshop on Small‐Cell Lung‐Cancer Antigens. From the intercellular location of the target antigen and Its reactivity with 3T3 cells transfected with nucleic acid sequences encoding for the neural cell adhesion molecule (NCAM), it was concluded that RNL‐1 is directed against NCAM. RNL‐1 was radiolabelled with either 125iodine or 111indium and injected into nude mice bearing NCI‐H82 SCLC xenografts. The biodistribution of the radiolabels was determined up to 120 hr post injection. Maximum tumour accretion for 111In‐RNL‐1 was 11.6% ID/g and 6.5% ID/g for 125I‐RNL‐1. The accumulation of 111In‐RNL‐1 could be visualized clearly by gamma scintigraphy without background subtraction techniques. Autoradiographs of whole‐body sections from animals injected with 125I‐RNL‐1 showed that activity in the SCLC xenografts was mainly peripheral, suggesting that tumour uptake is dependent on the vascularization of the tumour tissue.
Investigation of the assay of AFB1‐albumin adducts using proteolysis products in Elisa
Authors: Olubuyide I. O. , Makarananda K. , Judah D. J. , Neal G. E.
Published: February 2007

Epidemiological evidence of the involvement of aflatoxins in the aetiology of human liver cancer has led to an increasing interest in the development of appropriate techniques for monitoring human exposure. The assay for aflatoxin adducts in albumin has a better potential for assessing long‐term exposure than analyses of urine samples, and several protocols for ELISA of these adducts, following proteolysis of albumin, have been examined. However, there is usually an incomplete release of a major adduct, aflatoxin‐lysine, even after prolonged hydrolysis, and the adduct is very unstable under some conditions of proteolysis for unknown reasons. Therefore, before such techniques can be recommended for general application, the significance of such factors in the quantitive estimation of aflatoxin adducts needs to be evaluated. This study has detected the presence of a considerable fraction of aflatoxin‐modified material, produced by proteolysis of in vivo aflatoxin‐modified rat albumin or in vitro modified bovine albumin, and which is not recognized in ELISA by an anti‐aflatoxin polyclonal antibody having a wide spectrum of aflatoxin metabolite detection. This fraction increases in parallel with the proteolysis protocols.
Analysis of gene amplification in head‐and‐neck squamous‐cell carcinomas
Authors: Leonard J. Helen , Kearsley John H. , Chenevix‐Trench Georgia , Hayward Nicholas K.
Published: February 2007

The presence of gene amplification was determined in 66 fresh head‐and‐neck SCC specimens using a battery of 9 different probes. Amplification of at least one gene was found in 12 samples (18%), of which 7 were amplified at multiple loci (58%). We observed amplifications for EGFR (10% of samples) and c‐myc (9%), as well as co‐amplification of bcl‐1/int‐2 (7%). No amplifications were demonstrated for c‐Ha‐ras‐1, TGFα, c‐mos, c‐erb B‐2, or c‐erb A‐2. The incidence of proto‐oncogene amplification in head‐and‐neck SCC patients is comparable to that reported for other solid tumours. There was no statistically significant difference in survival between patients with or without gene amplification. However, the presence of multiple amplifications In several patients with advanced primary tumours suggests that the accumulation of genetic changes may correlate more closely with tumour size than with inherent biologic aggression.
Trends in cervical and breast cancer in Iceland. A statistical evaluation of trends in incidence and mortality for the period 1955–1989, their relation to screening and prediction to the year 2000
Authors: Sigurdsson Kristjan , Adalsteinsson Stefan , Ragnarsson Jonas
Published: February 2007

The time trends in incidence and mortality from cervical cancer and breast cancer in Iceland, from 1955 to 1989, were analyzed by fitting curvilinear regressions to the age‐standardized rates. The effect of the screening was evaluated by comparing the curvature of the fitted regression lines and changes in screening activity. The incidence and mortality rates for both cancer types were predicted up to the year 2000. At the commencement of cervical cancer screening in 1964, both the incidence and mortality rates were on the increase. After 1970, both rates decreased significantly. Assuming that regular attendance at screening will be 85%, It is predicted that the incidence and mortality rates will level out at about 7.5 and 2 cases per 100,000 women per year, respectively, by the year 1995 and remain at that level. The incidence of breast cancer has increased steadily since 1955. A sharp rise has been observed since 1987, due to screening with mammography. The mortality rate has shown small but significant fluctuations with time. The incidence rate is predicted to increase at the same rate as before 1987 (i.e. at 1.1 cases per 100,000 women per year), but at a slightly higher level and is predicted to reach 84 cases per 100,000 women per year by the year 2000. Breast cancer mortality is predicted to decrease to about 17 cases per 100,000 women per year by 1995 and to remain at that level.
Establishment and characterization of Epstein‐Barr virus gp350‐expressing transfected human lymphoid (Raji) cell clones
Authors: Khyatti Menem , Patel Pravin C. , Menezes José
Published: February 2007

Gp350, a late Epstein‐Barr‐virus (EBV) glycoprotein expressed on both the envelope of viral particles and EBV‐producing cells, is also the candidate for the development of an anti‐EBV subunit vaccine. This glycoprotein is thought to play an important role in anti‐EBV immunity. However, studies on the role of this viral antigen in cellular cytotoxicity and other immune functions have been hampered by the lack of a suitable model expressing gp350. We describe here a study in which we successfully transfected a gp350‐negative cell line resistant to natural‐killer(NK)‐cell activity (i.e., Raji) with a recombinant plasmid (pZIP‐MA) containing the EBV‐gp350 and the neomycin resistance gene. Three clones with a stable and strong expression of gp350 on their surface membrane, as demonstrated using a gp350‐specific (i.e., 2L10) monoclonal antibody (MAb) were isolated, characterized and used as targets in an antibody‐dependent cellular cytotoxicity (ADCC) assay. However, gp350 expression on 2 of the 3 isolated clones was not recognized by an anti‐gp350 MAb (72AI) which is specific to a unique gp350 epitope with a dual function (i.e., involved in both EBV binding to its target cell receptors and in Inducing virus‐neutralizing antibody). We have also found that gp350 expression on our 3 selected clones does not affect EBV‐receptor (CR2) density. Our model of gp350‐expressing, NK‐cell‐activity‐resistant targets revealed very useful In determining that gp350 serves as a target antigen for EBV‐specific ADCC. These gp350‐expressing cell clones appear to represent a valuable tool for diagnostic purposes (i.e., for detecting and titrating gp350 antibodies in patients with EBV‐associated diseases). Our approach should also prove useful for studying the expression of other cell‐surface‐associated viral and tumor antigens and their role in specific cellular immunity and immunosurveillance.