bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromogranin‐a expression in gastric and colon cancer tissues
Authors: Park Jae‐Gahb , Choe Ghee Young , Helman Lee J. , Gazdar Adi F. , Yang Han‐Kwang , Kim Jin‐Pok , Park Seong Hoe , Kim Yong Il
Published: February 2007

We studied the expression of chromogranin A (CgA) in human gastric (n = 17) and colorectal (n = 18) adenocarcinomas by nucleic acid hybridization and immunohistochemical analyses using a specific monoclonal antibody (MAb) to human chromogranin A (CgA). Some corresponding adjacent nonmalignant mucosal tissues were also examined. Results: (I) Northern blotting: of 3 normal gastric mucosas examined, 2 (67%) had an easily detected signal for expression of CgA. Only one of 14 gastric carcinomas (7%) and one of 18 colorectal carcinomas (6%) had easily detected RNA signals. (2) Immunohistochemical staining: all non‐malignant samples of gastric and colonic mucosa contained CgA‐positive neuroendocrine (NE) cells. Two of 17 (12%) gastric adenocarcinomas, and 3 of 18 (17%) of colorectal adenocarcinomas contained CgA‐positive tumor cells. Interestingly, the positive cases detected by immunohistochemistry included both cases detected by Northern blotting. Of the 5 cases detected by immunohistochemistry, 2 gastric cancers and I rectal carcinoma contained many diffusely scattered positive cells, occurring singly or in small clusters, while 2 colorectal carcinomas contained only occasional single CgA‐positive tumor cells. In one of the positive gastric cases, a well‐differentiated adenocarcinoma arising in a tubular adenoma, both the adenomatous and the carcinomatous elements contained positively staining cells. Our specific assays for CgA indicate that (I) a NE cell component, either diffusely scattered or occasional, occurs in about 15% of gastric and colorectal tumors; (2) there is no correlation between the presence of NE cells and degree of tumor differentiation; and (3) because only a minority of the tumor cells in positive cases stain for CgA, immunohistochemistry is a more sensitive method than Northern blotting.
Laminin expression by two clones isolated from the colon carcinoma cell line lovo that differ in metastatic potential and basement‐membrane organization
Authors: Rémy L. , Lissitzky J‐C. , Daemi N. , Jacquier M. F. , Bailly M. , Martin P. M. , Bignon C. , Doré J. F.
Published: February 2007

In the present report we describe the characteristics of 2 clones, E2 and C5, isolated from the human colon adenocarcinoma cell line LoVo. When grafted to immunosuppressed newborn rats, these clones formed tumors that varied with regard to differentiation rate, basement‐membrane organization and lung metastatic potential. Production and distribution of laminin by E2, C5 and related tumors was studied by immunohistochemistry with an anti‐laminin monoclonal antibody 4CI2 (MAb 4CI2). In lowly metastatic E2‐derived tumors, strong regular stainings were observed which were strictly peri‐tumoral and corresponded to the basal lamina. Since the antibody interacted with human laminin (the graft) but not with rat laminin (the host), this result indicated that basementmembrane laminin was supplied mainly by tumor‐cell synthesis. In highly metastatic C5‐derived tumors, the staining obtained with MAb 4CI2 was peri‐cellular and unorganized. Laminin synthesis by E2 and C5 cells in sub‐cultures or soon after dissociation from explanted tumors was studied by metabolic labelling with 35S‐methionine under steady‐state conditions followed by immunoprecipitation and SDS‐PAGE. High‐molecular‐weight laminin comprised by disulfide‐linked A and B chains, i.e., heterotrimeric laminin, was found in cell lysates and in the secretion medium of cell lines and tumor cells. In addition, BIB2 dimers and free B chains were observed in cell lysates. Quantitatively, Iaminin expression by E2 and C5 clones or tumor cells was not significantly different. These findings suggest that basementmembrane defects in invasive clone LoVo C5 were not due to laminin under‐expression.
BI‐modal differentiation pattern in a new human neuroblastoma cell line in vitro
Authors: Matsushima Hiroshi , Bogenmann Emil
Published: February 2007

We have isolated a human neuroblastoma (NB) cell line, HTLA230, from the bone‐marrow aspirate of a patient with stage‐IV disease. Subcutaneous tumors after inoculation of HTLA230 cells into nude mice were composed of primitive neuroblasts which rarely contained neuro‐secretory granules. Cytogenetic studies of the cell line demonstrated 2 distinct populations of cells with common chromosomal markers. Stable sub‐clones with a differentiated or undifferentiated cell morphology were isolated, demonstrating phenotypical heterogeneity of the HTLA230 parental cell line. Treatment with retinoic acid (RA) induced extensive neurite outgrowth in the parental cell line and in phenotypically differentiated sub‐clones, but rarely in undifferentiated ones. Long‐term treatment with RA was not associated with down‐modulation of mycN‐gene expression, which could be achieved only in cultures treated additionally with aphidicolin, a DNA‐synthesis inhibitor, thus eliminating growing NB cells. A RA resistant subclone (CI‐5) was isolated from parental HTLA230 cells grown at clonal cell density. Cells originally showed a homogeneously differentiated morphology; however, flat cells (F‐cells) appeared with time and were subsequently separately propagated. Transdifferentiation of isolated F‐cells into cells with neuron‐like (N‐cell) morphology was observed. Immunohistochemical analysis demonstrated that F‐cells had lost the expression of neuronal markers, including HNK‐l and A2B5, and expressed the intermediate filament, vimentin. Furthermore, F‐cells showed high incorporation of [methyl‐3H] thymidine (3H‐TdR) by autoradiography but no mycN protein could be detected, although present in the parental cell line. These results then suggest that the isolated NB cell line and the RA‐resistant variant line represent an excellent in vitro model with which the bi‐modal differentiation pathway of NB can be analyzed on a molecular biological level.
Enhanced clearance of radiolabeled murine monoclonal antibody by a syngeneic anti‐idiotype antibody in tumor‐bearing nude mice
Authors: Sharkey Robert M. , Boerman Otto C. , Natale Ana , Pawlyk David , Monestier Marc , Losman Michele J. , Goldenberg David M.
Published: February 2007

A syngeneic anti‐idiotype monoclonal antibody (MAb) (CM‐II) directed against an anti‐carcinoembryonic antigen (CEA) murine MAb (NP‐4) was evaluated as a second antibody (SA) to promote the rapid clearance of radiolabeled NP‐4 from the blood. Initial studies confirmed that CM‐II IgG removed 131‐NP‐4 IgG from the blood as effectively as a polyclonal donkey anti‐goat IgG removed 131I‐goat IgG. However, use of an F(ab′)2 in place of either the NP‐4 or CM‐II IgG was not as effective in removing primary radiolabeled antibody, despite the formation of high‐molecular‐weight complexes. In accordance with previous results, the timing and dose of the SA injection was critical for optimizing tumor uptake and improving tumor/non‐tumor ratios. In nude mice bearing GW‐39 human colonic tumor xenografts, a delay in the injection of CM‐II by 48 hr after injection of radiolabeled NP‐4 was optimal, since this allowed maximum tumor accretion. At a 200:1 CM‐II:NP‐4 ratio, tumor uptake was reduced, suggesting inhibition of NP‐4 binding to CEA within the tumor. Despite optimizing tumor uptake by delaying SA injection and adjusting its dose, the percentage of 131‐NP‐4 in the tumor decreased 2‐ to 3‐fold within 2 days after CM‐II injection. A similar effect was seen for 111In‐labeled NP‐4 IgG with CM‐II. Injection of excess unlabeled NP‐4 given to block CM‐II shortly after its injection failed to curtail the loss of NP‐4 from the tumor. Our results suggest that high blood levels of MAb are important for sustaining NP‐4 in the tumor. Radiation‐dose predictions derived from biodistribution studies indicate that a higher tumor dose may be delivered using the SA method than with either 131 I‐NP‐4 IgG or F(ab′)2 alone. Use of the SA method with 90Y‐labeled NP‐4 IgG, as modeled from biodistribution studies with 11In‐NP‐4 IgG, would likely be limited by liver toxicity.
No influence of beta‐carotene on smoking‐induced dna damage as reflected by sister chromatid exchanges
Authors: van Poppel G. , Kok F. J. , Duijzings P. , de Vogel N.
Published: February 2007

The putative cancer‐preventive potential of β‐carotene may be explained by its anti‐oxidant capacity to prevent free‐radicalinduced DNA damage. To evaluate this hypothesis, we studied the effect of 14 weeks of β‐carotene supplementation on the frequency of sister chromatid exchanges (SCE) in lymphocytes in 143 heavy smokers in a randomized, double‐blind, placebocontrolled intervention trial. Age, smoking habits and pretreatment blood levels of cotinine, β‐carotene, retinol and vitamins C and E were similar in the placebo group (n = 73) and the treatment group (n = 70). Plasma β‐carotene levels increased 13‐fold in the treatment group during intervention, whereas the other parameters remained stable in both groups. Initial SCE levels were similar in the treatment and placebo groups (5.10 ± 0.98 vs. 5.00 ± 0.99 SCE/lymphocyte). During the intervention, both groups showed an almost identical decrease, and at the end of the intervention period there was no difference in SCE levels between the treatment and the placebo groups (4.37 ± 0.38 vs. 4.24 ± 0.37 SCE/lymphocyte). This study shows no protective effect of β‐carotene on DNA damage as reflected by sister chromatid exchanges in lymphocytes. Our results thus do not yield support for a cancerpreventive mechanism of β‐carotene involving this form of DNA damage. It cannot be excluded, however, that β‐carotene prevents other forms of smoking‐induced DNA damage, affects other tissues, or is preventive in later stages of carcinogenesis.
Expression and different polarity of aminopeptidase N in normal human colonic mucosa and colonic tumors
Authors: Quaroni Andrea , Nichols Buford L. , Quaroni Elaine , Hurst Kelley , Herrera Lemuel , Weiser Milton M. , Hamilton Stanley R.
Published: February 2007

Expression and cellular localization of brush‐border enzymes (aminopeptidase N, dipeptidylpeptidase IV, lactase, maltase) in normal human colon, colonic polyps and malignant intestinal tumors were investigated with a panel of monoclonal antibodies reacting with either native or denatured proteins. The enzymes were detected on cryostat sections by indirect immunofluorescence staining, or affinity‐purified and analyzed by gel electrophoresis and immunoblotting. Dipeptidylpeptidase IV, lactase and maltase were absent from all samples examined, while aminopeptidase N (APN) was detected at the basal membrane of the epithelial cells in most specimens of colon obtained from individuals free of intestinal tumors. In contrast, APN was frequently localized at the luminal membrane of the surface epithelium in large‐intestinal mucosa distal to tumors, adenomas and hyperplastic polyps, and from members of hereditary colon cancer syndrome families. APN was also expressed in colonic tumors, where it was present in an apical cell membrane location in 3/23 adenomas and 14/35 adenocarcinomas examined. No correlation was found between tumor‐cell invasiveness (classified by „Dukes”︁ stage) and expression or cellular location of aminopeptidase N. Histologically, all positive tumors were moderately or well differentiated. These results suggest that aminopeptidase N is normally expressed in adult human colon, but epithelial cells in the large and small intestine differ in their ways of sorting this enzyme intracellularly and eventually inserting it into different aspects of their surface membrane, a process which may be altered at an early stage of carcinogenesis.
Protective single/combined treatment with betel leaf and turmeric against methyl (acetoxymethyl) nitrosamine‐induced hamster oral carcinogenesis
Authors: Azuine Magnus A. , Bhide Sumati V.
Published: February 2007

The inhibitory effect of oral administration of betel‐leaf extract (BLE) and 2 of its constituents, β‐carotene and α‐tocopherol, as single agents or in combination with dietary turmeric on methyl(acetoxymethyl)nitrosamine (DMN‐OAC)‐induced oral carcinogenesis in Syrian hamsters was studied. DMN‐OAC was administered twice monthly for 6 months. The chemopreventive effect of BLE or its constituents with turmeric was determined by comparing tumor incidence observed in treated groups with that seen in control animals. The apparent sitespecific chemopreventive effect of BLE or its constituents was demonstrated by inhibition of tumor incidence, reduction of tumor burden, extension of the tumor latency period and regression of established, frank tumors. The inhibitory effect of BLE or its constituents combined with turmeric was higher than that of the individual constituents. The study suggests that BLE could be developed as a potential chemopreventive agent for human oral cancer.
Hydrolyzable tannins: Potent inhibitors of hydroperoxide production and tumor promotion in mouse skin treated with 12‐O‐tetradecanoylphorbol‐13‐acetate in vivo
Authors: Gali Hala U. , Perchellet Elisabeth M. , Klish Darren S. , Johnson Jan M. , Perchellet Jean‐Pierre
Published: February 2007

The anti‐oxidant and the anti‐tumor‐promotion activities of several hydrolyzable tannins (HTs), including a commercial tannic‐acid (TA) mixture, were examined in mouse skin treated with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in vivo. A single application of TPA gradually increases the hydroperoxide (HPx)‐producing activity of the epidermis, which is maximally stimulated at 3 days and returns to control levels at 9 days. Pre‐treatments with TA and ellagic acid (EA) strongly inhibit, in a dose‐dependent manner, this HPx response to TPA. Total inhibition by TA lasts for about 16 hr, beyond which it is substantially reduced but not completely lost. TA can also reduce the level of epidermal HPx when it is applied 36 hr after the tumor promoter. EA is an antioxidant 10 times more potent than TA and n‐propyl gallate (PG), which are equally effective against TPA‐induced HPx production. Gallic acid is the least effective of the HTs in inhibiting HPx formation. TA also inhibits the production of HPx induced by several structurally different tumor promoters and the greater HPx responses produced by repeated TPA treatments. When applied 20 min before each promotion treatment, twice a week for 45 weeks, several HTs inhibit the incidence and yield of papillomas and carcinomas promoted by TPA in initiated skin. Overall, TA is more effective than EA and PG in inhibiting skin‐tumor promotion by TPA, suggesting that the anti‐oxidant effects of HTs are essential but not sufficient for their anti‐tumor‐promotion activity.
A monoclonal anti‐idiotypic antibody bearing the image of an epitope specific to the human carcinoembryonic antigen
Authors: Gaida Franz‐Josef , Fenger Ursula , Wagener Christoph , Neumaier Michael
Published: February 2007

One concept for immune therapy of patients bearing carcinomas involves monoclonal anti‐idiotypic antibodies (Malds) to trigger the immune system of the host into a response against the tumor cells. Current theory states that so‐called internal image Malds bearing epitopes specific to a given tumor associated antigen would be most suited for that purpose. We report here the generation of syngeneic Malds generated against the murine monoclonal immunoglobulin T84.66 (Abl), which defines a single epitope on the protein moiety of the carcinoembryonic antigen (CEA). This antigenic determinant is unique to CEA, as it is absent in other members of the CEA gene family that are expressed in a variety of normal human tissues, including granulocytes. The Mald 6G6.C4 (Ab2) exhibits the immunochemical features of an internal image antibody mimicking the epitope recognized by the idiotype T84.66. In enzyme immunoassays the binding of Abl to Ab2 is completely inhibited by CEA. In addition, Mald 6G6.C4 only binds to native but not to the denatured or reduced idiotype. Immunization of rabbits with F(ab′)2‐fragments of 6G6.C4 results in antisera (Ab3) that show specificity to CEA in both binding and inhibition enzyme immunoassays as well as in Western blots. Finally, Ab3 did not detect NCA, a major CEA‐related glycoprotein in Western blots, either in a purified form or in a crude tumor extract, indicating a high specificity of the anti‐anti‐idiotypic response. In summary, these immunochemical data show that the monoclonal anti‐idiotype 6G6.C4 can functionally mimic a CEA specific epitope in rabbits and may do so in humans. Therefore, this antibody may have a clinical potential as a network antigen for active immune therapy in patients suffering from CEA positive carcinomas.
Treatment of l1210 murine leukemia with liposome‐incorporated N4‐hexadecyl‐1‐β‐D‐arabinofuranosyl cytosine
Authors: Schwendener R. A. , Schott H.
Published: February 2007

N4‐alkyl‐1‐β‐D‐arabinofuranosyl cytosines as lipophilic derivatives of the widely used anti‐tumor drug 1 ‐β‐D‐arabinofurano sylcytosine (ara‐C) were synthesized and incorporated into unilamellar liposomes. The resulting preparations yielded stable unilamellar liposomes with diameters ranging between 40 and 70 nm. The liposomal derivatives exhibited an increased antitumor effect against the murine L1210 lymphoid leukemia at optimal molar concentrations which were 16 times lower than those previously reported for free ara‐C. The N4‐alkyl‐ara‐C derivatives with alkyl chains containing 14–16 C‐atoms were highly effective against L1 210 leukemia whereas shorter chains showed no cytostatic effects. The increased resistance to hydrolysis of the N4‐alkyl‐ara‐C derivatives and the improved anti‐tumor effect of the liposomal N4‐hexadecyl‐ara‐C preparation compared to other known N4‐acyl‐ara‐C prodrugs, together with the possibility of preparing large volumes of stable and sterile liposomes, hold out the prospect of more effective chemotherapy for leukemias.
The presence of a concomitant bulky tumor can decrease the uptake and therapeutic efficacy of radiolabeled antibodies in small tumors
Authors: Boerman O. C. , Sharkey R. M. , Blumenthal R. D. , Aninipot R. L. , Goldenberg D. M.
Published: February 2007

We describe the effects that a concomitant large tumor mass can exert on the therapeutic efficacy of radioimmunotherapy against small tumors, using the nude mouse/GW‐39 human colonic cancer model. The tumor uptake 7 days p.i. of i.v.injected 131l‐labeled anti‐CEA MAb (NP‐4) and anti‐CSAp MAb (Mu‐9) in small (<0.2 g) s.c. GW‐39 tumors was approximately 3‐fold lower in animals with a concomitant large (> 1.0 g) GW‐39 tumor than in the absence of a large tumor. An inverse correlation between the mass of the tumor burden and the 131l levels in the blood was observed, indicating that a large tumor mass may act as a sink for the injected radiolabeled antibody. Increasing antibody protein dose did not reverse the reduced uptake in the small s.c. tumors. The therapeutic efficacy of a single 0.25‐mCi injection of 131l‐labeled anti‐CSAp MAb Mu‐9 towards intrapulmonary GW‐39 metastases was tested in nude mice bearing either small or large GW‐39 s.c. tumors. Over 80% of the animals with small s.c. GW‐39 tumors survived 18 weeks after tumor transplantation, whereas less than 20% of the animals bearing large s.c. tumors survived past 13 weeks. Dosimetric calculations, based on biodistribution data over time, indicated that the presence of a large s.c. tumor mass may have decreased the radiation dose to the intrapulmonary tumors almost two‐fold. However, the radiation dose to the blood was also decreased in the animals with the large tumor burden. Therefore, the animals with larger tumor burden may also have been able to sustain higher doses of the radioantibody. The presence of a large tumor mass can thus affect the biodistribution and therapeutic efficacy of radioiodinated antibodies. We suggest that bulky tumors can adsorb a considerable amount of the injected dose, thereby reducing the total amount of MAb available for binding to the smaller tumors.
Hepatitis B Virus, cigarette smoking and alcohol consumption in the development of hepatocellular carcinoma: A Case‐Control study in Fukuoka, Japan
Authors: Tanaka Keitaro , Hirohata Tomio , Takeshita Setsuko , Hirohata Itsuyo , Koga Shunichi , Sugimachi Keizo , Kanematsu Takashi , Ohryohji Fumitake , Ishlbash Hiromi
Published: February 2007

The roles of the hepatitis B virus (HBV), cigarette smoking and alcohol consumption in the etiology of hepatocellular carcinoma (HCC) were examined in a case‐control study involving 204 patients with HCC and 410 control subjects in Fukuoka prefecture, where HCC risk is among the highest in Japan. Information on smoking and drinking habits was obtained by a detailed interview survey, and the results were analyzed in conjunction with serum hepatitis B surface antigen (HBsAg) status after adjustment for sex, age and other possible confounding factors. Individuals positive for serum HBsAg showed a relative risk (RR) for HCC of 13.8 (95% confidence interval, CI 5.9 to 32.5), whereas heavy drinkers experienced about a 2‐fold risk increase compared with non‐drinkers. Light or moderate drinkers, however, demonstrated RRs near the unity. Some risk excess was observed among ex‐smokers (RR = 1.5,95% CI 0.8 to 2.8) and current smokers (RR = 1.5, 0.8 to 2.7) compared with non‐smokers, but without evidence for a dose‐response relationship in terms of pack‐years. Analysis among HBsAg‐negative subjects revealed similar non‐significant association with smoking, and there was no clear interaction between alcohol and cigarette consumption on HCC risk. Other significant risk factors included positive histories of blood transfusion (RR = 3.7,2.2 to 6.3) and familial liver disease (RR = 2.6, 1.6 to 4.2). Attributable risk calculations suggest that chronic HBV infection and heavy drinking may account for 17% and 13% of HCC occurrence, respectively, in this high risk area. The association of cigarette smoking with HCC was not evident in our study.
Frequent expression of the tumor antigen cak1 in squamous‐cell carcinomas
Authors: Chang Kai , Pastan Ira , Willngham Mark C.
Published: February 2007

KI is a murine monoclonal antibody (MAb) derived from a hybridoma generated by the fusion of splenocytes of BALB/c mice immunized with a human ovarian tumor cell line, OVCAR‐3. This antibody reacts strongly with epithelial ovarian tumors and mesotheliomas. The antigen recognized by MAb Kl, designated CAKI, has recently been characterized as a 40‐kDa protein probably anchored to the cell surface by glycosyl‐phosphatidyli‐nositol. Using immunoperoxidase histochemical methods, we examined 37 squamous‐cell carcinoma (SqCC) samples from cervix, lung, esophagus and other origins, and 12 normal squamous epithelia of the cervix and esophagus for their reactivity with MAb KI. Of the SqCC specimens, 81% showed Kl reactivity with variable intensity, but none of 12 normal tissue samples of squamous epithelia did so. Two patterns of CAKI expression in tumor samples were found, i.e., a heterogeneous pattern with strong intensity, and a homogeneous pattern with weak intensity. Three carcinomas in situ of the larynx, vulva and esophagus were moderately positive with KI, suggesting that CAKI antigen may occur in the early stage of carcinogenesis of SqCC. The expression of CAKI was also compared with expression of CAI25, HER‐2/neu, p53 and P‐glycoprotein, and MAb KI was found to react most consistently with SqCC. Since KI reacts with a majority of cervical and esophageal carcinomas but has no detectable reactivity in normal epithelia of the cervix uteri and esophagus, MAb KI could be of value as a reagent to help distinguish between normal and neoplastic cells on sections as well as in cytological samples.
Prevalence of epstein‐barr virus DNA in different T‐cell lymphoma entities in a European population
Authors: Ott German , Ott M. Michaela , Feller Alfred C. , Seidl Stephan , Müller‐Hermelink Hans Konrad
Published: February 2007

The Epstein‐Barr virus (EBV) has been classically associated with nasopharyngeal carcinoma and Burkitt's lymphoma, a monoclonal B‐cell non‐Hodgkin's lymphoma. Since the EBV genome has also been found in post‐transplant lymphomas and lymphomas arising in individuals infected with the human immunodeficiency virus, evidence has now accumulated that EBV might be the initiator of a multi‐step process leading from polyclonal B‐cell hyperplasias to monoclonal lymphoma. In a retrospective study of 60 T‐cell lymphomas of various types, we found EBV DNA in 21 (35%) using Southern‐ and/or dot‐blot techniques. Eight of 14 nodal samples of angio‐immunoblastic lymphadenopathy (57%) were shown to harbour detectable EBV DNA. The tumour with the next highest frequency, 47% (7/15 cases analyzed) was pleomorphic T‐cell lymphoma, medium‐ and large‐cell type; EBV was found both in nodal and in extranodal lymphomas of this type. Lymphoepitheloid (Len‐nert's) lymphoma and large‐cell anaplastic lymphoma were positive in 2/5 and 3/8, respectively, of the cases analyzed. No viral DNA could be demonstrated in 3 T‐immunoblastic and 5 T‐lymphoblastic lymphomas. Clonotypic analysis revealed monoclonal as well as oligoclonal virus populations. Our data suggest that, at least in some of these entities, the presence of the EBV genome might be due to secondary mechanisms such as escape from immune surveillance.
Immunorecognition of different ganglioside epitopes on human normal and melanoma tissues
Authors: Bernhard Helga , Roth Sigrid , Bauerschmitz Jürgen , Büschenfelde Karl‐Hermann Meyer Zum , Dippold Wolfgang
Published: February 2007

There is increasing evidence that cell‐surface gangliosides play a role in tumor growth, progression and metastases. In order to determine the frequency of ganglioside GD3 in patients with metastatic malignant melanoma for further therapeutic trials, GD3 ganglioside expression was determined in 119 tissue samples. Of these melanomas, 93% (111/119) were R‐24‐positive, which indicates the value of this diagnostic marker for melanoma. To study the structural epitopes of gangliosides, 10 ganglioside antibodies with defined specificities and affinities were tested on over 100 fresh‐frozen tissue specimens of human normal and melanoma tissues. All the antibodies tested recognize the ganglioside GD3, but vary in their cross‐reactivity with other gangliosides. According to their epitope specificity, they can be divided into 5 groups. For example, the antibodies Z‐21 and A‐4 react like the previously established MAb R‐24 with gangliosides GD3 and GQIb, and one MAb (Q‐4) detects all gangliosides containing 2 connected sialic acids (GD3, GD2, GDIb, GTIb, GQIb). Specificity on TLC does not always correlate with specificity to melanoma tissues and vice‐versa. For example, MAb A‐4, which recognizes only GD3 and GQI b on TLC, shows no specific reactivity on tissues. Furthermore, antibodies with the same ganglioside specificity do not have the same staining pattern on human tissues. For example, MAb Z‐21, which is directed against the same gangliosides as MAb R‐24 on TLC, does not cross‐react with as many neuroectodermal tissues as MAb R‐24. Because of their distinct properties, some of these antibodies may be even more useful for immunodiagnosis and immunotherapy of malignant melanoma than MAb R‐24.
High HTLV‐I proviral DNA level associated with abnormal lymphocytes in peripheral blood from asymptomatic carriers
Authors: Tachibana Nobuyoshi , Okayama Akihiko , Ishihara Shirou , Shioiri Shigemasa , Murai Koichi , Tsuda Kazunori , Goya Naoko , Matsuo Yasuko , Essex Max , Stuver Sherri , Mueller Nancy
Published: February 2007

The level of proviral DNA in peripheral blood mononuclear cells from a representative group of asymptomatic HTLV‐I carriers in Miyazaki district, an HTLV‐I endemic area in Japan, was determined by a single‐cycle polymerase chain reaction method (PCR). Of 217 subjects, 26% had a high level of proviral DNA, 43% a medium level, 18% a low level, and 13% an undetectable level. In the high‐DNA group, 60% had at least 0.6% abnormal lymphocytes on peripheral blood smears, significantly higher than in those with low DNA levels (19%). This association was present for men of all ages and for women under 55. Men were more than twice as likely to have abnormal lymphocytes as well as high levels of proviral DNA. These differences may reflect different host responses to the virus by sex or by the time or route of infection. This study supports the utility of PCR for molecular screening in epidemiologic studies of the natural history of HTLV‐I, and may lead to the identification of those carriers who are at greatest risk of developing HTLV‐l‐induced malignancy.
Enhancement by stable butyrate derivatives of antitumor and antiviral actions of interferon
Authors: Pouillart Philippe , Cerutti Italina , Ronco Gino , Villa Pierre , Chany Charles
Published: February 2007

The use of n‐butyric acid has been associated with induction of cell differentiation and bypassing of genetic defects in the suppression of malignancy. This biological response modifier satisfies the requirements for specificity and low toxicity, and its use can be considered as an alternative approach to conventional cancer chemotherapy. However, a lack of clinical efficacy has been observed with butyrate and attributed mainly to the rapid metabolism of the compound. Butyric acid pro‐drugs derived from monosaccharides such as 3‐O‐butanoyl‐1,2‐O‐isopropylidene‐α‐D‐glucofuranose (MAG=3but) have consequently been devised. Pharmacokinetic and biological advantages of MAG=3but have been previously described. In the present report, we have studied the effect of MAG=3but on murine interferon‐α,β (IFN) anticellular, antitumor and antiviral activities, In vitro, it appears that MAG=3but predisposes malignant MSV cells to a later, complete establishment of the antiproliferative and the cell‐differentiating effects of IFN, and the antiviral action of the latter in the same line of cells infected with encephalomyocarditis (EMC) virus. In vivo, combined treatment with MAG=3but and IFN protects mice effectively against the fatal development of ascitic sarcoma 180 TG and the lethal effect of EMC virus infection.
The growth rate of two transplantable murine tumors, 3ll lung carcinoma and b16f10 melanoma, is influenced by Hyal‐1, A locus determining hyaluronidase levels and polymorphism
Authors: de Maeyer Edward , De Maeyer‐Guignard Jaqueline
Published: February 2007

The effect of 2 different levels of serum hyaluronidase on tumor development was studied by comparing the development of 2 transplantable tumors, the 3LL lung carcinoma and the B16F10 melanoma, in mice of the C57BL/6 and the congenic HW23 strains. The reasoning behind the study was that, in vitro, removal by hyaluronidase of the hyaluronan present in the extracellular matrix of tumor cells renders the latter more accessible to effector T cells. In the mouse, the levels and molecular forms of circulating hyaluronidase are under the influence of different alleles at the Hyal‐1 locus on chromosome 9. C57BLJ.6 mice which have the Hyal‐1b allele have only a 60,000‐kDa form of hyaluronidase in the circulation, whereas the congenic HW23 strain has, on a C57BL/6 background, the BALB/c‐derived Hyal‐1,2 allele, characterized by the presence of the 60‐, 120‐ and 140‐kDa forms and of 3 times as much enzyme activity as the CS7BL/6 strain. These 2 mouse strains that are genetically almost identical can therefore be used to compare the effect of different levels of circulating hyaluronidase on tumor development. Two different tumors were studied: the 3LL lung carcinoma and the B16F10 melanoma. After intra‐footpad inoculation, both tumors developed more slowly in the congenic Hyal‐1,2 HW23 strain, as measured by a slower rate of increase in local tumor size and by a prolonged survival time. These results are in favor of the hypothesis that the Hyal‐1,2 allele, determining higher hyaluronidase levels, enhances resistance to tumor development.
Inhibitions by 6‐hydroxydopamine and neostigmine singly or together of gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐n‐nitrosoguanidine in wistar rats
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Baba Miyako , Taniguchi Haruo
Published: February 2007

The effects of chemical sympathectomy induced by 6‐hydroxydopamine (6‐OHDA) and administration of the acetylcholinesterase inhibitor neostigmine, singly or together, on gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG), and on the tissue catecholamine concentration of the gastric wall and the labeling index of the gastric mucosa, were investigated in inbred Wistar rats. Rats received s.c. injections of neostigmine (0.075 mg/kg), and/or i.p. injections of 6‐OHDA (42 mg/kg twice within 24 hr, and then 105 mg/kg every 2 weeks from I week later) 25 weeks after oral treatment with MNNG. Prolonged administration of 6‐OHDA or neostigmine significantly reduced the incidence of gastric cancers by week 52, and in combination they had a significantly greater inhibitory effect. 6‐OHDA and/or neostigmine had no influence on the histology of gastric cancers. Administration of 6‐OHDA, but not neostigmine, significantly decreased the norepinephrine concentration in the antral portion of the gastric wall. The labeling index of the antral mucosa was decreased significantly by treatment with 6‐OHDA or neostigmine, and decreased even more significantly by 6‐OHDA plus neostigmine. Our findings indicate that 6‐OHDA and neostigmine have protective effects against gastric carcinogenesis and that in combination their effects are additive. These results imply that the activities of the sympathetic and parasympathetic autonomic systems together influence gastric carcinogenesis. © 1992 Wifey‐Liss, Inc.
A combination of two immunotoxins exerts synergistic cytotoxic activity against human breast‐cancer cell lines
Authors: Crews Jennie R. , Maier Lisa A. , Yu Yin Hua , Hester Susan , O'Briant Kathy , Leslie David S. , Desombre Karen , George Stephen L. , Boyer Cinda M. , Argon Yair , Bast Robert C.
Published: February 2007

In previous studies, combinations of immunotoxins reactive with different cell‐surface antigens have exerted additive cytotoxicity against tumor cells in culture. In this report we describe a combination of 2 immunotoxins that produce synergistic cytotoxic activity. Recombinantly derived ricin A chain (RTA) was conjugated with murine monoclonal antibodies (MAbs) 317G5, 260F9, 454A12 and 741F8 that bound to cell‐surface determinants of 42, 55, 180 (transferrin receptor) and 185 kDa (HER‐2/neu) expressed by the SKBr3 human breast‐cancer cell line. When inhibition of clonogenic growth was measured in a limiting dilution assay, the combination of 260F9‐RTA and 454A12‐RTA produced synergistic cytotoxic activity against SKBr3 and 2 other breast‐cancer cell lines. All other combinations produced only additive inhibition of clonogenic growth. Simultaneous binding of 260F9 and 454A12 was not supra‐additive, but sub‐populations of cells which lacked one or the other antigen could be detected. Kinetic studies of internalization, using antibodies conjugated with gold particles, indicated that 454A12 remained within peripheral endosomes for a longer interval in the presence of 260F9. This change in the traffic of the transferrin receptor may contribute to synergy between 260F9‐RTA and 454A12‐RTA. © 1992 Wifey‐Liss, Inc.
The effect of parity, tumor latency and transplantation on the activation of int loci in mmtv‐induced, transplanted C3H mammary pre‐neoplasias and their tumors
Authors: Schwartz Marlene S. , Smith Gilbert H. , Medina Daniel
Published: February 2007

Mouse mammary tumor virus (MMTV) infection of mammary glands results in proviral insertion into host DNA and activation of cellular genes. Clonal expansion of cells bearing insertional mutations results in hyperplastic alveolar nodules (HAN) and tumors. HAN, transplanted into epithelium‐cleared mammary fat pads, form hyperplastic alveolar outgrowths (HOGs). Previous work indicates the commonly MMTV‐activated genes wnt‐1 and int‐2 are rarely affected in HOGs and HOG‐derived tumors. To determine the basis of the dichotomy between the frequency of wnt/int gene activation in HOG‐derived tumors and tumors from breeders of the identical inbred mouse strain, we compared the activation of wnt‐1, int‐2 and int‐3 in tumors from virgin and breeding C3H mice, in consecutive primary tumors arising in individual C3H breeders and in C3H HOGs at early passages. Activation of wnt‐1 or int‐2 was rare in HOG‐derived tumors (6% and 0%) compared with primary tumors in breeders (52% and 14%). int‐3 was never found to be activated, wnt‐1 was activated in the same percentage of primary tumors from virgins as from breeders, int‐2 was activated only in tumors from breeders, wnt‐1 activation also did not correlate with shorter tumor latency in multiple tumors from individual breeders, wnt‐1 RNA was not detected in HOGs at early transplant generations, however, low levels of wnt‐1 RNA were variably found in the epithelium of virgin mammary glands. We cannot explain why C3H HOGs and their derivative tumors develop without wnt‐1 expression when the majority of C3H primary mammary tumors possess an MMTV‐activated wnt‐1 gene. © 1992 Wifey‐Liss, Inc.
Accumulation of allelic loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma
Authors: Nishida Naoshi , Fukuda Yoshihoro , Kokuryu Hiroyuki , Sadamoto Tetuo , Isowa Gohei , Honda Kazuo , Yamaoka Yoshio , Ikenaga Mituo , Imura Hiroo , Ishizaki Kanji
Published: February 2007

We examined loss of heterozygosity at 13 loci on 5 chromosomes in hepatocellular carcinomas (HCCs) from 56 patients. In 42 of these cases, regenerative nodules of liver cirrhosis were also analyzed. High frequencies of allelic losses were detected on chromosomes 13q (47%), 16q (40%) and 17p (64%), whereas losses on chromosome 4p and 11 p were observed in less than 22% of cases in HCCs. In contrast, LOH was not detected on any loci in cirrhotic nodules. On chromosome 13q, the common region of allelic loss was mapped to the region including the retinoblastoma (RB) locus, by using 8 polymorphic probes. Furthermore, one case with 13q loss had an interstitial deletion of the RB gene, indicating the involvement of inactivation of the RB gene in hepatotumorigenesis. Losses were associated with portal‐vein thrombosis or intrahepatic metastasis, increased tumor size, a poorly differentiated phenotype and clinical stage. Losses occurring together on 13q, 16q and 17p were significantly higher in patients in clinical stage IV or histologically poorly differentiated tumors, suggesting that the accumulation of allelic loss occurs in advanced tumors and that patients with multiple allelic losses may have a worse prognosis than those with a single loss.
Immunocytodiagnosis of atypical hyperplasia and endometrial carcinoma in post‐menopausal women
Authors: Mottolese Marcella , Vocatjro Amina , Bartolazzi Armando , Vocaturo Giuseppe , Benevolo Maria , Sedati Alfonso , Atlante Giuseppe , Prat Maria , Bigotti Aldo , Natali Pier Giorgio
Published: February 2007

In the present study we have evaluated whether monoclonal antibodies (MAbs) B72.3 and AR‐3 which display, on histological preparations, a differential reactivity with normal and transformed endometrium, could be a useful adjunct to endometrial cytology in the identification of pre‐neoplastic and neoplastic conditions. Immunocytochemical (ICC) tests, using the 2 reagents, were performed on normal cycling endometrium and on hyperplastic and malignant lesions collected by the endocyte technique both from 86 surgically resected specimens and from 62 postmenopausal symptomatic and asymptomatic outpatients. The results obtained showed that the combination of the 2 MAbs can complement conventional morphology in the identification of pre‐malignant atypical lesions and endometrial carcinoma of unclear cytological features, thus allowing a selection of those patients who are candidates for fractional curettage.
Expression of c‐sis and c‐fos genes in human meningiomas and neurinomas
Authors: Riva P. , Larizza L.
Published: February 2007

The HindIII c‐sis RFLP was analyzed in constitutional and tumor DNAs of 19 meningioma patients. Loss of a c‐sis allele (allele 1 in all cases) was observed in 6 out of 10 tumors from heterozygous patients. No alteration in the structure or dosage of the c‐sis gene was detected in any tumor sample. Northern analysis of c‐sis evidenced sis transcripts in 7 out of 8 meningiomas which were amenable to analysis. All tumors expressing c‐sis also expressed c‐fos, suggesting that the autocrine loop elicited by sisactivation may have c‐fos as its nuclear target. Co‐expression of c‐sis and c‐fos was also observed in 5 neuromas out of 7 analyzed. Very high levels of fos‐mRNA were observed in 2 neuromas, but were not found to be caused by apparent alteration or amplification of the c‐fos gene.
HOX gene expression in normal and neoplastic human kidney
Authors: Cillo C. , Barba P. , Freschi G. , Bucciarelli G. , Magli M. C. , Boncinelli E.
Published: February 2007

As a consequence of transformation, cancer cells generally lose some of their differentiative properties. Thus, alterations interfering with the genetic mechanisms required to maintain embryonic determination could lead to tumorigenesis. Ho‐meobox genes are a network of genes encoding nuclear proteins containing DNA‐binding homeodomains that are highly conserved throughout evolution. They are expressed in a stage‐related fashion in the developing embryo and, in adult life, in normal tissues. In mice and humans, homeobox genes of the HOX family are organized in 4 clusters on different chromosomes which have presumably evolved by duplication of a primordial gene cluster. Strikingly, the order of genes within each cluster is also highly conserved throughout evolution, suggesting that the physical organization of HOX genes might be essential for their expression. Recent reports indicate that homeobox mutant mice display morphological abnormalities or show neoplastic alterations, and that growth factors can turn on homeobox genes. We have studied the expression of the Antennapedia‐like HOX genes in normal human kidney and in renal carcinomas. The great majority of the HOX genes analyzed are expressed in a peculiar manner in normal kidney: blocks of genes, even entire HOX loci, are coordinately regulated. Alterations in HOX gene expression in renal carcinoma can be observed in 2 genes of the HOX‐2 locus, HOX‐2A and HOX‐2E, which are actively expressed in normal kidney and silent in cancer biopsies. The HOX‐3H gene is not expressed in normal kidney whereas the HOX‐3H transcripts are present in renal carcinomas. Homeobox genes within the 4 HOX loci can be aligned on the basis of the maximal sequence homology of their homeodomains: this alignment defines 13 paralogous gene groups. In renal carcinomas, genes of group 10 (HOX‐1D, 2F, 3E, 4B) display a marked difference in their transcript classes when compared to those of normal kidney. Our findings suggest an association between altered HOX gene expression and kidney cancer.
Alcoholism and liver cirrhosis in the etiology of primary liver cancer
Authors: Adami Hans‐Oiov , Hsing Ann W. , McLaughlin Joseph K. , Trichopoulos Dimitrios , Hacker David , Ekbom Anders , Persson Ingemar
Published: February 2007

The aim of this study was to determine the risk of developing primary liver cancer in patients with a diagnosis of alcoholism, liver cirrhosis, or both. Three population‐based, mutually exclusive cohorts were defined on the basis of hospital discharge diagnoses between 1965 and 1983. Complete follow‐up through 1984—excluding the first year of follow‐up—showed that among 8,517 patients with a diagnosis of alcoholism, 13 cancers occurred, vs. 4.2 expected (standardized incidence ratio (SIR) = 3.1; 95% confidence interval (CI) = 1.6 to 5.3); among 3389 patients with liver cirrhosis, 59 cancers occurred, vs. 1.7 expected (SIR = 35.1; 95% CI = 26.7 to 45.3), and among 836 patients with both diagnoses, 11 cancers occurred, vs. 0.3 expected (SIR = 34.3; 95% CI = 17.1 to 61.3). Thus, alcoholism alone entailed a moderately increased risk and alcoholism with liver cirrhosis did not increase the high relative risk for liver cancer more than cirrhosis alone. We conclude that alcohol intake may be a liver carcinogen only by being causally involved in the development of cirrhosis; and further, that the risk of developing liver cancer following cirrhosis in this population is similar to or higher than that after chronic hepatitis‐B‐virus infection in other Western countries.
The effect of schedule, protein binding and growth factors on the activity of suramin
Authors: Lopez Rafael Lopez , Peters Godefridus J. , van Loenen Arie C. , Pizao Paulo E. , van Rijswijk Ruud E. N. , Wagstaff John , Pinedo Herbert M.
Published: February 2007

Suramin has been shown to have antiproliferative activity, either by blocking the binding of growth factors to their receptors or by inhibiting critical cellular enzymes. In 6 different cell lines from 5 tumour types (MCF‐7, MCF‐7/ADRR, PC3, HT‐29, UM‐SCC‐IIB and SW‐1573/1R500), we studied the effect of scheduling of suramin, of FCS and of human serum albumin (HSA), of epidermal growth factor (EGF) and of the addition of growth factors in serum‐free medium on the activity of suramin. The concentration of suramin which gave 50% growth inhibition (IC50) varied from 45 μM in SW‐I573/IR500 to 153 μM in PC3 cells grown in medium supplemented with 5% FCS, after 6 days of continuous exposure. Exposure for more than 4 days did not enhance the sensitivity to suramin, except in PC3. At exposure to suramin for 1 day followed by 5 days recovery, high IC50 values (>0.5 mM) were observed in MCF‐7 cells. In medium with 1% and 0.5% FCS these values were 3 to 8 and 14 to 26 times lower respectively. Addition of HSA increased the IC50 in PC3 and MCF‐7 cells. Suramin binding to protein was dependent on the concentration of protein and of suramin. Excess of EGF in medium with different FCS concentrations did not change the IC50 values of suramin in PC3 and MCF‐7 cells. Addition of EGF, fibroblast growth factor or platelet‐derived growth factor in PC3 cells cultured in serum‐free medium did not increase the IC50 values. Suramin was active against these 6 cell lines at clinically achievable concentrations. This activity varied depending on the cell line, exposure time and suramin concentration. The most significant factor interfering with sensitivity to suramin was the amount of protein present in the culture medium.
Correlation of myc expression with the growth‐arrested and transformed phenotypes in hybrids between A T lymphoma and an antigen‐responsive T‐cell line
Authors: Kubota Koichi , Imreh Stephan , Katoh Hideki , Babonits Magdalena , Wiener Francis
Published: February 2007

Fusion of the YACUT lymphoma cell line with the Mls‐Ia‐antigen‐specific non‐tumorigenic T‐cell line G4 produced growth‐arrested hybrids that could be induced to proliferate in the presence of Mls‐Ia antigen. Prolonged growth of such hybrids by repeated antigenic stimulation resulted in the appearance of autonomously growing hybrid lines. Of the 4 antigen‐independent hybrid clones, I was weakly tumorigenic (25% incidence) while the other 3 were highly tumorigenic (100% incidence). In the growth‐arrested hybrids the de‐regulated c‐myc expression characteristic of the YACUT cells was suppressed. In the autonomously growing clones, however, c‐myc expression had reverted to the levels of the lymphoma parent and 1 to 2 extra copies of chromosome 15 were consistently present. These results indicate that repeated antigenic stimulation somehow abrogated the down‐regulation of c‐myc in the growth‐arrested hybrid lines. The increase in the number of copies of chromosome 15, however, suggests that genes located on this chromosome may abolish the effect of the negative regulatory functions of the non‐malignant parent in a gene‐dosage‐dependent manner.