lewis-y-antigen and Adenocarcinoma

The task of rationally designing vaccines that can effectively impact on the survival of cancer patients remains challenging. Monoclonal antibodies and T cell receptors have proven to be viable templates for the application of pharmacophore design principles to develop antigens and immunogens as these immune system molecules recognize a variety of sequentially and structurally unrelated ligands. This structural information combined with immunological assessment has contributed to the development of strategies to elicit effective humoral and cellular responses to cancer cells. Understanding the structural requirements for antibody and T cell recognition provides a basis for identifying potentially new sets of immunogens that may have both fundamental immunological and clinical value. Here we review the structural concepts and approaches used in vaccine design applications that illustrate the value and limitations of using chemical (peptide libraries) and immunological information to define novel peptide immunogens that function as mimotopes to generate immune responses targeting tumor associated carbohydrate antigens.

Topics: Adenocarcinoma; Amino Acid Sequence; Cancer Vaccines; Carbohydrates; Humans; Lewis Blood Group Antigens; Models, Molecular; Molecular Mimicry; Molecular Sequence Data

This study was conducted to gain a better understanding of the underlying cellular events involved in the development of prostatic intraepithelial neoplasia (PIN) and to clarify the relationship of PIN to invasive prostatic adenocarcinoma (PCa).. This article reviews previous studies from our laboratory and others of biomarker expression in PIN and PCa.. The development of PIN is characterized by increased expression of several biomarkers which may influence the proliferative potential of the dysplastic cells. Increased expression of the growth factor receptors P185erbB-2, p180erbB-3, as well as the product of the c-met proto-oncogene is frequently detected in the dysplastic luminal cells as well as malignant cells of the prostate. Likewise, the expression of the nm-23H1 gene product is strongly expressed in dysplastic and malignant cells. Increased proliferative potential of the dysplastic cells is directly reflected by increased expression of PCNA. In contrast to the enhanced expression of the biomarkers associated with proliferation, decreased expression of prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and Leu 7 by dysplastic luminal cells is indicative of an impairment of the process of cellular differentiation. Aberrant glycosylation as well as the inappropriate expression of glycosylated tumor antigens is demonstrated by enhanced binding of the lectin Ulex europaeus and increased expression of tumor-associated glycoprotein 72 (TAG-72) and the Lewis Y antigen in dysplastic and malignant cells. Finally, enhanced expression of proteolytic enzymes such as cathepsin D and the 72-kD form of collagenase IV by dysplastic cells may represent an integral event in the development of invasive PCa.. The studies described in this review clearly demonstrate phenotype similarities of PIN to invasive PCa and furthermore support the concept that PIN represents a preinvasive lesion.

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers; Gene Expression Regulation, Neoplastic; Glycoproteins; Glycosylation; Humans; Lewis Blood Group Antigens; Male; Oncogene Proteins; Phenotype; Prostate-Specific Antigen; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Proto-Oncogene Mas; Receptors, Growth Factor

Tumor-associated macrophages (TAMs) are key components of tumor microenvironment (TME) during tumorigenesis and progression. However, the role of TAMs in lung adenocarcinoma is still unclear. In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and epithelial-mesenchymal transition (EMT) of lung adenocarcinoma. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was aberrantly elevated in various solid tumors, it plays critical role in the invasion and metastasis. Here, we found that in lung adenocarcinoma samples, the density of TAMs correlates with E-cadherin level and LeY level. In vitro assays, M2 macrophages promoted FUT4/LeY expression through the transforming growth factor-β1(TGF-β1)/Smad2/3 signaling pathway. FUT4/LeY was indispensable in M2 macrophages-mediated cytoskeletal remodeling and EMT. Furthermore, fucosylation of Ezrin mediated by FUT4/LeY can promote the phosphorylation of Ezrin, which was the critical mechanism of M2 macrophages-induced EMT. In vivo assays confirmed that M2 macrophages promoted EMT through the up-regulation of LeY and phosphorylated Ezrin. Together, our results revealed that TAMs promote Ezrin phosphorylation-mediated EMT in lung adenocarcinoma through FUT4/LeY- mediated fucosylation. Targeting this newly identified signaling may offer new possibilities for immunotherapy in lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Biomarkers; Cadherins; Cell Count; Cell Line, Tumor; Cytoskeletal Proteins; Cytoskeleton; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Fucosyltransferases; Heterografts; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Lung Neoplasms; Macrophages; Mice; Models, Biological; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; Up-Regulation

Immunohistochemistry with panels of antibodies is a standard procedure to distinguish between malignant mesothelioma and metastatic adenocarcinoma. Most studies assess only the sensitivity and specificity for single antibodies, even when the paper concludes by recommending an antibody panel. It was the aim of this study to use a novel statistical approach to identify a minimal panel of antibodies, which would make this distinction in the majority of cases.. Two hundred consecutive cases of pleural malignancy (173 pleural mesotheliomas of epithelial type and 27 cases of secondary adenocarcinoma) were investigated using a standard panel of 12 antibodies (CAM5.2, CK5/6, calretinin, HBME-1, thrombomodulin, WT-1, EMA, CEA, CD15, B72.3, BG8, and TTF-1). Regression and classification tree-based methods were applied to select the best combination of markers. The modelling procedures used employ successive, hierarchical predictions computed for individual cases to sort them into homogeneous classes.. Labelling for calretinin and lack of labelling for BG8 were sufficient for definite correlation with a diagnosis of malignant mesothelioma. CD15 provided further differentiating information in some cases.. A panel of three antibodies was sufficient in most cases to diagnose, or to exclude, epithelial mesothelioma. Calretinin exhibits the strongest correlative power of the antibodies tested.

Topics: Adenocarcinoma; Antibodies; Biomarkers, Tumor; Cadherins; Diagnosis, Differential; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Lewis X Antigen; Mesothelioma; Regression Analysis; Sensitivity and Specificity

Lewis(y) (Le(y)), also designated CD174, represents a carbohydrate blood group antigen which is strongly expressed in neoplastic gastrointestinal tissues. Previous reports indicated an association between Le(y) expression and apoptosis. Therefore, we tried to elucidate its clinicopathological relevance in a series of 160 gastric and 215 colorectal carcinomas by immunohistochemical detection of Le(y) and visualization of apoptotic cells applying the in-situ-end labelling (ISEL) method, followed by semiquantitative scoring of the specimens. In both gastric as well as colorectal carcinomas, between 40 and 50% of the cases were Le(y) reactive. Signet-ring cell carcinomas of the stomach exhibited a significantly stronger Le(y) expression compared to other tumor types. In colorectal cancers, Le(y) was associated with increased tumor staging, showing the strongest positivity in stage IV. Further correlations with clinicopathological variables or prognosis were not observed. On the other hand, the amount of apoptotic cells was significantly reduced in mucinous adenocarcinomas of the colorectum compared to non-mucinous carcinomas. Scoring of apoptotic cells did not result in any other clinicopathologically relevant correlations. In addition, a significant association between Le(y) antigen expression and apoptosis score could not be established. Therefore, the hypothesis of a functional relationship between these two aspects of gastrointestinal tumor biology is not confirmed by our data.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Apoptosis; Carcinoma, Signet Ring Cell; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Male; Middle Aged; Neoplasm Staging; Prognosis; Stomach Neoplasms; Survival Analysis

Ovarian carcinoma has a high mortality rate, because most ovarian carcinomas are detected at a late stage. Traditional therapies, such as surgical debulking and chemotherapy, have not been successful in improving the long-term survival of these patients. Alternative therapies targeting various biomarkers, such as carcinoembryonic antigen (CEA), Tag-72, and Lewis-Y antigen, have been developed to treat patients with advanced ovarian cancers. To ensure that therapies targeting these biomarkers are effective, it is imperative to determine whether there is any differential expression of these targeted biomarkers between primary and metastatic ovarian carcinomas. In the present study, primary and metastatic lesions from 68 and 58 patients, respectively, including primary and matched metastatic lesions from 31 patients, were evaluated for cytoplasmic and membranous expression of CEA (clone Col-1), Tag-72 (clone CC-49), and Lewis-Y antigen (clone BR-96) by immunohistochemistry. No significant differences were observed with cytoplasmic and membranous expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) in the primary and metastatic, matched and unmatched lesions (Wilcoxon signed-rank test). Although there was no statistically significant difference in the scores of CEA (Col-1) between primary and metastatic lesions, 5 of 11 (45%) cases with positive staining with CEA (Col-1) demonstrated discordant results between primary and metastatic lesions. There was a moderate positive correlation of the cytoplasmic and membranous expression of Tag-72 (CC-49), as well as cytoplasmic expression of BR-96 between primary and metastatic ovarian carcinomas. There was a weak negative correlation between the membranous expression of CEA (Col-1) and that of Lewis-Y antigen (BR-96); however, the difference was not statistically significant. No correlation was observed with other combinations of biomarkers. Our findings suggest that samples from either primary or metastatic ovarian carcinomas can be used for the evaluation of the expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) to identify targets for novel therapies in patients with disseminated ovarian carcinomas. CEA (Col-1), due to its low expression and variation in phenotypic expression between primary and metastatic lesions, should be evaluated carefully in metastatic lesions before targeting the CEA antigen with CEA (Col-1)-like antibodies.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Female; Glycoproteins; Humans; Lewis Blood Group Antigens; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms

There is mounting evidence to suggest that immunization-based strategies can be used to mobilize the human immune system against specific carbohydrate antigens displayed on the surface of cancer cells. Following isolation and identification, such antigens can be administered as conjugate vaccines. The tumor-associated carbohydrate antigen KH-1 is 1 such antigen and may serve as a potential target for immunization against adenocarcinoma. However, a serious impediment to the application of a vaccine-based approach involving this antigen is that its availability from natural sources is severely limited. In order to overcome this limitation, we have developed an efficient total synthesis of this complex glycolipid. We have extended our synthesis to reach a structurally related analog in which the ceramide portion of KH-1 is replaced with an allyl substituent. These synthetic advances have led to the preparation of 2 potential vaccine constructs, each based on the conjugation of the KH-1 nonasaccharide and the carrier protein keyhole limpet hemocyanin (KLH). In 1 construct (KH-1-Et-KLH), the nonasaccharide is conjugated to KLH via a simple ethyl linkage, while in the other (KH-1-MMCCH-KLH), conjugation is mediated by a 4-(4-N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide (MMCCH) cross-linker. We report here the immunological properties of these 2 constructs. Mice were immunized with either of the 2 KH-1-KLH vaccine candidates or the KH-1 ceramide, along with the immunological adjuvant QS-21. Immunization with the ceramide served as a negative control and, as expected, failed to stimulate the production of antibodies against the KH-1 glycolipid. The construct in which the KH-1 nonasaccharide is linked to KLH via a simple alkyl chain stimulated significant quantities of IgM antibodies, whereas the construct linked to KLH by MMCCH induced high titers of both IgM and IgG antibodies. Inhibition data demonstrated that antibodies generated in response to immunization with the KH-1-KLH constructs recognize not only the KH-1 antigen but also the Lewis(y) (Le(y)) antigen, which, from a structural perspective, is similar to the 4 residues located at the non-reducing end of the KH-1 nonasaccharide. Thus, the KH-1-KLH constructs elicit an immune response that successfully targets 2 adenocarcinoma markers. As assessed by FACS analysis, the antibodies raised were strongly reactive with the KH-1/Le(y) positive cell line MCF-7 but not with KH-1 and Le(y) negative melanoma c

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Antibody Formation; Antibody Specificity; Antigens, Tumor-Associated, Carbohydrate; Cancer Vaccines; Carbohydrate Conformation; Carbohydrate Sequence; Ceramides; Cross-Linking Reagents; Female; Flow Cytometry; Hemocyanins; Immunization; Immunoglobulin G; Immunoglobulin M; Lewis Blood Group Antigens; Mice; Molecular Sequence Data; Oligosaccharides; Saponins

The chimeric monoclonal antibody cBR96 conjugated to doxorubicin (cBR96-Dox) is selectively internalized by a wide variety of human carcinomas expressing an extended form of Lewis Y antigen (Le(y)). Endocytosis is followed by cleavage and release of free doxorubicin from the endocytic vesicles and subsequent cytotoxicity. Combination studies with standard anti-cancer agents, undertaken to further increase the potency of this targeted therapy, identified significant synergistic anti-tumor activity of cBR96-Dox and either of the taxanes paclitaxel or docetaxel. Treatment with cBR96-Dox 24 hr prior to paclitaxel resulted in a steady increase in the percentage of G(2) tumor cells and corresponding increase in sensitivity to taxanes. Cell cycle analysis indicated the cBR96-delivered doxorubicin was most effective against S-phase cells, yet cells exposed to even subtoxic levels progressed to and arrested in G(2), at a point of high sensitivity to the anti-tubulin agent paclitaxel. The synergy obtained by staged combination of cBR96-Dox and paclitaxel in vitro was reflected in significant anti-tumor efficacy in vivo against xenograft models of human lung and breast tumors that could not be achieved by either agent alone. The staged combination elicited significant or complete regressions of established human Le(y)-positive tumor xenografts using significantly reduced drug levels. Taken together, these data demonstrate a mechanistic approach to the selective elimination of Le(y)-positive tumors by using targeted doxorubicin followed by taxane treatment.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Colonic Neoplasms; Docetaxel; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Immunotoxins; Inhibitory Concentration 50; Lewis Blood Group Antigens; Lung Neoplasms; Mice; Mice, Nude; Paclitaxel; Taxoids; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Tumor procoagulant is associated with cancer at advanced stages of malignancy such as infiltration and metastasis. In the present study, we investigated the role of Ley glycolipid in the mechanism of cancer metastasis. Ley glycolipid acts as an important cofactor in the expression of the blood-coagulating activity of cancer cell-derived coagulating activity 1 (CCA-1), which is one of the known tumor procoagulants. Monoclonal antibody (MoAb) FS01, which serves as the Ley-recognizing epitope, inhibits the procoagulant activity of CCA-1 was found to dose-dependently inhibit the procoagulant activity of normal plasma induced by the human lung adenocarcinoma cell line, HAL8, which shows a high level of Ley expression. It did not, however, inhibit the procoagulant activity of the human colon cancer cell line, RPMI4788, which does not express Ley. Administration of FS01 MoAb inhibited lung metastasis of HAL8 cells, but not that of RPMI4788. The absence of antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity of FS01 MoAb against the HAL8 cell line suggests that the inhibition of HAL8 metastasis by FS01 MoAb derives from the inhibition of blood-coagulating activity of the latter. These findings indicate that Ley glycolipid plays an important role in the mechanism of cancer metastasis via the procoagulant activity of CCA-1.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Blood Coagulation Factors; Blood Coagulation Tests; Carcinoma, Squamous Cell; Colorectal Neoplasms; Cysteine Endopeptidases; Drug Screening Assays, Antitumor; Flow Cytometry; Glycolipids; Lewis Blood Group Antigens; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Tumor Cells, Cultured

The distinction between malignant pleural mesotheliomas and adenocarcinomas, particularly those originating in the lung, is a difficult diagnostic problem that can be facilitated by the use of immunohistochemical markers. In this study, the immunoreactivity of thyroid transcription factor-1 (TTF-1), E-cadherin, BG8, WT1, and CD44S was investigated in 50 epithelial mesotheliomas, and 40 pulmonary and 95 nonpulmonary adenocarcinomas. After analyzing the results, it was concluded that E-cadherin and BG8 are useful markers for distinguishing between epithelial mesotheliomas and adenocarcinomas of various origins, including the lung. Because TTF-1 expression is found almost exclusively in adenocarcinomas of the lung but is absent in mesotheliomas, immunostaining for this marker is particularly useful for distinguishing between these two malignancies. Although WT1 immunostaining may also be useful, its value, as determined in this study, is lower than that reported by other investigators. CD44S immunostaining does not have any practical value in discriminating between epithelial mesothelioma and lung adenocarcinoma.

Topics: Adenocarcinoma; Biomarkers, Tumor; Cadherins; Diagnosis, Differential; DNA-Binding Proteins; Epithelial Cells; Humans; Hyaluronan Receptors; Lewis Blood Group Antigens; Lung Neoplasms; Mesothelioma; Nuclear Proteins; Pleural Neoplasms; Thyroid Nuclear Factor 1; Transcription Factors; WT1 Proteins

The biodistribution characteristics of a humanized anti-Lewis(y) antibody (hu3S193) radiolabeled to three radioisotopes, 125I, 111In, and 90Y, were examined in a BALB/c nude mouse xenograft model of breast cancer. The immunoreactivity of both 125I- and 111In-bound hu3S193 exceeded 50% and was 20% for 90Y. In vivo, labeled antibody was shown by gamma camera imaging and immunohistochemical and autoradiographic techniques to localize to Lewis(y)-expressing breast xenografts with minimal normal tissue uptake. Maximal radioisotope uptake peaked at 48 h for all three isotopes; however, the percentage of injected dose/gram and tumor retention were greater for 111In- and 90Y-bound antibody than for 125I-bound antibody. Although immunoreactivity of 111In- and 125I-labeled hu3S193 in serum was stable over a 5-day period, the amount of unlabeled 111In in serum was lower than 125I, which together with higher tumor uptake indicates better retention of 111In-labeled hu3S193 and catabolites within the tumor cells. Superior tumor uptake and retention of 111In-labeled hu3S193 and similar blood clearance compared with 125I-labeled hu3S193, suggest that radiometals are the preferred radioisotope for this antibody-antigen system. Humanized 3S193 is a promising new construct for the targeting and potential therapy of Lewis(y)-expressing tumors.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Autoradiography; Breast Neoplasms; Drug Stability; Female; Half-Life; Humans; Immunohistochemistry; Indium Radioisotopes; Iodine Radioisotopes; Isotope Labeling; Lewis Blood Group Antigens; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Radionuclide Imaging; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured; Yttrium Radioisotopes

Monoclonal antibody therapy may provide new treatment options in the management of metastatic breast cancer by selectively targeting tumors and producing a therapeutic effect, by delivering radiation or other toxins directly to tumor cells, or by producing an intrinsic immune inflammatory response. The effect of 131I-labeled humanized anti-Lewis(y) monoclonal antibody 3S193 (hu3S193) was compared with that of placebo and radiolabeled huA33 control antibody in a series of radioimmunotherapy experiments in a MCF-7 xenografted BALB/c nude mouse breast cancer model. The maximum tolerated dose of 131I-labeled antibody occurred at 200 microCi/mouse, at which dose level three of six mice that received 131I-hu3S193 showed significant tumor growth inhibition in contrast to no responses in the comparable 131I-huA33 control treatment arm. Breast cancer is an ideal model to test the efficacy of combined modalities given its known sensitivity to both radiotherapy and chemotherapy. The synergy between radioimmunotherapy and chemotherapy was therefore also explored using a combination of 131I-labeled hu3S193 antibody and Taxol using subtherapeutic doses of each agent. The combination of Taxol and 100 microCi of 131I-hu3S193 produced significant tumor inhibition in 80% of mice, whereas no responses were seen with either treatment modality alone or the combination of Taxol and 131I-huA33. These results support a potential therapeutic role of radiolabeled hu3S193 in the treatment of breast cancer, including combination therapy with Taxol, and warrants further investigation of this promising new agent.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Division; Combined Modality Therapy; Dose-Response Relationship, Radiation; Female; Humans; Immunotoxins; Iodine Radioisotopes; Lewis Blood Group Antigens; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel; Radioimmunotherapy; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We have developed a highly specific gene transfer method for adenocarcinoma using a monoclonal antibody against tumor-specific antigen coupled with a plasmid containing the carcinoembryonic antigen (CEA)-specific promoter. The chimeric CEA promoter (CC promoter), which contained an enhancer from the immediate early gene of cytomegalovirus and the CEA promoter, achieved 4- to 5-fold higher transgene expression in CEA-producing cells than the original CEA promoter while maintaining CEA specificity. Furthermore, a complex of a monoclonal antibody against Lewis Y antigen (LYA), the CC promoter-containing plasmid and cationic liposomes (DOTAP) achieved specific gene expression in CEA-producing and LYA-positive adenocarcinoma cell lines that was 200-fold more efficient than in CEA-non-producing and LYA-negative cell lines during a short in vitro incubation. This strategy may be applicable for clinical gene therapy.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Neoplasm; Carcinoembryonic Antigen; Colorectal Neoplasms; Combined Modality Therapy; Gene Transfer Techniques; Genetic Therapy; Humans; Lewis Blood Group Antigens; Liposomes; Lung Neoplasms; Organ Specificity; Promoter Regions, Genetic; Tumor Cells, Cultured

Topics: Adenocarcinoma; Adjuvants, Immunologic; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Complement Inactivator Proteins; Humans; Lewis Blood Group Antigens; Lung Neoplasms; Tumor Cells, Cultured

Expression of Le(a) (Lewis(a)), Le(b) (Lewis(b)), X (Lewis X), Y (Lewis Y), SPan-1 and CEA was detected by an immunohistochemical method using a panel of antibodies in paraffin-embedded materials from 45 rectal adenocarcinomas and the corresponding normal mucosa. The relationships between antigen expression and grade of differentiation and survival were analyzed. Compared to the expression in normal mucosa, the expression of Le(a) was decreased in tumors while the expression of Le(b), X, Y. SPan-1 and CEA was increased. The expression of Le(a) and SPan-1 was associated with the grade of differentiation (p = 0.0001 and p = 0.02, respectively). Positive expression of Le(a) and SPan-1 correlated with poor prognosis (p = 0.0001 and p = 0.002, respectively), but positive expression of Y predicated favorable prognosis (p = 0.01). Our findings indicate that some of the tumor-related antigens might provide information important for the diagnosis, determining histologic differentiation and prognosis in rectal adenocarcinomas.

Topics: Adenocarcinoma; Antigens, Neoplasm; Carcinoembryonic Antigen; Cell Differentiation; Humans; Immunoenzyme Techniques; Intestinal Mucosa; Lewis Blood Group Antigens; Lewis X Antigen; Rectal Neoplasms

Complement-dependent cytotoxicity (CDC) mediated by a chimeric anti-Lewis Y monoclonal antibody (cH18A; human IgG1) was investigated in this study. Human lung adenocarcinoma cell lines (PC7, PC9, and PC14) were used as the target cells. PC7 and PC9 cells, expressed Lewis Y antigen and were lysed by cH18A as effectively as by the parent mouse anti-Lewis Y antibodies (mH18A) in a concentration-dependent manner. PC14 cells did not express Lewis Y antigen and were not lysed by either cH18A or mH18A. cH18A mediated CDC activity against PC7 and PC9 cells was enhanced by the combined use of monoclonal antibodies directed against CD46(MCP), CD55(DAF), and CD59. These molecules are complement-regulatory proteins which protect host cells from CDC. PC7 and PC9 cells, showed high levels of surface expression of these proteins, PC7 cells were more susceptible to cH18A-mediated CDC than PC9 cells. Use of multiple blocking antibodies to the complement-regulatory proteins produced more enhancement of cH18A-mediated CDC than a single antibody. Moreover, expression of CD55 and CD59 by PC7 and PC9 cells was decreased after treatment with PI-PLC, resulting in increased susceptibility to cH18A-mediated CDC. Although the reason is unknown, PC7 cells became more susceptible to CDC than PC9 cells after PI-PLC treatment even in the absence of cH18A. These data suggest that chimeric monoclonal antibodies can be used to induce CDC against lung adenocarcinoma, and that such CDC is potentiated by a variety of antibodies blocking compliment-regulatory proteins on the tumour cell surface.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antigens, CD; CD55 Antigens; CD59 Antigens; Cell Line, Transformed; Humans; Lewis Blood Group Antigens; Lung Neoplasms; Membrane Cofactor Protein; Membrane Glycoproteins; Mice

The natural history and biological behavior of adenocarcinoma and related lesion of the uterine cervix remain controversial issues, but the dynamic alterations in glycosylation in the cancer cells are well known. Recently, it was recently documented that the Ley antigen might be correlated with apoptosis. Over the past eight years, we have encountered 12 cases of invasive adenocarcinoma (AD), 11 cases of early adenocarcinoma (early AD) including 6 adenocarcinoma in situ and 5 microinvasive adenocarcinoma, 16 cases of endocervical glandular dysplasia (EGD) and 10 patients with normal endocervix (control) among 2,165 postoperative cases. Immunohistochemical localizations of Le(y), sialyl Le(x) and epidermal growth factor receptor (EGFR) antigens were examined in serial sections. The localization of Le(y) antigen was predominant in the subcolumnar reserve cells in controls. The localization of sialyl Le(x) was predominant in the perinuclear portion of cells in cases of EGD. The localization of EGFR was presented in cases of tubal metaplasia, tubal type EGD, early AD and AD. These antigens were present in cases of EGD, early AD and AD, with AD cases showing the highest concentrations. To conclude, the presence of the Le(y) antigen might be correlated with differentiation, development and oncogenesis rather than with apoptosis in these lesions, EGD might indicate a precancerous lesion, and localization of the EGFR antigen indicates that tubal metaplasia, tubal type EGD, early AD and AD may have a common origin.

Topics: Adenocarcinoma; Adult; Aged; Apoptosis; Autoantigens; ErbB Receptors; Female; Humans; Lewis Blood Group Antigens; Middle Aged; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

We used the monoclonal antibody BR96 to determine the expression of the Lewis Y antigen in benign and malignant prostatic tissues. Strong immuno-staining was detected within the basal cells of benign glands in 29 of 30 specimens examined. In contrast, weak immuno-staining of the secretory (luminal) epithelium was detected in only 10 of these same 30 specimens. Moderate to strong immuno-staining of luminal cells, however, was observed in prostatic intraepithelial neoplasia in 15 of 17 specimens. Immuno-staining was detected within the malignant cells in all 49 specimens of primary prostatic adenocarcinoma examined. We used a semiquantitative technique to compare the extent of immuno-staining among well (combined Gleason score less than 6), moderately (combined Gleason score 6 to 7) and poorly (combined Gleason score more than 7) differentiated tumors as well as metastatic lesions. Poorly differentiated tumors demonstrated the greatest extent of immuno-staining compared to moderately and well differentiated adenocarcinoma. Strong immuno-staining was also detected within the malignant cells in 7 metastatic (5 nodal lesions and 2 bone marrow biopsies) tumors. The extent of immuno-staining in the metastatic lesions was similar to that observed in the poorly differentiated primary tumors. In summary, the Lewis Y antigen, as detected by BR96, is widely expressed within prostatic adenocarcinomas. Furthermore, the poorly differentiated as well as metastatic lesions frequently demonstrated the highest expression of the Lewis Y antigen.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Neoplasm; Humans; Immunoenzyme Techniques; Lewis Blood Group Antigens; Male; Prostate; Prostatic Neoplasms