lewis-y-antigen and Liver-Neoplasms

Lewis Y (Le(y)) is a blood group antigen with robust expression on the surface of epithelial tumors, including small cell lung cancer (SCLC), making it a potential target for antibody-based immunotherapy. 3S193, an immunoglobulin G3 monoclonal antibody, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-Le(y) antibodies. A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m2 demonstrated tumor targeting without serious toxicities or the development of human anti-human antibodies.. We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three previous chemotherapy regimens, measurable disease not previously irradiated, and tumor samples positive for 3S193 by immunohistochemistry. Patients received four weekly injections of hu3S193, five patients at 10 mg/m2 and five patients at 20 mg/m2. The first and fourth injections were radiolabeled with indium-111 for gamma camera imaging.. Of 40 patients screened, 25 of 34 (74%) assessable SCLC tumor samples were 3S193 positive by immunohistochemistry. Ten patients were treated with hu3S193; nine completed all four injections. All fluorodeoxyglucose (FDG)-avid lesions >2 cm were visualized on antibody single-photon emission computed tomography. Some lesions overlying vascular structures could not be visualized. No difference was noted in imaging or pharmacokinetics between the first and fourth injections. Toxicities included grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion at the higher dose.. Given the strong tumor targeting, particularly at the higher dose, the favorable toxicity profile, and the potential for immunomodulatory effects, hu3S193 warrants further investigation in SCLC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Brain Neoplasms; Carcinoma, Small Cell; Female; Humans; Indium Radioisotopes; Lewis Blood Group Antigens; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Radioimmunotherapy; Time Factors; Tissue Distribution; Treatment Outcome

The expressions of Lewis (Le) antigens, alpha-1,3/1,4 fucosyltransferases (alpha-1,3/1,4 FuTs), and metastatic potential after the treatment of 2 differentiation inducers, all- trans retinoic acid (ATRA), 8-bromo-cyclic 3',5'adenosine monophosphate (8-Br-cAMP); and 2 proliferation inducers, epidermal growth factor (EGF) and phobol-12-myristate-13-acetate (PMA), on 7721 human hepatocarcinoma cell line were studied. Cell adhesion to human umbilical vein endothelial cells (HUVEC), cell migration through transwell and invasion through matrigel were selected as the indexes of metastatic potential-related phenotypes. Using fluorescence-labelled antibodies and flow-cytometric analysis, it was found that 7721 cells mainly expressed sialyl Lewis X (SLe(x)) and a less amount of sialyl dimeric Lewis X (SDLe(x)) antigens on the cell surface. Their expressions were down-regulated by ATRA, and up-regulated by EGF. SLe(x)antigen was also decreased and increased by the treatment of 8-Br-cAMP and PMA respectively. With Northern blot to detect the mRNAs of alpha-1,3/1,4 FuTs, the main enzymatic basis for the change in SLe(x)expression was found to be the alteration of the expression of alpha-1,3 FuT-VII. It was evidenced by the observations that alpha-1,3 FuT-VII was the main alpha-1,3/1,4 FuT in 7721 cells, while alpha-1,3/1,4 FuT-III and alpha-1,3 FuT-VI were expressed rather low. The changes in the expressions of SLe(x)antigen and alpha-1,3 FuT-VII resulted in the altered cell adhesion to tumour necrosis factor-alpha stimulated HUVEC, since only the monoclonal antibody of the SLe(x), but not other monoclonal antibodies blocked the adhesion of 7721 cells to HUVEC. The migration and invasion of 7721 cells were also reduced by the treatment of ATRA or 8-Br-cAMP, and elevated by EGF or PMA. The above findings indicate that the metastatic potential of 7721 cells is suppressed by differentiation-inducers and promoted by proliferation-inducers.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Adhesion; Cell Differentiation; Cell Division; Cell Movement; Epidermal Growth Factor; Fucosyltransferases; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Liver Neoplasms; Neoplasm Metastasis; Phenotype; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

The purpose of this study was to assess the immunocytochemical status of bone marrow aspirates from patients with clinically isolated hepatic metastases to test the hypothesis that such findings would allow improved patient selection for liver-directed treatment.. All patients had biopsy-proven or presumed colorectal cancer metastatic to the liver and were scheduled for an operative procedure for hepatic resection or for hepatic artery catheter and chemotherapy pump implant. Immunocytochemical analysis of bone marrow aspirate smears was performed with a panel of monoclonal antibodies directed toward cytokeratins, Lewis Y antigen and A-33 colorectal epitopes.. Data from 80 patients indicated that bone marrow reactivity was present in 9.5 percent of those with resectable hepatic metastases and in 34 percent of those not resected (P = 0.03). No single monoclonal antibody or combination produced better discrimination.. Presence or absence of presumed occult colorectal cancer cells in the bone marrow of patients with isolated hepatic metastases is biologically interesting, but not useful in selecting or altering patient management.

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Bone Marrow; Bone Marrow Examination; Bone Marrow Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Humans; Immunoenzyme Techniques; Keratins; Lewis Blood Group Antigens; Liver; Liver Neoplasms; Prognosis

In situ expression of apoptosis and its related antigens has rarely been evaluated in human liver tumors. Therefore, investigation using in situ nick end-labeling and immunohistochemical methods of the in situ expression of apoptosis, proliferating cells, and apoptosis-related antigens in 7 normal livers, 20 cholangiocarcinomas (CC) and 17 hepatocellular carcinomas (HCC) was done. Apoptotic cells as determined by the nick end-labeling method and proliferating cell nuclear antigen-positive cells were present in all specimens, and the percentage of them was significantly higher in CC than in HCC. Bcl-2 protein was present only in one CC and one HCC, but was occasionally noted in bile ducts in non-cancerous livers. C-myc and Fas antigens were not found in any of the cases. Lewisy antigen was expressed in 8 CC, but was absent in the other cases although bile ducts in non-cancerous livers frequently expressed Lewisy. p53 protein was present in 8 CC, but was absent in the other cases. Serial section observations showed that apoptotic cancer cells were consistently negative for proliferating cell nuclear antigen; bcl-2-positive cells did not show apoptosis; p53-positive cancer cells showed apoptosis. Some Lewisy-positive cancer cells showed apoptosis, while others did not. These data suggest that apoptosis and cell proliferation are involved in CC and HCC, and their degree is more severe in CC than in HCC. p53 protein (stimulative) may regulate apoptosis in some cases, whereas c-myc, Fas and Lewisy are not related to apoptosis in CC and HCC in vivo. Many other factors may regulate apoptosis in CC and HCC in vivo.

Topics: Apoptosis; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; DNA Nucleotidylexotransferase; fas Receptor; Humans; Immunohistochemistry; In Situ Hybridization; Lewis Blood Group Antigens; Liver; Liver Neoplasms; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Tumor Suppressor Protein p53

The altered expression of the Lewis blood group-related antigens during malignant transformation can be used clinically as a tumor marker or as a prognostic indicator. The Lewis Y (LeY) antigen, which is one of the Type 2 human blood group-related antigens, also is thought to behave as an oncodevelopmental cancer-associated antigen. In this study, the authors examined the association between human LeY antigen expression and the clinicopathologic features of HCC, including its proliferative activity.. Forty-six histologically confirmed cases of HCC were studied retrospectively. Liver biopsy specimens from the main tumor of each case were obtained under ultrasonic guidance before treatment was initiated. The formalin fixed, paraffin embedded serial sections were immunostained using a modification of the avidin-biotin-peroxidase complex method, with a primary monoclonal antibody (MoAb) directed against the LeY antigen (BM-1/JIMRO). The relationship between LeY antigen expression and the HCC's proliferative activity was analyzed similarly by immunohistochemical methods using a primary MoAb directed against the Ki-67 antigen (MIB 1). In addition, to clarify the relationship between LeY antigen expression and the histologic heterogeneity within HCC, seven cases of surgically resected HCC also were immunostained.. The LeY antigen was detected on the membrane and in the cytoplasm of the cancer cells. Of the 46 HCC cases, 20 (43.5%) expressed the LeY antigen in the tumor cells. There was no correlation between LeY antigen expression and the maximum tumor dimension or the Stage. However, the incidence of LeY antigen-positive cases in poorly differentiated HCCs was found to be significantly higher than that in well or moderately differentiated HCCs (P < 0.01). In resected HCC cases, LeY antigen expression within HCC nodules was frequently greater in the less differentiated tumor than in adjacent differentiated tumor. Moreover, the incidence of LeY antigen expression in alpha-fetoprotein (AFP)-positive (AFP > or = 200 ng/ml) HCC cases was significantly higher than that in AFP-negative (AFP < 200 ng/ml) HCC cases (P < 0.05). Furthermore, the mean value of the Ki-67 labeling index in LeY antigen-positive HCC cases (25.2 +/- 11.3%) was significantly higher than that in LeY antigen-negative HCC cases (9.4 +/- 4.1%) (P < 0.001).. These results suggest that LeY antigen expression correlated closely to the dedifferentiation and proliferative activity of HCC.

Topics: alpha-Fetoproteins; Antibodies, Monoclonal; Carcinoma, Hepatocellular; Female; Humans; Immunohistochemistry; Lewis Blood Group Antigens; Liver; Liver Neoplasms; Male; Middle Aged; Retrospective Studies