PubMed Health⌕ Search

Biomedical subjects

M A Tempero

Publications and source records attributed to M A Tempero.

At least 37 records · Page 2Linked to original sources
PubMed1994

The effect of garlic extract on human metabolism of acetaminophen.

Several studies suggest that the constituents of garlic may inhibit experimentally induced carcinogenesis. To evaluate the chemopreventive properties of garlic in humans, the effects of chronic administration of an aged garlic extract on the disposition of acetaminophen and metabolites were studied. This commonly used drug was chosen because it forms a reactive electrophilic metabolite after oxidative metabolism. Sixteen subjects ingested daily doses of garlic extract (approximately equivalent to six to seven cloves of garlic) for 3 months. Before the course of garlic, at the end of each month and 1 month after termination of garlic administration, a 1-g oral dose of acetaminophen was given to each subject. Plasma and urine were measured for acetaminophen and the glucuronide, sulfate, cysteinyl, mercapturate, and methylthio metabolites. It was found that garlic treatment had no discernible effect on oxidative metabolism but was associated with a slight increase in sulfate conjugation of drug. These findings suggest that garlic extract has limited potential as a chemopreventive agent.

Acetaminophen↗
PubMed1992

Characterization of bilirubin transport system by human peripheral blood mononuclear cells.

Decreased immune responses have been observed in hyperbilirubinemic patients. This study investigates bilirubin transport into human peripheral blood mononuclear cells (PBMNCs). In vitro incubation of PBMNCs at 37 degrees C with 0-12 mg/dl bilirubin in solution with a fixed bovine serum albumin (BSA) concentration (3.0 g/dl) resulted in a dose-dependent increase of intracellular bilirubin in both monocytes and lymphocytes. Bilirubin uptake in monocytes was significantly higher (up to 2.7 times) than in lymphocytes under the same culture conditions. When PBMNCs were incubated with varying concentrations of bilirubin (0-16 mg/dl) in fixed BSA (3.0 g/dl) solution or at a fixed bilirubin/albumin molar ratio (0.4), the initial velocity of uptake in both cell fractions was proportional to the free (unbound to albumin) bilirubin concentration rather than the total bilirubin concentration. Bilirubin uptake by both cell fractions was significantly inhibited by treatment with metabolic inhibitors. Bilirubin uptake by monocytes continued to increase in parallel with incubation temperature from 0 degrees C to 40 degrees C, whereas uptake by lymphocytes reached a maximal level at 20 degrees C and remained constant thereafter. These results suggest that monocytes and lymphocytes incorporate bilirubin in proportion to the free bilirubin concentration and this function may rely on different energy-dependent mechanisms.

Adult↗
PubMed1992

Flow cytometric measurement of intracellular bilirubin in human peripheral blood mononuclear cells exposed to unconjugated bilirubin.

Human peripheral blood mononuclear cells were incubated at 37 degrees C with bilirubin in bovine albumin solution. Histological analysis of bilirubin-treated cells demonstrated a prominent brown pigment deposited in the cytoplasm. Homogenates of these cells in chloroform-methanol solution showed an identical absorption spectrum with pure bilirubin dissolved in the same solution. When bilirubin-treated cells were excited at 488 nm, a significant autofluorescence was detected by flow cytometry at 585 nm in a dose-dependent manner, which had a significant correlation with the amount of bilirubin chemically extracted from the cells (r = 0.963, n = 34, p less than 0.001). Intraassay and interassay variability of the autofluorescence by flow cytometric analysis was small (both less than 5%). When bilirubin-treated cells were stained with fluorescein-labeled anti-CD14 antibody, the CD14 positive cell population can be fractionated without interference of autofluorescence derived from intracellular bilirubin. These results suggest that flow cytometric analysis of bilirubin-treated cells can quantitate intracellular bilirubin, and that bilirubin does not interfere with analysis of surface antigens.

Adult↗
PubMed1992

Purification and analysis of glycoproteins bearing blood group-A determinants from hamster pancreatic ductal adenocarcinomas.

Although the hamster pancreas does not express A, B or H blood group antigens, all hamster pancreatic ductal adenocarcinomas induced by treatment with N-nitrosobis(2-oxopropyl)amine express blood group-A antigen. Thus, the acquisition of blood group-A antigen expression in this system is a cancer-associated alteration. We have purified three major blood group-A antigen bearing glycoproteins (gp120, gp135 and gp150) from hamster pancreatic cancer cell membrane preparations using affinity chromatography on DBA (Dolichos biflorus) agglutinin-agarose. When assayed by immunoblotting, gp120 and gp135 showed strong blood group-A reactivity, which was removed by treating membrane samples with peptide-N-glycosidase F. Blood group-A reactivity was unchanged by treatment of the membrane fractions with endoglycosidases F and H. In addition, these two glycoproteins bearing blood group-A antigen also bound L-PHA (Phaseolus vulgaris leucoagglutinin). These results demonstrate that gp120 and gp135 express blood group-A antigen on Asn-linked multi-antennary complex type glycan structures. The gp150 showed weak blood group-A expression. This is the first demonstration of the neoexpression of cancer-associated blood group-A determinants which reside on Asn-linked glycan structures.

ABO Blood-Group System↗
PubMed1992

Quantitation of metastatic tumor burden from human colon tumor xenografts using radiolabelled monoclonal antibody 17-A fragments.

In realistic models of human tumor xenograft metastasis, the metastatic foci arise in perivascular sites and rarely grow to sizes which are easily quantifiable by visual inspection. As an alternative approach, we have used monoclonal antibody (MAb) 17-1A F(ab')2 fragments labelled with radioiodine (125I) to study the differential accumulation of label in xenografts and metastatic tumor sites as well as in noninvolved tissues of NIH Swiss nude mice receiving HT-29 human colon tumor cells. Images of the whole-body distribution and sites of localization were determined using a pinhole-collimated Angergamma camera. Radioactivity was determined in tissue samples using a well scintillation system, and pharmacokinetics were assessed during the initial 72 h after injection of antibody fragments. The half-life of 125I-F(ab')2 fragments in the blood, 8.6 h, was similar in nontumor-bearing control and tumor-bearing mice. The half-life in subcutaneous tumor xenografts was 30.1 h. The tumor xenograft to tissue activity ratios per unit weight (radiolocalization indices) at 72 h were: blood 90, lung 65, pancreas 50, muscle 35, spleen 20, liver and mesenteric lymph node 10. All subcutaneous xenografts were successfully imaged, and images of 5 of 9 mice (55%) appeared to demonstrate the presence of metastatic tumor by differential and focal accumulation of MAb fragments after 48 or 72 h in the lung (2 cases) or abdominal cavity (3 cases). Necropsy and subsequent histological and biodistribution studies confirmed the presence of metastatic tumor in these sites and identified tumor in several additional sites. The smallest volume of metastatic tissue in liver or lung determined at necropsy which appeared to have been detected by imaging was about 20 mm3. Generally, for mice with metastatic tumors, the radioactivity per unit weight of metastatic tumor-bearing organs compared to tumor-free organs was 2- to 7-fold greater. The results indicate that a radiolocalization index of > or = 2 is generally necessary for metastatic tumor detection by imaging although this is influenced by the extent of anatomical location of the tumor. It was possible to predict the tissue distribution of the fragments from the planar image for the amounts of radioactivity (approximately 1 mCi/kg body weight) employed in this study. These results demonstrate the utility of this approach to quantitate the metastatic burden arising from human colon tumor xenografts in this experimental model.

Animals↗
PubMed1991

Immunotherapy with monoclonal antibody (Mab) in pancreatic adenocarcinoma.

Conventional therapy of pancreatic exocrine cancer is disappointing. The poor prognosis of the disease challenges development of novel therapeutic strategies. We report the results of clinical trials of the monoclonal antibody (Mab) 17-1A in patients with histologically verified unresectable pancreatic exocrine cancer. No antitumor response was seen in 18 patients treated with Mab 17-1A (500 mg) admixed with 10(9) autologous mononuclear cells, and 81% of the patients developed antimouse antibody response. Combination of recombinant gamma interferon and Mab 17-1A mixed with autologous mononuclear white cells resulted in complete response of 4-mo duration in 1 out of 25 evaluable patients and unusually stable disease from 4 to 48+ mo in another 6 patients. High intermittent doses of infused Mab 17-1A did not show any objective antitumor response and caused serious anaphylaxis in two of the patients in the trial. Because examination of six pancreatic adenocarcinoma cell lines with different doses of Mab 17-1A and IL-2 failed to augment lytic activity of mononuclear effector cells against all cancer cell lines tested, there seemed to be no rationale for pursuing clinical studies with IL-2 and Mab 17-1A in either the murine or chimeric form. Attractive therapeutic approaches include active immunotherapy with immunization using idiotypic antibodies or targeted toxicity with the use of radioimmunoconjugates, particularly 125I-labeled chimeric Mab 17-1A.

Adenocarcinoma↗
PubMed1991

Progress in chemoprevention of gastrointestinal cancers.

Carcinogenesis is a complex and multistep process. Numerous inhibitors (either naturally occurring or synthetic) have been identified that can interfere with various phases of carcinogenesis, including the endogenous formation of carcinogens, the activation or detoxification of carcinogens, or events in tumor promotion. Many of these compounds have survived a complex screening program and are currently in or ready for clinical application. In gastrointestinal malignancies, colon neoplasia has been a popular target for chemoprevention. The identification of preneoplastic events in colon mucosa or in the progression of malignancy from adenomas to adenocarcinomas has permitted the study of numerous compounds such as calcium salts, difluoromethylornithine, and prostaglandin synthesis inhibitors on intermediate biomarkers or on the development of recurrent adenomas or cancers. A variety of other compounds with general efficacy in other tumor models have also been shown to be effective inhibitors of tumorigenesis in preclinical models of esophageal, gastric, pancreatic, and hepatic carcinogenesis. This review provides an overview of carcinogenesis and principles of chemoprevention and highlights certain developments in the past year that exemplify the experience and progress in this area.

Gastrointestinal Neoplasms↗
PubMed1990

Phase II trial of interferon gamma and monoclonal antibody 17-1A in pancreatic cancer: biologic and clinical effects.

Thirty patients with advanced measurable pancreatic adenocarcinoma were entered onto a phase II trial with recombinant interferon gamma (Biogen, Cambridge, MA; 10(6) U/m2 daily for 4 days) and monoclonal antibody (Mab) 17-1A (Centocor, Malvern, PA; 150 mg in autologous leukocytes on days 2, 3, and 4 following interferon infusion). The effect of a single interferon gamma treatment on natural and antibody-dependent cellular cytotoxicity (ADCC), Fc receptor occupancy by antibody, and human leukocyte antigen-DR (HLA-DR) expression on monocytes and lymphocytes was also studied. Toxicity was modest and generally limited to grade I to II fever, nausea and vomiting, and hepatotoxicity. Five patients were considered to be nonassessable for response. Of the 25 assessable patients, one objective response (complete remission for a duration of 4 months) was observed. Stable disease for 2 months or greater was noted in nine patients. The median survival for the group was 5 months. Analysis of cytotoxicity data obtained prior to treatment showed reduced natural cytotoxic activity in these patients compared with normal volunteers. A significant improvement in natural cytotoxic activity to normal levels occurred within 24 hours following the interferon gamma infusion. This was also associated with augmented antibody-dependent cellular cytotoxicity. Although HLA-DR expression was not increased on either monocytes or lymphocytes, an increased capacity of both lymphocytes and monocytes to bind Mab 17-1A was observed. In all in vitro assays of ADCC, the presence of antibody excess was associated with improved cytolytic activity. In spite of the favorable modulation of cytolytic activity and improved ability of effector cells to bind Mab, we failed to demonstrated adequate clinical efficacy in the treatment of patients with pancreatic adenocarcinoma using this dose and schedule of interferon gamma and Mab 17-1A. Future trials will focus on alternate schedules of Mab 17-1A with the hope of improving tumor antigen saturation and circulating levels of infused antibody.

Adenocarcinoma↗
PubMed1989

Chemoprevention of mouse colon tumors with difluoromethylornithine during and after carcinogen treatment.

alpha-Difluoromethylornithine (DFMO) treatment has been shown to modify carcinogenesis in many experimental tumor models, including skin, breast, and colon. This study was designed to determine whether DFMO treatment can inhibit experimental mouse colon tumors after carcinogen treatment and whether an associated effect of DFMO on cell proliferation in colon mucosa occurs. Male CD1 mice (40 per group) received dimethylhydrazine (30 mg/kg/week x 6 weeks, s.c.) and various schedules of DFMO, 1% in drinking water: Group A, none; Group B, following dimethylhydrazine treatment; Group C, during dimethylhydrazine treatment; and Group D, continuously throughout the study. Measurements of RBC polyamine levels showed that DFMO treatment ablated putrescine levels and confirmed that a systemic biological effect was achieved. Analysis of tumor data showed a significant inhibitory effect of DFMO treatment on colon tumor (adenomas and adenocarcinomas) incidence in Groups B (24%) and D (20%) compared to control Group A (52%, P less than 0.05 A versus B, P less than 0.02 A versus D) and on squamous cell carcinomas of the anus in all groups (P less than 0.001 A versus B, P less than 0.05 A versus C, A versus D). No consistent effect of DFMO treatment on cell proliferation in colon mucosa was identified. This study supports the hypothesis that DFMO treatment alters events in the postinitiation phases of mouse colon tumorigenesis.

Animals↗
PubMed1989

Reactivity of CO17-1A and B72.3 in benign and malignant pancreatic diseases.

The immunoreactivity of two monoclonal antibodies, CO17-1A (recognizing 17-1A antigen) and B72.3 (recognizing TAG-72), was examined in pancreatic tissues from individuals without pancreatic disease and from those with benign and malignant pancreatic disease. 17-1A antigen was found in all cells in the normal tissue, whereas TAG-72 was present in the duct cells in only one case. Both antigens were present in benign diseases; however, in some cells and in some conditions, TAG-72 was significantly less common (P less than .01 to .001) than 17-1A antigen. In pancreatic cancer, 17-1A antigen was present in 87% of cases and TAG-72 antigen was present in 92% of cases. The results indicate that B72.3 is more specific to pancreatic cancer than C017-1A.

Acute Disease↗
PubMed1988

Comparative studies on the expression of tumor-associated glycoprotein (TAG-72), CA 19-9 and DU-PAN-2 in normal, benign and malignant pancreatic tissue.

Expression of tumor-associated glycoprotein (TAG-72) was examined by immunohistochemistry in pancreatic specimens from normal donors, and from patients with chronic pancreatitis and pancreatic cancer, and was compared with expression of CA 19-9 and DU-PAN-2. In the normal pancreas, TAG-72 was expressed in fewer ductal and ductular cells than were CA 19-9 (p less than 0.05) and DU-PAN-2 (p less than 0.01 and 0.001 respectively), whereas in chronic pancreatitis all 3 antigens were expressed in ductal cells but only CA 19-9 and DU-PAN-2 in ductular cells (p less than 0.001). In the specimens from normal pancreas and chronic pancreatitis cases, TAG-72 was localized in the Golgi region, whereas CA 19-9 and DU-PAN-2 showed diffuse cytoplasmic and glycocalyx patterns. In pancreatic cancer, although the rate of expression of all 3 antigens was similar, their cellular localization differed significantly: only TAG-72 was expressed in the Golgi region (p less than 0.001), whereas CA 19-9 showed mainly glycocalyx (p less than 0.05) and/or intra-luminal patterns (p less than 0.01) compared with that of the other 2 antigens. We conclude that, due to differences in expression of TAG-72 in benign versus malignant cells, the monoclonal antibody against TAG-72 (B72.3) may be suitable for radio-immunodetection or radio-immunotherapy of pancreatic cancer.

Adenocarcinoma↗
PubMed1988

Correlative study on expression of CA 19-9 and DU-PAN-2 in tumor tissue and in serum of pancreatic cancer patients.

The serum levels of CA 19-9 and DU-PAN-2 antigens and their expression in tumor tissue were examined in 22 pancreatic cancer patients and the results were correlated with the Lewis (Le) blood group phenotypes of the individuals. In tumor tissue, CA 19-9 was expressed in 17 of 22 (77%) specimens. The negative cases included three patients with Lea-b-, one with Lea+b- and the other with Lea-b+ phenotypes. DU-PAN-2 antigen was expressed in 20 of 22 (91%) cancer tissues. The two DU-PAN-2-negative cases were CA 19-9-positive. The combination of two markers increased the sensitivity to 100%. In the serum, CA 19-9 level was elevated (greater than 37 U/ml) in 16 of 21 (73%) cases. All Lea-b- patients had values less than 37 U/ml. An elevated level of DU-PAN-2 (greater than 300 U/ml) was detected in 14 of 21 (67%) patients including three cases with Lea-b- type. In only one patient were both antigens below the cutoff levels so that the combination of two biomarkers elevated the sensitivity to 95%. The study indicated that the cocktail of 19-9 and DU-PAN-2 antibodies might increase the sensitivity and specificity for clinical diagnosis of pancreatic cancer. In 19 of 21 (90%) cases, the serum CA 19-9 level correlated with the expression of the antigen in the cancer tissue. Discrepancy was seen in two cases; one patient had an elevated level of CA 19-9 in the serum, but lacked this antigen in the cancer cells. In the second case, the situation was reversed. For DU-PAN-2, positive correlation was seen in 14 of 21 (67%) cases. Six of seven patients with low DU-PAN-2 levels expressed the antigen in their tumor cells, and one patient with DU-PAN-2-negative cancer tissue had an elevated level of this marker in the serum. Thus, CA 19-9 expression in serum corresponded more closely to expression in tissue than did that of DU-PAN-2 antigen. The serum levels of these antigens, however, is likely due to multiple factors, only one of which is the qualitative and quantitative expression of the antigens in tumors.

Adult↗
PubMed1988

Immunohistochemistry with monoclonal antibody B72.3 as an adjunct in the cytologic diagnosis of pancreatic carcinoma.

Due to the morbidity of open tissue biopsy, the cytologic diagnosis of pancreatic carcinoma by fine needle aspiration or examination of biliary tree fluid is highly desirable. Immunohistochemistry with monoclonal antibody B72.3 has been advocated as an adjunct in the identification of tumor cells in body fluids. To assess its usefulness as an adjunct in the diagnosis of pancreatic carcinoma, we examined cytologic specimens of the pancreas from 35 patients [24 pancreatic carcinoma, 6 metastases (4 adenocarcinoma and 1 each of Hodgkin's disease and melanoma), 5 with benign conditions] with an immunohistochemical procedure using B72.3 directly over the Papanicolaou-stained slides. Of the pancreatic carcinomas, 21 of 24 (87%) were cytologically positive and 21 of 24 (87%) marked with B72.3. With both techniques, 23 of 24 cases (96%) could be identified. Three of four metastatic adenocarcinomas were positive by both cytology and B72.3. No staining occurred in the metastatic melanoma, Hodgkin's disease, or 3 of 5 benign conditions. In two benign duodenal aspirates, an unusual reticular B72.3 staining occurred in the mucin of acinar and goblet cells which could be misinterpreted as positive staining. In our experience, B72.3 enhances the sensitivity of the cytologic diagnosis of pancreatic cancer. Unrecognized single tumor cells, cytologically uninterpretable cells, and tumor cell clusters that could be misinterpreted as reactive epithelium mark with B72.3. Care should be taken to avoid misinterpretation of nonspecific mucin staining with this antibody.

Adenocarcinoma↗
PubMed1988

Relationship of dietary cholesterol and cellulose in the prevention of colon cancer.

To study the effect of dietary cholesterol and cellulose on fecal sterol output and colon tumors in dimethylhydrazine-treated animals, rats were fed a basal diet supplemented with cholesterol (0.07% w/w) and/or cellulose (20% w/w). The addition of cholesterol alone to the basal diet failed to modify bile acid excretion or colon carcinogenesis. The addition of cellulose alone also failed to modify colon carcinogenesis, although it significantly decreased fecal bile acid concentration and increased daily bile acid excretion. However, when dietary cellulose was added to a cholesterol-containing diet, there was a significant decrease in colon tumor incidence (47% vs. 80%, P less than .05), accompanied by a significant increase in excretion of unmetabolized cholesterol. These data suggest that 1) the protective effect of certain fibers in colon carcinogenesis may be dependent on other dietary variables and 2) certain fecal neutral sterol profiles may be associated with colon tumor inhibition.

Animals↗
PubMed1987

Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer.

Carbohydrate antigen (CA) 19-9 identified by a murine monoclonal antibody against a colorectal carcinoma antigen is thought to be a sialylated Lewis (Le)a blood group antigen and occurs in high concentration in serum of patients with pancreatic carcinoma. This study was designed to identify the relationship between Lewis antigens and CA 19-9 in patients with pancreatic cancer. The following analyses were performed in 20 pancreatic cancer patients: Lea and Leb antigen phenotype in saliva (modified enzyme-linked immunosorbent assay) or on red cells (hemagglutination); CA 19-9 levels (radioimmunoassay) in serum; and CA 19-9 and Lea and Leb expression (immunoperoxidase assay) on tumor tissue. Lea-b- patients based on salivary phenotype failed to express CA 19-9 in tumor tissue and had normal or low levels of CA 19-9 (less than 37 units/ml) in serum (P = 0.0011, versus Lea+b- and Lea-b+ patients). Eighty-eight % of Lea+b- and Lea-b+ patients had elevated serum CA 19-9 levels (greater than 37 units/ml). All Lea+b- and Lea-b+ patients expressed both Lea and Leb antigens in tumor tissue. These results support the view that Lea-b- pancreatic cancer patients cannot manufacture CA 19-9. Surprisingly, Lea-positive patients express Leb antigen in tumor tissue; in this subgroup, Leb antigen may be a tumor-specific biomarker.

Adenocarcinoma↗
PubMed1987

Effects of sodium cholate on experimental carcinogenesis and cell proliferation in an excluded colonic segment.

Bile salts appear to be important promoters of colon carcinogenesis. This study was designed to assess the importance of the fecal stream in cholic acid-induced colon tumor promotion. Male Sprague-Dawley rats underwent transverse colostomy after induction with dimethylhydrazine (DMH) and the excluded distal colon was irrigated with saline or sodium cholate (23 microM) 5 times per week until sacrifice. Controls initially injected with saline were similarly treated. All surviving animals were sacrificed at 28 weeks after the last DMH injection. Five animals from each group were randomly chosen to assess tritiated thymidine labeling and distribution by autoradiography in normal appearing colon mucosa of irrigated bowel. Cholate irrigation failed to increase tumor yield or modify the proportion of adenomas and adenocarcinomas in this model. Paradoxically, fewer tumors per affected rat were noted with sodium cholate irrigation. Cholate irrigation also failed to affect crypt cellularity, thymidine labeling indices, and labeling distribution in DMH-treated rats and controls. An effect of DMH was seen, however, with an increase in thymidine labeling index and increased labeling in the top half of the crypt in all DMH-treated groups. This study suggests that tumor promotion with primary bile salts is not a direct affect and may result from further bile salt metabolism within the fecal stream. DMH-induced changes in cell proliferation were reproduced with this model. Use of an excluded colon segment to assess the effect of suspected tumor promoters on carcinogenesis or colon mucosal cell proliferation is feasible and may be a useful model for future studies.

Animals↗
PubMed1987

Correlative studies on antigenicity of pancreatic cancer and blood group types.

Blood group-related antigenicity in 14 pancreatic cancer patients was examined by immunohistological method using monoclonal antibodies (MoAbs) against A, B, H, Lea, Leb, and CA 19-9 and compared with the phenotypic expression of the individuals' blood groups. MoAb-A reacted strongly with tumor tissue in four of five blood group A patients. Two of two patients with blood type B showed a weak, focal reactivity of their cancer with MoAb-B. H antigen was found in four of five patients from blood group A, while it was present in only one blood group O person and absent in B-type individuals. B antigen was inappropriately expressed in one person with type A blood and in two with type O. Lea antigen was expressed in all but two tumor tissues and Leb antigen in all tumorous tissues, irrespective of Le blood group status. MoAb 19-9 reacted with 11 of 14 cases.

ABO Blood-Group System↗