Carcinoembryonic antigen expression of resurgent human colon carcinoma after treatment with therapeutic doses of 90Y-alpha-carcinoembryonic antigen monoclonal antibody

We have previously shown that the colon carcinoma (LS174T) xenografts that emerged shortly after radioimmunotherapy with 90Y-labeled anti-CEA monoclonal antibody (MAb) ZCE025 lacked significant expression of CEA in comparison with the untreated tumors. The present study was designed to establish if the immunophenotype of the treated tumors was the result of CEA specific therapy and if the effect was permanent. Athymic mice bearing LS174T tumors were treated either with 120 mu Ci of 90Y-ZCE025, an equal dose of 90Y-96.5 (nonspecific MAb), or received no treatment. When the treated tumors grew to approximately 1.5 cm in diameter (6 weeks after therapy), they were resected and aliquoted to be transplanted to other mice, plated in tissue culture, fixed in formalin, and homogenized for CEA quantitation. The procedure was repeated 3 times (a total of 4 months after treatment). The CEA content was evaluated 2 and 6 weeks after therapy and when the tumors were transplanted. We confirmed a 4-fold decrease of CEA in the resurgent tumors 6 weeks after specific 90Y-ZCE025 therapy, which was twice the decrease experienced by the tumors treated with nonspecific 90Y-96.5, indicating substantial and specific killing of CEA-expressing cells. The CEA content slowly but progressively increased with each new pass of the tumor in the mice, reaching approximately one-half the value of the controls at the end of the study. The resurgent tumors were also studied by immunohistochemistry with MAbs detecting different epitopes of CEA, keratin, TAG-72, and epithelial membrane antigen to evaluate possible additional immunophenotypic changes induced by radioimmunotherapy. Only the expression of TAG-72 (recognized by MAb B72.3) increased immediately after therapy, but it returned to the original levels by the end of the study. These results suggest that: (a) specific radioimmunotherapy with 90Y-ZCE025 selectively kills cells that express higher levels of CEA; (b) the immunophenotype of the surviving fraction of the tumor appears to slowly revert to its original form; and (c) other tumor markers unrelated to CEA can also be affected. These observations have important implications for the design of radioimmunotherapy trials.     

32nd Annual Meeting of the Scandinavian Society for Psychopharmacology Copenhagen,Denmark April 10–12, 1991 Abstracts

32nd Annual Meeting of the Scandinavian Society for Psychopharmacology Copenhagen, Denmark April 10–12, 1991 Abstracts     

Cerebrovascular and metabolic perturbations in delayed heavy charged particle radiation injury

Focal heavy charged particle irradiation of the rabbit brain created defined lesions which were observable by nuclear magnetic resonance (NMR) and positron emission tomography (PET) imaging techniques. The lesions appeared approximately 9-11 months after left partial hemibrain irradiation with 30 Gy (230 MeV/u helium ions), and were restricted to the white matter tracts and deep perithalamic and thalamic regions. 82Rubidium PET and Gadolinium DTPA enhanced NMR imaging were used to detect blood-brain barrier perturbations. 18Fluordeoxyglucose PET studies demonstrated widespread decreases in cerebral glucose uptake in the cortex and thalamus of the irradiated hemisphere. NMR and PET imaging results correlated well with histological findings. Rabbits irradiated with 15 Gy did not demonstrate any abnormalities in the brain with sequential NMR scans through 14 months post-irradiation.     

Enhanced take of spontaneous murine tumors in mice treated with inhibitors of macrophage and/or NK cell function

Both macrophages and NK cells have been suggested to play a role in recognizing and eliminating early, in situ neoplasms. Therefore we studied the effect of inhibitors of macrophage and/or NK cell function on the take of transplantable spontaneous murine tumors in syngeneic mice. The treatment of animals with trypan blue, a selective inhibitor of macrophage function, decreased considerably the period of latency of BSP3 adenocarcinoma; however, it did not increase the take of SP4, SP82 and SP84 adenocarcinomas. The treatment of recipients with neutral red, a selective inhibitor of NK cell function, enhanced the take of SP4 adenocarcinoma. The treatment of mice with agents depressing both macrophage and NK cell function (silica or carrageenan) decreased the both macrophage and NK cell function (silica or carrageenan) decreased the period of latency and/or increased the take of SP4, SP82 and SP84 adenocarcinomas. Carrageenan or a combined treatment with both trypan blue and neutral red also enhanced the take of BaF1, a benzo(a)pyrene-induced fibrosarcoma. We concluded that both macrophages and NK cells may function as effector cells of an antitumoral surveillance system.     

PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells

PADGEM protein (PADGEM), also known as GMP140, is a platelet alpha- granule membrane protein that is translocated to the external membrane after platelet activation. Although the biosynthesis of this protein was originally thought to be confined to megakaryocytes, the synthesis of PADGEM in endothelial cells was recently demonstrated (McEver et al: Blood 70:1974a, 1987). We now describe the subcellular localization of this protein in endothelial cells. Immunofluorescence staining of permeabilized human umbilical vein endothelial cells with KC4, a well characterized monoclonal antibody to PADGEM, showed positively stained elongated structures similar in distribution and shape to Weibel-Palade bodies. Their identity as Weibel-Palade bodies was confirmed by double label immunofluorescence using KC4 and a polyclonal antiserum to von Willebrand factor (vWf), a protein known to be specifically stored in these organelles. All Weibel-Palade bodies were found to contain PADGEM. In contrast to strong perinuclear staining produced with anti- vWf antibodies, no significant perinuclear staining was obtained with KC4, indicating that relatively little PADGEM is present in the endoplasmic reticulum and in the Golgi apparatus. In endothelial cells treated with secretagogues that stimulate vWf release the elongated structures positive for PADGEM disappeared, further identifying these structures as Weibel-Palade bodies. This observation extends the parallels between Weibel-Palade bodies and alpha-granules and suggests a possible functional association between vWf and PADGEM.     

Effects of isometric exercise on blood cell adrenoceptors in essential hypertension

The effect of handgrip (HG) isometric exercise on plasma catecholamines, alpha 2-adrenoceptors on platelets and beta 2-adrenoceptors on lymphocytes was studied in normotensive subjects (NT) and essential hypertensive subjects (HT). Whereas systolic blood pressure (SBP) increases were similar in NT and HT subjects, diastolic blood pressure (DBP) and heart rate (HR) increased more in the former group. Baseline values and changes in plasma epinephrine (E) and norepinephrine (NE) did not differ between both groups. No differences were apparent in alpha 2-adrenoceptor density and affinity between NT and HT subjects before or after the test. HG isometric exercise induced a similar increase in beta 2-adrenoceptors on lymphocytes of 22 +/- 7 and 13 +/- 5% in NT and HT subjects, respectively. Affinity to the beta 2-adrenoceptors under baseline conditions was somewhat lower in HT (8.1 +/- 0.4 pM) than in NT subjects (6.5 +/- 0.5 pM), and this difference persisted during the test. Our results indicate that there are no differences in alpha 2- and beta 2-adrenoceptor densities either at baseline conditions or after HG isometric exercise between NT and HT subjects. Small differences noted in affinity to the beta 2-adrenoceptors require further investigation.     

A 90-Day Inhalation Toxicity Study with Benomyl in Rats

A 90-Day Inhalation Toxiaty Study with Benomyl in Rats. WARHEIT,D. B., KELLY, D. P., CARAKOSTAS, M. C., AND SINGER, A. W. (1989).Fundam Appl Toxicol./ 12, 333-345. Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate,CAS Registry No. 17804-35-2] is a fungicide and the possibilityfor inhalation exposure exists for field workers. To assessthe toxicity of benomyl, groups of 20 male and 20 female CDrats were exposed nose-only 6 hr a day, 5 days a week, to concentrationsof 0, 10, 50 or 200 mg/m³ of a benomyl atmosphere. At the midpoint(approximately 45 days on test) and at the end of the exposureperiod, blood and urine samples for clinical evaluation werecollected from 10 rats/group/sex, and these animals were sacrificedfor pathological examination. Similar evaluations were performadon all remaining rats at the end of the 90-day test period.After approximately 45 days on test, compoundrelated degenerationof the olfactory epithelium was observed in all males and in8 of 10 female rats exposed to 200 mg/m³ benomyl. Two male ratsexposed to 50 mg/m³ had similar, although less severe, areasof olfactory epithelial degeneration. After approximately 90days of exposure, the remaining 10 rats/group/sex were sacrificedand examined. Of these rats, all of the males and females exposedto 200 mg/m³ had olfactory degeneration, along with 3 malesexposed to 50 mg/m³ of benomyl. No other observed lesions wereinterpreted to have been caused by the benomyl exposure. Inaddition, male rats exposed to 200 mg/m³ benomyl had depressedmean body weights compared to controls and this finding correlatedwith a reduction in food consumption. Based on pathologicalobservations, 10 mg/m³ represents the no-observable-effect level(NOEL) for the male rats, and 50 mg/m³ is the NOEL for the femalerats.