Biomedical subjects
Publications and source records attributed to K Endo.
Generally, non-ventilated segments are not perfused on lung scans (V/Q match). Now we report a very rare case with pulmonary alveolar proteinosis whose scintigraphy shows the decreased ventilation, but well perfused (reverse V/Q mismatch).
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A 31-year-old man was admitted to our hospital because of miction pain and gross hematuria in August, 1988. Cystoscopic examination revealed a solid mass in the bladder. The histological diagnosis was pheochromocytoma of urinary bladder by biopsy. He had a history of syncope on urination several times. Abnormal elevation of serum noradrenaline was observed in hormonal studies and abnormal accumulation was seen in the bladder by 131I-MIBG scintigraphy. Total cystectomy, lymphadenectomy and urinary diversion were performed in November, 1988. Pathological diagnosis was pheochromocytoma of the urinary bladder with metastasis to both iliac lymph nodes.
Radiogallium (Ga) labeling of an immunoglobulin-G-deferoxamine conjugate (DF-IgG) to a high-specific radioactivity was performed to allow the development of a radiometallic immunoradiometric assay (IRMA) system. To increase the specific radioactivity of Ga-DF-IgG, we used dialdehyde starch (DAS) as a multi-site spacer for the binding of DF to IgG. Six DF molecules bound to each IgG molecule after DAS conjugation. DF-DAS-IgG was then labeled with the previously reported 67Ga labeling solution, producing labeled IgG with a specific radioactivity of 11,766 MBq/mg IgG. Using this method, we labeled an anti-CA125 tumor-associated antigen monoclonal antibody (130-22), allowing the first application of 67Ga-DF-DAS-IgG to an IRMA system. With this system, a higher sensitivity could be obtained than with 125I IRMA. In addition, a very high correlation (r = 0.995) was obtained between serum CA125 levels as determined by 67Ga IRMA and 125I IRMA. Gallium-67-labeled antibodies with a high-specific radioactivity appear to hold promise for use in highly sensitive radioassay systems.
Antigen, anti-IgE and concanavalin A (Con A) induced an increase in both the incorporation of the 3H-methyl moiety into phospholipids and histamine release. Maximal incorporation of the 3H-methyl moiety into the lipid fraction of the cells was observed within 15 sec and 1 min after being challenged with antigen (100 micrograms/mL) and anti-IgE (200 micrograms/mL) respectively. However, the methylated phospholipid decreased rapidly. The addition of Con A (10 micrograms/mL) also increased phospholipid methylation, which reached a maximum at 5 min after challenge. Trans-4-guanidinomethylcyclohexanecarboxylic acid p-tert-butylphenyl ester hydrochloride (NCO-650; 27 microM) strongly inhibited the incorporation of the 3H-methyl moiety into phospholipid by antigen, anti-IgE and Con A. The IC50 values of NCO-650 for phospholipid methylation in response to antigen, anti-IgE and Con A were 1.5, 4.7 and 1.1 microM respectively. Although the Ca2(+)-ionophore A23187 did not induce phospholipid methylation, it caused histamine release.
Monoclonal antibodies (MoAbs) are expected to carry radionuclides selectively to target tissues and to offer antigen-specific diagnosis. Indium (In)-111 has many favorable nuclear properties and is efficiently labeled with MoAbs using DTPA as a bifunctional chelating agent. In-111 labeled MoAbs are clinically employed for the diagnosis of malignant melanoma, colorectal cancer and acute myocardial infarction in Japan. Although non-specific deposit of In-111 was seen in liver and bone-marrow, scintigraphy using In-111 labeled MoAbs was encouraging, since it detected about 80% of tumors, tumors missed by conventional diagnostic methods such as CT, and tumors in patients with normal serum CEA values, and acute myocarditis as well as acute myocardial infarction was positive with In-11 labeled Fab fraction of anti-myosin Ab. Acute or subacute toxicity was not observed. Human anti-murine antibody (HAMA) was detected in 53 of 64 (82.8%) patients who were intravenously administered with 20 to 42 mg of anti-melanoma or anti-CEA MoAbs (whole IgG). In contrast, only 5 of 406 (1.2%) patients had detectable levels of HAMA in their serum after receiving 0.5 mg of Fab fraction of MoAb. Recently mouse-human chimeric Ab has been produced by recombinant DNA techniques, which localized well in xenografted tumors and seems to be promising for clinical use. Investigations are under way to increase the tumor to non-tumor ratio by modifying chelating agents for coupling MoAbs with radionuclides.
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A 67 year-old-female had multiple metastases to her lung, liver and paraaortic lymph nodes from a post-operative malignant pheochromocytoma. She was treated with 3.7 GBq (100 mCi) of I-131 metaiodobenzylguanidine (MIBG). Metastatic nodules in lung and liver almost disappeared and the secretion of catecholamines decreased than baseline rates. However, major but temporary untoward response, such as hypertension and hyperglycemia, was seen after the I-131 MIBG administration.
A new line of human serous cystadenocarcinoma of the ovary, designated OVA-5, has been established in athymic nude mice. A strong correlation was noted between tumor volume and plasma CA125 levels in mice bearing OVA-5 tumor. Growth of the OVA-5 tumor in castrated male nude mice was accelerated by s.c. administration of estradiol-17 beta and 5 alpha-dihydrotestosterone but not by progesterone. Estradiol-17 beta and 5 alpha-dihydrotestosterone also accelerated the growth of the OVA-5 tumor heterotransplanted into sialoadenectomized castrated male nude mice. No remarkable change was observed in the histological appearances of the tumors between control groups and hormone-treated groups. Receptor assays revealed that the OVA-5 tumor had both estrogen and androgen receptors. Growth of the OVA-5-tumor is thus responsive to estrogen and androgen.
The presence of cancer-associated antigens CA125, CA19-9, and carcinoembryonic antigen (CEA) in apparently normal respiratory system was demonstrated histochemically and immunochemically. Epithelial cells lining central airways (trachea, bronchi, and bronchioli) and respiratory glands were specifically stained by antibodies recognizing CA125, CA19-9, and CEA. Most, if not all, bronchial mucus obtained from patients without pulmonary diseases during general anesthesia contained remarkably high levels of CA125, CA19-9, and CEA ranging from 190 to 41,000 U/ml (594-4803 U/mg protein), 210 to 95,000 U/ml (294-197,917 U/mg protein), and 6 to 940 ng/ml (14-209 ng/mg protein), respectively, whereas serum antigen levels were normal in all cases examined. These results suggest that CA125, CA19-9, and CEA are synthesized and secreted by normal epithelial cells of central airways and/or respiratory glands and that these substances are not specific indicators of abnormal cellular activity.
Indium-111(111In)-antimyosin scintigraphy was investigated in 27 patients with myocardial infarction. 111In-antimyosin Fab was administered intravenously, and planar and single photon emission computed tomographic images were obtained 48 hours later. Uptake of 111In-antimyosin was present in 9 of 10 patients (90%) studied within 6 days of infarction. During the second week positive scans were seen in 16 of 16 patients (100%) including 13 (81%) who had normal creatine kinase levels. The mechanism of persistent positive antimyosin images in the subacute stage of myocardial infarction remains to be clarified. 111In-antimyosin scintigraphy may be useful as a noninvasive method for the detection of myocardial injury late and early after a suspected acute myocardial infarction.
The pharmacokinetics of indium-111-labeled antimyosin monoclonal antibody Fab were investigated with use of murine experimental viral myocarditis as a model. The biodistribution of indium-111-labeled antimyosin antibody Fab on days 3, 5, 7, 14, 21 and 28 after encephalomyocarditis virus inoculation demonstrated that myocardial uptake increased significantly on days 5, 7 and 14 (maximum on day 7) in infected versus uninfected mice (p less than 0.001). In vivo kinetics in infected mice on day 7 demonstrated that the heart to blood ratio reached a maximum 48 h after the intravenous administration of indium-111-labeled antimyosin Fab, which was considered to be the optimal time for scintigraphy. The scintigraphic images obtained with indium-111-labeled antimyosin Fab demonstrated positive uptake in the cardiac lesion in infected mice. The pathologic study demonstrated that myocardial uptake correlated well with pathologic grades of myocardial necrosis. High performance liquid chromatography revealed the presence of an antigen-antibody complex in the circulation of infected mice after the injection of indium-111-labeled antimyosin Fab. This antigen bound to indium-111-labeled antimyosin Fab in the circulation might be whole myosin and this complex may decrease myocardial uptake and increase liver uptake. It is concluded that indium-111-labeled antimyosin monoclonal antibody Fab accumulates selectively in damaged heart tissue in mice with acute myocarditis and that indium-111-labeled antimyosin Fab scintigraphy may be a useful method for the visualization of acute myocarditis.
Mouse-human chimeric antibody specific for human carcinoembryonic antigen (CEA) was produced by recombinant DNA techniques. The genes of the mouse variable regions of heavy and light chains were cloned from the mouse hybridoma, 2.7.1G.10., which secreted anti human CEA antibody (IgG1, kappa), and were joined with human gamma 1 and kappa constant genes. The affinity of the resultant chimeric antibody to its relevant antigen was the same as that of the parental mouse monoclonal antibody when analysed by Scatchard plot analysis. The chimeric antibody showed a potent antibody dependent cell-mediated cytotoxicity (ADCC) activity with human peripheral blood mononuclear cells against CEA-positive human adenocarcinoma cells. In vivo imaging analysis revealed that the present chimeric antibody was specifically localized on the tumor site. These results indicate that our mouse-human chimeric antibody is a promising reagent for the diagnosis and therapy of CEA-positive human cancers.
By immunizing a mouse with HOUA-1 cells established from an endometrial cancer patient, two murine monoclonal antibodies designated 196-14 and 196-28 were generated, which were reactive with ovarian cancer-associated antigen CA125, originally defined by OC125 antibody. Antigenic determinants of these antibodies, although overlapping each other, were different from that of OC125 and the combined use of 125I-labeled 196-14 and OC125-coated beads markedly increased the sensitivity of measuring CA125 antigen. Both radioiodinated and 111In-labeled 196-14 localized well in CA125-producing human ovarian cancer tissues OVA-5 xenografted in nude mice. The biodistribution of radioiodinated 196-14 was quite different from that of 111In-labeled 196-14. Radioiodine was cleared faster from the OVA-5 tumor, making a clear contrast to the prolonged retention of 111In the tumor. Initial tumor uptake of radioiodinated 196-14 was the same as that of 111In-labeled 196-14 but decreased thereafter, due to the dehalogenation of radioiodinated antibody in the tumor. This antibody-tumor model seems to be suitable for examining the usefulness of monoclonal antibody-conjugates in the diagnosis and therapy of CA125-producing endometrial or ovarian cancers.
In order to evaluate the usefulness of cocktails of labeled monoclonal antibodies (MoAbs) recognizing different antigen molecules to localize human cancer xenografts, we have compared the potential of three MoAbs recognizing representative cancer-associated CA 19-9, 17-1A and CEA antigens when administered alone or in combination. Specific binding of radioiodinated F(ab')2 fragments of these three MoAbs was observed to human colorectal cancer cell lines SW1116, LS180 and Co-3. The percentage of in vitro cell binding of a cocktail of any two MoAbs to cancer cells was equal to the average of those obtained with the two MoAbs alone. The three MoAbs were preferentially localized in tumor tissues xenografted in nude mice. When cocktails of any two MoAbs were used, the obtained tumor-to-normal tissue ratios and percent of injected dose per gram of tumor were between the levels obtained for each MoAb when administered alone, in all three tumors transplanted in nude mice. These data suggest that, although cocktails of labeled MoAbs recognizing different antigens may extend the spectrum of tumor specificities, their use does not improve the tumor localization ability of MoAb-conjugates.
A murine monoclonal antibody, 130-22, produced against a human lung adenocarcinoma cell line (PC-9) has been suggested as recognizing an antigenic determinant (CA130) which is different from an epitope recognized by OC125 on CA125 glycoprotein molecules. The immunohistochemical reactivity with the 130-22 antibody (anti-CA130) was examined in human fetal tissues, and normal and neoplastic tissues of female genital tracts, and compared to those using OC125. Among the fetal tissues, the amnion and the cells of coelomic epithelium and mullerian-derived epithelia reacted with anti-CA130. In normal adult tissues, cervical and endometrial gland cells, tubal epithelial cells, and ovarian surface cells reacted with anti-CA130. In addition, predecidual cells in the late secretory endometrium and decidual cells during gestation were positive. Among the neoplastic tissues, tubal and endometrial adenocarcinomas and epithelial ovarian tumors were positive for anti-CA130. There were no differences in the respective specimens between the immunohistochemical localization of anti-CA130 and of OC125. Therefore, anti-CA130 is considered to be useful in the immunohistochemical detection of CA125 glycoprotein molecules as well as OC125.
To evaluate the potential of dextran-coated magnetite (DM) particles in enhancing the detection of hepatocellular carcinoma with magnetic resonance (MR) imaging, the authors induced liver tumors in rats by oral administration of diethylnitrosamine and examined the rats before and after intravenous injections of DM with various iron concentrations. Because of the intense and preferential T2 relaxativity of DM, use of DM with an iron concentration of 10 mumol/kg yielded effective MR signal reduction in each normal liver at 1 hour after the injection. Because no significant signal change in the tumors was observed on DM-enhanced MR images, the contrast between hepatocellular carcinoma and adjacent uninvolved liver increased remarkably on even relatively T1-weighted images. The detection rate for the 89 tumors, including small tumors less than 2 mm in diameter, increased from 10% (nine of 89) before DM administration to 65% (58 of 89) with DM-enhanced T1-weighted imaging. Iron staining of rat liver performed about 1 hour after DM administration showed sparse deposits of DM selectively in reticuloendothelial cells but not in liver tumors.
MY-1250, an active metabolite of Repirinast (MY-5116), strongly and dose-dependently inhibited the in vitro histamine release from rat peritoneal mast cells induced by antigen. The IC50 value of MY-1250 for histamine release was in the order of 0.3 microM. Moreover MY-1250 strongly inhibited calcium ion mobilization from the intracellular Ca2+ store. In the presence of 3.6 x 10(-5) M of MY-1250, the initial rise in [Ca2+]i reached a maximum of only 13 nM, and the inhibitory effect was 81% for the initial rise. The IC50 value for this event was 0.25 microM. The inhibitory effect of MY-1250 on the initial rise in [Ca2+]i was closely correlated with that on histamine release.