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PubMed1991

Pulmonary applications of nuclear medicine.

Nuclear medicine techniques have a long history in pulmonary medicine, one that has been continually changing and growing. Even longstanding methods, such as perfusion scanning for embolic disease or for pretherapy pulmonary function evaluation, have largely withstood the test of recent careful scrutiny. Not only have these techniques remained an important part of the diagnostic armamentarium, but we have learned how to use them more effectively. Furthermore, because of technical advances, we are in a phase of expanding roles for nuclear imaging. Gallium citrate scanning for the mediastinal staging and follow-up of lymphoma has been recognized as a valuable adjunct to the anatomic information provided by CT and MRI. With the growth of PET technology in areas that have been explored in a limited fashion until now, such as noncardiogenic pulmonary edema and lung carcinoma, evaluation and management of these patients may substantially improve. Finally, in the field of radiolabeled monoclonal antibodies, attention is now being turned to both the diagnostic and the therapeutic problems presented by lung carcinoma. As radiolabeling methods are refined and as new and better antibodies are developed, radioimmunodetection and therapy in lung carcinoma may begin to make inroads on this common and hard to control disease.

Gallium Radioisotopes↗
PubMed1991

Radioimmuno positron emission tomography with monoclonal antibodies: a new approach to quantifying in vivo tumour concentration and biodistribution for radioimmunotherapy.

Radioimmunodetection of tumours with monoclonal antibodies is becoming an established procedure. Positron emission tomography (PET) shows better resolution than normal gamma camera single photon emission tomography and can provide more precise quantitative data. Thus, in the present study, these powerful methods have been combined to perform radioimmuno PET (RI-PET). Monoclonal antibodies directed against carcinoembryonic antigen (CEA) an IgG, its F(ab')2 and a mouse-human chimeric IgG derived from it were labelled with 124I, a positron-emitting radionuclide with a convenient physical half-life of four days. Mice, xenografted with a CEA-producing human colon carcinoma, were injected with the 124I-MAb and the tumours were visualized using PET. The concentrations of 124I in tumour and normal tissue were determined by both PET and direct radioactivity counting of the dissected animals, with very good agreement. To allow PET quantification, a procedure was established to account for the presence of radioactivity during the absorption correction measurement (transmission scan). Comparison of PET and tissue counting indicates that this novel combination of radioimmunolocalization and PET (RI-PET) will provide, in addition to more precise diagnosis, more accurate radiation dosimetry for radioimmunotherapy.

Animals↗
PubMed1990

[CEA in lung cancer: CEA immunohistochemical study of 150 cases].

CEA (Carcinoembryonic Antigen) was examined histochemically with PAP method in 150 lung cancer cases. Positive stainings were observed in 89% of adenosquamous cancers, 79.2% of adenocarcinomas (ACs), 63.3% of squamous cell cancers (SCCs), 55.6% of large cell cancers (LCCs) and 51.6% of small cell lung cancers (SCLCs). In ACs and SCCs, the higher cancer cells differentiated, the higher positive rates were observed. The intensities from high to low as followings: ACs and adenosquamous cancers; SCLCs and SCCs; and LCCs. Cytoplasmic staining was predominantly found in ACs (76%) and adenosquamous cancers (68.8), membranous in SCCs (63%) and LCCs (60%), and intercellular in SCLCs (68.8%). The results suggests that CEA is significantly related to differential degree of lung cancers. The different staining patterns and positive rates and intensities of CEA may be helpful for the pathological classification of lung cancers. Finally, the author indicates that CEA immunohistochemical examination will be a useful measure for exactly selecting lung cancer cases suitable for radioimmunodetection and antibody-mediated therapy.

Adenocarcinoma↗
PubMed1990

Imaging of pharyngeal and laryngeal carcinomas with indium-111-labeled monoclonal anti-CEA antibodies.

Localization of primary tumors, metastases, or recurrences in 13 consecutive patients with histological verification of squamous cell or adenocarcinoma was made with radioimmunodetection using monoclonal radiolabeled anti-CEA antibody. All surgical specimens stained immunohistochemically, except one, were positive for CEA. Of the known 19 tumor sites 17 were visualized in antibody scans. There were two positive findings that did not prove to be positive during 12 month follow-up. The scintigram findings did not correlate with CEA serum concentrations that, with one exception, were normal in all patients.

Adenocarcinoma↗
PubMedDate not supplied

Comparative in vitro binding characteristics and biodistribution in tumor-bearing athymic mice of anti-ovarian carcinoma monoclonal antibodies.

The interactions of four monoclonal antibodies (OV-TL 3, OV-TL 16, OV-TL 30 and OC 125) with ovarian carcinoma cells (NIH: OVCAR-3) were compared in vitro as well as in a nude mouse model. The affinity constants of the antibodies ranged from 1.0 X 10(9) M-1 (OC 125) to 3 X 10(9) M-1 (OV-TL 30). The cell binding kinetics of the antibodies were studied in vitro: OV-TL 30 associated fastest (50% binding after 25 min), OV-TL 3 and OV-TL 16 associated more slowly (50% binding after 75 min), while the association of OC 125 was slowest (50% binding after 120 min). Dissociation rates of the antibodies also differed: OC 125 displayed the lowest dissociation rate (t1/2 = 360 min). The OV-TL antibodies showed a faster, biphasic dissociation characteristic. The biodistribution of the radioiodinated antibodies in NIH:OV-cAR-3 xenograft-bearing athymic mice, following intravenous injection, was compared. Highest tumor accumulation 48 h p.i. was found with OV-TL 3 (13.3 +/- 2.1% ID/g) and OV-TL 16 (11.0 +/- 2.0% ID/g), while the uptakes of OV-TL 30 and OC 125 were markedly lower (4.9 +/- 0.9% and 6.0 +/- 0.9% ID/g, respectively). The fact that in this experimental model the in vivo tumor accumulation of OV-TL 3 and OV-TL 16 was approximately twice as high as the tumor accumulation of OC 125 could not be fully ascribed to parameters of the antibodies determined in vitro (immunoreactive fraction, affinity constant, antigen density, association and dissociation rate). It is suggested that the antibodies OV-TL 3 and OV-TL 16 are suitable tools for clinical radioimmunodetection of ovarian carcinomas.

Animals↗
PubMedDate not supplied

[Radioimmunoscintigraphy with monoclonal antibodies in recurrences and metastases of colorectal tumors].

An experimental follow-up plan based on immunoscintigraphy was evaluated in 48 patients, who had undergone resection for colorectal cancer. The results were compared with those concerning other 317 patients submitted to a traditional follow-up (physical examination, blood analysis, endoscopy, ultrasonography, CT scan, barium enema, etc.). Immunoscintigraphy was performed with Iodine 131--or Indium 111--labeled anti-CEA and-19.9 monoclonal antibody, using a gamma-detecting probe (GDP) enabling to perform radioimmunodetections. In addition, radioimmunoguided surgery was performed in two cases of highly suspected recurrence, and radioimmunoguided endoscopy was made in two cases of suspected recurrence after anterior resection for tumor of the rectum. Our gamma-detecting probe differs from the other ones because of its collimator which enables to detect all the radioisotopes that are used for external scanning and because of its particular shape that enables to perform endoscopic radioimmuno detections. The experimental follow-up plan showed cancer recurrence in 27% of the patients vs. 13% of extensive instrumental investigations. Radioimmunoguided surgery appears to provide a higher level of radicality. The same GDP used for intraoperative immunoscintigraphies seems to be effective in the endoscopic study of the pelvis after anterior resection, a clinical occurrence which can hardly be investigated by means of other instrumental diagnostic procedures.

Antibodies, Monoclonal↗
PubMed1990

Immunolymphoscintigraphy and immunoscintigraphy of ovarian and fallopian tube cancer using F(ab')2 fragments of monoclonal antibody OC 125.

We have used immunolymphoscintigraphy (ILS) alone or in combination with immunoscintigraphy with 131I-labeled F(ab')2 fragments of monoclonal OC 125 antibodies to improve detection of retroperitoneal lymph node metastases of ovarian and fallopian tube cancer. ILS was carried out with bilateral dorsopedal s.c. injections on nine patients and with bilateral iliopelvic injections into the ischiorectal fossa on two other patients. Radioimaging was performed 2-4 times between 0 and 5 days. An additional dose of labeled antibody fragments was given i.v., and imaging was done 2-3 days later. Conventional immunoscintigraphy without preceding ILS was carried out on another nine patients. Dorsopedal ILS improved detection of pelvic and paraaortic lymph node metastases. Malignant lymph nodes were detectable as early as 3 h after s.c. injection of the tracer. Combined results of ILS and immunoscintigraphy in 16 surgically verified cases indicated a true positive finding in 9 patients, true negative finding in 5, false positive in one, and false negative in 1. Calculated from these figures the sensitivity, specificity, and accuracy of the method were 90, 83, and 88%, respectively. Involved lymph nodes were found more frequently in those patients whose serum CA 125 concentration was elevated demonstrating that an elevated serum CA 125 level does not preclude successful radioimmunodetection.

Adult↗
PubMed1990

Comparative binding and preclinical localization and therapy studies with radiolabeled human chimeric and murine 17-1A monoclonal antibodies.

Murine MoAb 17-1A is an IgG2a antibody reactive with a gastrointestinal cancer-associated cell surface antigen. Human-mouse chimeric 17-1A MoAbs were constructed in which the murine variable region of 17-1A was joined with human IgG1, IgG2, IgG3, and IgG4 constant regions. Human-mouse IgG1, IgG2, and IgG4 chimeric antibodies were compared with the parental murine antibody and its F(ab')2 fragments for their ability to bind to colon carcinoma cells in vitro, for their blood clearance in normal nude mice, and for their localization and tumor growth inhibition of colon carcinoma xenografts in nude mice. Indirect immunofluorescence experiments with fluorescein-conjugated goat anti-mouse or goat anti-human antibody verified that the substitution of human constant regions in the chimeric MoAbs did not significantly alter the ability of the murine variable region to bind to colon adenocarcinoma cell lines (LS174T, SW948, and C0112). The immunoreactivities of 125I-labeled murine and chimeric 17-1A MoAbs measured in a live cell-binding assay with LS174T, SW948, and C0112 cells revealed that chimeric IgG1, IgG4, and 17-1A F(ab')2 were comparable to murine 17-1A while chimeric IgG2 showed lower binding. The blood half-lives of 125I-labeled murine 17-1A, its F(ab')2 fragments, and chimeric IgG1, IgG2, and IgG4 in normal nude mice determined by serial eye bleeding were 7.5, 0.5, 5.2, 6.9, and 1.9 days, respectively. In biodistribution studies at 4 days after injection of 125I-labeled MoAbs in nude mice bearing LS174T tumors, chimeric IgG1 had the highest tumor concentration of 20.5% injected dose/g with a tumor/blood ratio of 3.2. 131I-labeled murine 17-1A administered in a single injection of 300 microCi or 3 injections of about 300 microCi each to nude mice bearing established LS174T tumors inhibited tumor growth, whereas a comparable amount of unlabeled murine 17-1A did not inhibit tumor growth. 131I-labeled chimeric IgG1 MoAb showed a similar level of tumor growth inhibition. The results of the present study indicate that 17-1A chimeric IgG1 antibody may be the best choice for clinical radioimmunodetection and radioimmunotherapy studies.

Animals↗
PubMed1990

An experimental immunoscintigraphic study with anti-CEA monoclonal antibody (DG2).

Monoclonal antibody D11-DG2 (DG2) against carcinoembryonic antigen (CEA) was examined for suitability for radioimmunodetection of human tumors grown in nude mice. Antibodies DG2 and a control antibody of the same IgG1 subclass were labeled with 131I and injected into mice bearing one of three types of CEA-containing tumors (cell lines LS 174T, HT-29 and Rec S) and/or a CEA-negative tumor (Rec R). Gamma-camera imaging and distribution studies revealed that CEA-containing tumors selectively accumulate DG2 but Rec R does not. As the tumors differ in CEA-content, the highest accumulation of 131I-DG2 (corresponding to the best scintigraphic imaging) was found in LS 174T tumors, intermediate in Rec S and lowest in HT-29 tumors. The mean tumor-to-blood ratios on the sixth day after antibody administration were 4.6, 3.2, and 2.1, respectively, in the control experiments the value of this parameter was always lower than 1. The results showed the applicability of DG2 for immunoscintigraphic studies in patients. Furthermore, a positive correlation was found between the uptake of anti-CEA antibody and CEA-content in the tumors.

Animals↗
PubMed1990

Radiolabelled monoclonal antibodies in tumour diagnosis and therapy.

Tumour associated monoclonal antibodies HMFG1, HMFG2, H17E2, AUA1, EGFR1, labelled with 123-Iodine or 111-Indium, were used to detect primary and metastatic cancer by external body scintigraphy in patients with ovarian, breast and non-small cell lung cancer (NSCC). Successful localisation was seen in all patients with primary and 80% of the metastatic NSCC, 50% of primary and 70% of metastatic breast cancer lesions and in 80% of patients with metastatic ovarian cancer. On the other hand, imaging carried with a radiolabelled non-specific monoclonal antibody produced positive results in 3 out of 5 cases with primary NSCC. Therefore non-specific imaging should be further studied in clinical research for the evaluation of the specificity of radioimmunodetection. In our therapeutic trials we have so far treated 29 patients with resistant ovarian cancer, with intraperitoneal 131I-labelled antibodies (HMFG1, HMFG2, AUA1, H17E2), 11 patients with recurrent pleural and pericardial effusions by intracavitary 131I-labelled antibodies, 10 patients with brain gliomas by intravenous or intracarotid infusion of 131I-EGFR1 and two patients with hepatic metastases from colon carcinoma by intrahepatic infusion of 131I-anti-CEA antibodies. The preliminary results from these therapeutic studies seem to be encouraging and are discussed in detail in this review.

Adolescent↗
PubMed1988

[Recent advances in tumor-seeking agents--radioimmunoimaging of cancers using monoclonal antibodies].

Development of biotechnology has made it possible to produce monoclonal antibodies (MoAbs) which associate with tumors. Injected RN-labeled MoAbs would be expected to accumulate in specific tumors. This concept can be evaluated not only from the point of diagnosis but also the therapy of cancers. Before applying RN-labeled MoAbs to patients with cancers, certain factors influencing radioimmunodetection should be investigated, such as (1) Labeling nuclides:RN should be selected by considering its physical properties. Biodistributions of RN-labeled MoAbs differ from one RN to another. (2) Labeling method: labeling techniques and optimum conditions should be established for each MoAb, in order to retain the immunoreactivity and stability of RN-labeled MoAb in vivo. (3) Circulating antigen:RN-labeled MoAb, once injected, may be challenged by the circulating antigen in the blood. We found that uptake of MoAbs against tumor markers (AFP, DU-PAN II) into tumors (hepatoma or pancreatic tumor) was decreased, and that the background activity was increased when the concentration of AFP or DU-PAN II in the blood was high. In addition to this fundamental information with respect to each MoAb, some clinical considerations are necessary for the application of RN-MoAbs to humans, mainly possible side effects. Clinical applications of immunoscintigraphy have not been well developed in Japan, although more than 2,000 cases utilizing this technique have been reported in Europe. In Europe and the U.S.A., tumors were detected with about 70% positivity without any serious side effects. General concerns regarding MoAb products, which have been proposed by the FDA, are also discussed in this paper.

Antibodies, Monoclonal↗
PubMedDate not supplied

Cross-comparison of PSA and PAP values in a wide spectrum of prostate cancer conditions.

Serum PAP, PSA, and testosterone values were measured in 101 men with prostatic nodule. In 71 patients prostatic cancer was detected and in 62 of those patients monitoring studies of the same parameters were assessed on 153 sera by applying a radioimmunodetective procedure. The PSA test, when compared to PAP values, offers significantly greater sensitivity towards small tumor burdens in early stages of the disease, and enables, in some cases, the prediction of tumor recurrence before clinical symptoms have been manifested. The results of this study indicate that the addition of the PSA assessment to the standard protocol of prostate cancer diagnosis and treatment, either alone or together with PAP in a double-marker assay, is promising for more accurate staging and monitoring of patients with prostatic tumors.

Acid Phosphatase↗
PubMed1988

Serum levels of tumor markers and presence of human antimouse antibodies: implications for diagnosis and treatment with radiolabeled monoclonal antibodies.

Our study is based on 100 radioimmunodetections and five immunotherapies in 84 patients with advanced carcinomas. We used a monoclonal anti-CEA F(ab')2 and anti-CA 19.9 F(ab')2 antibody "cocktail" in 75% of the cases and monoclonal anti-alpha FP, anti-beta HCG, and OC 125 F(ab')2 antibodies in the other cases. In all cases, we determined plasma tumor marker levels immediately before imaging. The positivity of the scans was analyzed in relation to the levels of plasma markers. We found that the imaging should be planned only in the cases in which marker levels exceed minimum thresholds. We developed an enzymoimmunologic assay to measure antimouse antibodies. We found that patients who received monoclonal antibodies developed in the mouse produce such antimouse antibodies. The kinetics of this production are analyzed to define the optimal sequence for more than one administration of monoclonal antibodies.

Antibodies, Monoclonal↗
PubMed1985

Non-cross-reactive monoclonal antibodies to human chorionic gonadotropin generated after immunization with a synthetic peptide.

Noncross-reactive monoclonal antibodies specific for human chorionic gonadotropin (hCG) were obtained after pre-selection for submolecular specificity with a synthetic peptide immunogen. Mice were immunized with a synthetic peptide representing a segment unique to the beta-subunit of hCG (amino acid residues 109-145), conjugated to diphtheria toxoid. We then derived nine different hybridomas that secreted monoclonal antibodies reactive with both native hCG and isolated C-terminal peptide, after somatic cell hybridization of immune spleen cells with a nonsecretory myeloma cell line. None of the nine monoclonal antibodies, termed beta-hCG-CTPa1----a9, reacted with hLH, hFSH, or hTSH, although these pituitary hormones display extensive amino acid sequence homology with hCG. The noncross-reactive anti-beta-hCG monoclonal antibodies show apparent association constants on the order of 10(9) to 10(10) M-1. A sandwich-type enzyme-linked immunosorbent assay was set up with cut-off values of around 5 mIU/ml. These antibodies might have important implications for: a) improving the diagnosis and clinical management of pregnancy; b) monitoring the course of development of carcinomas which secrete the hormone, through in vitro assays or in vivo radioimmunodetection; c) evaluating the antibodies' therapeutic potential against such carcinomas; d) studying the biologic functions of the C-terminal segment of beta-hCG; and e) addressing the anti-fertility effect of antibodies raised against that segment.

Animals↗
PubMed1985

Radioimmunolocalization of monoclonal antibodies to human chorionic gonadotropin in choriocarcinoma transplanted into athymic mice.

Radioimmunodetection of monoclonal antibodies to human Chorionic Gonadotropin (hCG) or its beta-subunit in choriocarcinoma tissue was investigated in athymic mouse model system. Antibody to hCG exhibited a higher localization index (L.I.) in tumor tissue than those in other organs, but the tissue/blood ratio of this antibody in tumor tissue was not so high as expected (0.38 and 0.5 on Day 2 and 5 respectively). On the other hand, antibody to beta-subunit showed the same L.I. in tumor tissue as those in other organs. Gel filtration of serum of mouse given an antibody to hCG showed that the antibody was forming immune complexes in the blood stream. Autoradiography showed many grains in the capillary vessels and intercellular spaces in the tumor tissue. We concluded that a monoclonal antibody to hCG localized in choriocarcinoma tissue via a mechanism of retention of immune complexes in the tissue, and that there may be a limitation to the clinical application of localization of antibodies to secretory products such as hCG of tumor cells from their low specific localization.

Animals↗
PubMed1988

Biochemical and immunochemical analysis of gangliosides of human small cell lung carcinoma: production of monoclonal antibodies against a unique marker of small cell lung carcinoma, ganglioside Fuc GM1.

Immunization of mice with a pure preparation of the ganglioside adsorbed on Salmonella typhimurium and hybridization of splenocytes with myeloma P3-X63-Ag 8.653 have resulted in hybridomas producing monoclonal antibodies against ganglioside Fuc GM1, a marker of human small cell lung carcinoma. Characterization of four hybridomal clones and data on the antigenic specificity of the monoclonal antibodies are given. All four monoclonal antibodies reacted only with Fuc GM1 in an enzyme-linked immunosorbent assay. In radioimmunodetection of the antigen on thin-layer plates, two of the four monoclonal antibodies gave cross-reactions with Fuc GD1b. The obtained monoclonal antibodies have revealed the presence of Fuc GM1 in all seven cases of small cell lung carcinoma we have studied and the absence of Fuc GM1 in the normal human lung tissue and in lung adenocarcinomas.

Antibodies, Monoclonal↗
PubMed1987

Technetium-99m-labeled monoclonal antibody with preserved immunoreactivity and high in vivo stability.

Recent availability of monoclonal antibodies (MoAb) and their radiolabeling through the use of the bifunctional chelating agents (BCA) have become an alternative procedure for in vivo radioimmunodetection. Using a newly synthesized BCA, a p-carboxyethylphenylglyoxal-di(N-methylthiosemicarbazone) (CE-DTS), the coupling and technetium-99m (99mTc) labeling of monoclonal IgG against hCG were carried out. In the system presented, factors affecting stability and immunoreactivity were examined. Immunoreactivity of the original IgG (56C) was preserved by conjugating one CE-DTS molecule per molecule of IgG (56C) using the phosphorylazide method, however, 99mTc labeling pH affected the immunoreactivity and limited the 99mTc labeling reaction between pH 4.5 and 6.2. A screening of labeling conditions, such as pH, reaction time, and reducing agent system were then carried out. Technetium-99m-labeled IgG (56C), [99mTc]CE-DTS-IgG (56C), showed good stability upon incubation with mice sera and comparable mice biodistribution to that of indium-111 (111In) DTPA-IgG (56C). Thus, these results indicate the excellent potential of CE-DTS as a BCA for labeling MoAb with 99mTc.

Animals↗
PubMed1987

Mouse monoclonal antibodies to human epithelial differentiation antigens expressed on the surface of ovarian carcinoma ascites cells.

Four different human epithelial differentiation antigens (MT179, MW162, MW207, and MX35) have been defined by mouse monoclonal antibodies obtained from mice immunized with either an ovarian carcinoma cell line or fresh ovarian carcinoma cells. In an attempt to identify tissue-specific antigens restricted to ovarian epithelial cells, sections of a benign ovarian cyst were used as the initial target for screening hybridoma supernatants. The distribution of the antigens detected by these monoclonal antibodies was determined on frozen sections of 24 normal tissues and on 103 cultured cell lines of various histological types. In spite of the method used to select these monoclonal antibodies, they all reacted to some degree with normal epithelial cells in tissues other than ovary. All antibodies were unreactive with nonepithelial cells in frozen sections. These antibodies also reacted with frozen sections of most or all fresh ovarian carcinomas and benign ovarian cysts. All antibodies were unreactive with ABH, Lewis blood group-related antigens and appeared to be different in specificity from previously described well-characterized antigens of ovarian carcinoma cells. MW162 was characterized as a high-molecular-weight mucin-like molecule, and the determinant recognized is probably carbohydrate in nature. MW207 was identified as a Mr 37,000 protein. These monoclonal antibodies and 24 other previously derived antibodies that react with epithelial differentiation antigens were tested for reactivity with the surface of fresh ovarian carcinoma ascites cells and for nonreactivity with normal mesothelial cells. This assay was designed to select monoclonal antibodies that might be effective agents for i.p. therapy or radioimmunodetection of human ovarian carcinoma. Five antibodies with the desired specificity were selected; these were the four new antibodies described herein and MH99, which was characterized previously and recognizes a glycoprotein having Mr 38,000 and 29,000 subunits. The degree of heterogeneity of antigen expression on ascites carcinoma cell was dependent on the particular antigen being examined and was related to the biochemical nature of the antigen. In particular, most ABH and Lewis blood group-related antigens showed a striking degree of heterogeneity.

Animals↗