Experimental approaches to increase radiolabeled antibody localization in tumors.

Approaches have been developed to improve the localization of radiolabeled monoclonal antibodies (MAbs) in experimental tumors, to reduce their uptake in normal tissues, and, thus, to improve the time-dependent tumor: normal tissue (T:NT) ratios so that higher and more frequent doses of radionuclide could be used for radioimmunotherapy. These approaches involve three general strategies: (a) modifying antibodies or radiolabeling techniques; (b) increasing the clearance of radiolabeled MAbs; and (c) modifying tumor delivery, tumor antigen expression, or increasing tumor vascular permeability or blood flow. The use of animal models permits the assessment of a wide range of MAbs, radiolabeling conditions, and the efficacy of administration methods before their initial use in clinical trials.

Screening for drinking problems by patient self-report. Even 'safe' levels may indicate a problem.

Background: Physicians often screen their ambulatory patients for serious drinking problems by asking questions related to the quantity of alcohol that they consume. Never previously reported is whether this "quantitative" approach to screening can be used to effectively screen ambulatory patients for the presence of a serious drinking problem.

Methods: The project interviewed 510 patients attending an inner city general medicine practice with the alcohol module of the Diagnostic Interview Schedule, revised for the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.

Sensitization of radiolabeled monoclonal antibody therapy using bromodeoxyuridine.

Background: Although treatment with radiolabeled monoclonal antibodies (MoAb) against tumor-associated antigens offers the potential for targeted therapy, the efficacy of this approach is limited by the low dose-rate delivered. This could be overcome by increasing tumor sensitivity through the use of radiation sensitizers.

Methods And Results: In vitro studies using LS174T human colon cancer cells showed that exposure to 1 microM bromodeoxyuridine (BrdUrd), a thymidine-analog radiation sensitizer, at a plasma concentration easily achievable through systemic administration in both animals and patients, increased the cytotoxicity of continuous low dose-rate irradiation delivered by a cesium-137 irradiator (at 12 cGy/h which resembles the dose-rate delivered by radiolabeled MoAb therapy).

Three-dimensional reconstruction of monoclonal antibody uptake in tumor and calculation of beta dose-rate nonuniformity.

Background: The measurement of the heterogeneity of radiolabeled monoclonal antibody uptake in tumor has an essential role in the calculation and interpretation of the absorbed dose of radiation. Large data arrays and long calculation times have been limiting factors in the calculation of three-dimensional dose-rate distributions used to study the relationship between uptake heterogeneity and dose.

Methods: Serial autoradiographs of tumor sections were digitized with approximately 100 microns resolution using a laser densitometer.

Radioiodination of monoclonal antibodies D612 and 17-1A with 3-iodophenylisothiocyanate and their biodistribution in tumor-bearing nude mice.

Background: The development of a metabolically stable radioiodination reagent for coupling to monoclonal antibodies is a desirable goal. The radioiodination of monoclonal antibodies D612 and 17-1A reactive with human colon cancer with 3-iodophenylisothiocyanate has been investigated. This new ligand, on coupling with monoclonal antibodies, should form a stable thiourea linkage via a reaction of the isothiocyanate moiety with the epsilon-amino group of lysine.

A peptide-based bifunctional chelating agent for 99mTc- and 186Re-labeling of monoclonal antibodies.

Background: The development of new bifunctional chelating agents for the labeling of monoclonal antibodies with radiometals is a desirable goal in the area of radioimmunodetection and radioimmunotherapy of cancer. The authors have developed a new N3S-ligand, N-(S-acetylmercaptoacetyl) (p-NCS)phenylalanylglycylglycine ethyl ester (MAIPGG) for technetium-99m (99mTc) or rhenium-186 (186Re) labeling of monoclonal antibody D612 reactive with human colon cancer. The biodistribution of 99mTc/186Re-MAIPGG-D612 conjugates was studied in nude mice bearing human colon cancer xenografts.

Effectiveness of Treatment in General Medicine Patients With Drinking Problems.

As many as 40 percent of patients in general medicine and family medicine practices have or have had serious alcohol-related problems. Detection of drinking problems and subsequent intervention by the primary care physician can significantly improve the outcome for these patients. Studies have shown that even brief interventions, administered during a regular office visit, can have therapeutic effects on many patients on many patients.

Quality of life of alcoholics and non-alcoholics: does excessive drinking make a difference in the urban setting?

The current study assessed whether perceived quality of life differed between alcoholics and non-alcoholics. Patients attending an urban-based hospital were screened for alcoholism using the CAGE questionnaire. Patients were recruited from an out-patient clinic setting as well as from an in-patient substance abuse unit.

A program of screening and prompting improves short-term physician counseling of dependent and nondependent harmful drinkers.

Background: Physicians in the general medical setting commonly encounter but rarely counsel patients with dependent or harmful drinking behaviors. We tested whether providing physicians with their patients' results on the alcohol module of the Diagnostic Interview Schedule and counseling directives would prompt them to counsel these patients.

Methods: We randomly assigned 83 first-, second-, and third-year medical residents to receive or not to receive diagnostic information and counseling directives on 214 patients who reported at least one symptom of alcohol impairment as defined in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition.

Synthesis of N-[tris[2-[[N-(benzyloxy)amino]carbonyl]ethyl]methyl]succinamic acid, trisuccin. Hydroxamic acid derivatives as a new class of bifunctional chelating agents.

In an effort to generate bifunctional chelating agents (BCAs) with improved labeling, conjugation, and biodistribution properties, the synthesis of trisuccin is reported. This new hydroxamate BCA, after synthesis and characterization, was used for conjugation and radiolabeling of monoclonal antibodies with 99mTc. This new class of synthetic BCAs may be useful in the radioimmunodiagnosis and radioimmunotherapy of cancer.

Projective resolutions of Weyl modules.

We present a projective resolution of the two-rowed Weyl module, using techniques of supersymmetric algebra.

Comparison of 131I- and 90Y-labeled monoclonal antibody 17-1A for treatment of human colon cancer xenografts.

The choice of radionuclide remains an important question in clinical radioimmunotherapy. Therefore, a study was initiated, using an in vivo model system, to assess the relative merits of 131I- and 90Y-labeled 17-1A monoclonal antibody as therapeutic agents in the treatment of colon cancer. 131Iodine- and 90Y-labeled 17-1A were assessed in animal therapy trials using athymic nude mice bearing LS174T human colon cancer xenografts.

Experimental radioimmunotherapy.

Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies.

Therapy with unlabeled and 131I-labeled pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt's lymphoma xenografts.

Clinical trials of radioimmunotherapy (RIT) of lymphoma have produced frequent tumor regressions and remissions, but it has been difficult to determine to what extent these tumor responses have been due to antibody-specific targeted radiation, nontargeted radiation, and/or cytotoxicity mediated by the carrier monoclonal antibody (MoAb). In this report, RIT was studied in athymic nude mice bearing s.c.

Development of 3-iodophenylisothiocyanate for radioiodination of monoclonal antibodies.

A new radioiodination reagent, 3-iodophenylisothiocyanate (3-IPI) has been developed for coupling to monoclonal antibodies. The starting material, 3-tri-n-butylstannylphenylisothiocyanate was prepared via a reaction of hexabutylditin with 3-bromoaniline, followed by treatment with thiophosgene with an overall yield of 72%. The radioiodination of this tin precursor with Na[125I]I/iodogen in chloroform gave 3-[125I]IPI in 23-55% radiochemical yield and 81-99.

Physician detection of drinking problems in patients attending a general medicine practice.

Objective: To assess the patient and physician characteristics that influence physicians' detection of problem drinking in their medical patients.

Setting: The outpatient medical clinic at an urban university teaching hospital staffed by interns and residents.

Design: Cross-sectional study of a randomly chosen subsample of consecutive patients.

Screening for drinking disorders in the elderly using the CAGE questionnaire.

Objective: To assess the performance of the CAGE questionnaire in identifying elderly medicine outpatients with drinking problems.

Design: Cross-sectional design, with the alcohol module of the Diagnostic Interview Schedule as the criterion standard.

Setting: The outpatient medical practice of an urban university teaching hospital.

Improved delivery of radiolabeled anti-B1 monoclonal antibody to Raji lymphoma xenografts by predosing with unlabeled anti-B1 monoclonal antibody.

A human B-cell lymphoma xenograft model was used to test whether the administration of unlabeled MoAb prior to injection of radiolabeled monoclonal antibody (MoAb) improves delivery of the radiolabeled MoAb to tumor prior to testing in clinical radioimmunotherapy trials. The anti-B1/CD20 pan-B-cell MoAb reactive with human B-cell lymphomas and leukemias but not reactive with mouse B-cells was used in this study. Athymic nude mice bearing human Raji Burkitt lymphoma xenografts were given injections of 2.

Three-dimensional tumor dosimetry for radioimmunotherapy using serial autoradiography.

Three-dimensional dose distributions have been calculated for LS174T human colon cancer xenografts in athymic nude mice treated with 131I-labeled 17-1A monoclonal antibody. Autoradiographs were made for fifteen to twenty 32-micron-thick representative serial sections of tumors removed 1 and 4 days postinjection. Film density readings were converted to activity density and entered into a radiotherapy treatment planning system.

Screening for alcohol abuse using CAGE scores and likelihood ratios.

Objective: To assess the performance of the CAGE (acronym referring to four questions, see below) questionnaire in discriminating between medicine outpatients with and without an alcohol abuse or dependence disorder.

Design: A cross-sectional design of a sample of consecutive patients who received both the alcohol module of the diagnostic interview schedule and the CAGE (Cut down, Annoyed, Guilty, Eye-opener) screening questionnaire.

Setting: The outpatient medical practice of an urban university teaching hospital.

A sensitivity study of micro-TLDs for in vivo dosimetry of radioimmunotherapy.

The sensitivity and precision of teflon-imbedded CaSO4:Dy microthermoluminescent dosimeters (micro-TLDs) were determined. The micro-TLDs were sectioned from miniature TLDs (200 microns x 400 microns x 5 mm) that were fabricated using standard techniques. In order to measure absorbed dose, the miniature TLDs can be implanted directly into tissues (e.

Effect of backscatter on cell survival for a clinical electron beam.

Relative to homogeneous scattering conditions in tissue-like materials, a large increase in dose for clinical electron beams can occur upstream from high atomic number heterogeneities due to backscattered electrons. The degree of this dose increase is uncertain due to the unknown energy distribution of the backscattered electron fluence. Cell survival after irradiation was studied for Chinese hamster cells at the depth of maximum dose in a clinical 6 MeV electron beam under normal scattering conditions and with the addition of a lead backscatter.

The expression of epidermal growth factor receptor on human bladder cancer: potential use in radioimmunoscintigraphy.

Monoclonal antibody 425, which binds to an extracellular domain of the epidermal growth factor receptor, was used to evaluate the expression of this antigen on bladder cancer cells. Epidermal growth factor receptor was found on all bladder cancer cell lines tested. Immunoperoxidase staining of fourteen invasive human bladder cancers with monoclonal antibody 425 demonstrated that ten showed strong staining, one showed weak staining and three were negative.

Radiotherapy in mice with yttrium-90-labeled anti-Ly1 monoclonal antibody: therapy of established graft-versus-host disease induced across the major histocompatibility barrier.

A monoclonal antibody recognizing Ly1, the murine homologue of CD5, was labeled with 90Y. In vivo biodistribution studies showed that 90Y-anti-Ly1 selectively localized in lymphoid tissue. Groups of B10,BR mice (H-2k) were lethally irradiated and given major histocompatibility complex-disparate C57BL/6 (H-2b) bone marrow and spleen cells to induce graft-versus-host disease (GVHD).