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D A Goodwin

Publications and source records attributed to D A Goodwin.

At least 19 recordsLinked to original sources
PubMed1992

Pretargeted immunoscintigraphy: effect of hapten valency on murine tumor uptake.

A method of radioimmunoscintigraphy using bivalent "Janus" haptens with an apparent enhanced affinity ("avidity") for the antibody is described. Janus with 50 micrograms pretargeted Mab WC3A11 resulted in significantly higher murine tumor concentrations (approximately 7%/g) compared to monovalent haptens (approximately 1.4%/g, p < 0.001), and the same high tumor-to-background ratios (approximately 3/1). Janus was synthesized by coupling two molecules of BABE together with a 1,4 butanedithiol linker. Janus itself was rapidly excreted (T1/2b = 42 min) by the kidneys and did not concentrate in any other organs or tissues. Three-step pretargeted immunoscintigraphy (binder, chaser, tracer) with 111In- or 67Ga-Co(III) Janus produced excellent mouse tumor images in 3 hr with high tumor-to-background ratios. The use of short-lived tracers, such as 99mTc and 68Ga, with a T1/2p of hours to image antibodies that localize slowly over several days in vivo is accessible with this new technology.

Animals↗
PubMed1989

The in vivo distribution of human peripheral blood lymphocytes and lymphokine-activated killer cells adoptively transferred in human pancreatic cancer-bearing nude mice.

In this study we evaluated human pancreatic cancer xenotransplanted into nude mice as a model suitable for adoptive immunotherapy studies. A pancreatic cancer cell line (MIA PaCa-2) was chosen and its growth in nude mice and sensitivity to lysis by human lymphokine-activated killer (LAK) cells were characterized. This line grew in 96% of the cases when young (4- to 6-week-old) Swiss/NIH nude mice were used. The line was highly sensitive to lysis by LAK cells in a standard chromium-51 release assay (67.8%), similarly to other cell lines known to be highly sensitive, such as K562 (75.6%) and the melanoma cell line SU.102 (53.1%). To assess their in vivo distribution, human peripheral blood lymphocytes (PBLs) and LAK cells were adoptively transferred into nude mice after labeling with indium-111 oxine. The results of this study show that adoptively transferred PBLs and LAK cells localize in this heterologous system as they do in autologous systems. PBLs are taken up mostly by the liver and spleen. The percentage of the administered dose of radioactivity taken up corrected by weight (percent dose per gram tissue) is 64.3 +/- 15.6%d/gm (liver) and 43.5 +/- 9.5%d/gm (spleen). LAK cells are taken up by liver (43.2 +/- 5.3%d/gm) and spleen (28.0 +/- 4.9%d/gm) but also localize significantly more than PBLs in other organs such as lungs (12.9 +/- 3.5%d/gm vs 1.4 +/- 0.3%d/gm, p less than 0.01), kidneys (19.1 +/- 2.1%d/gm vs 6.3 +/- 1.5%d/gm, p less than 0.001), and pancreatic tumors growing in orthotopic position (1.93 +/- 0.36%d/gm vs 0.56 +/- 0.06%d/gm, p less than 0.05). When the nude mice are pretreated with human recombinant tumor necrosis factor, localization of LAK cells compared with PBLs is even further enhanced both in tumors implanted in the pancreas (3.1 +/- 0.5%d/gm vs 0.56 +/- 0.06%d/gm, p less than 0.01) and in the subcutis (12.5 +/- 8.3%d/gm vs 0.95 +/- 0.29%d/gm, p less than 0.001).

Animals↗
PubMed1988

Chelate radiochemistry: cleavable linkers lead to altered levels of radioactivity in the liver.

Bifunctional chelating agents based on benzyl-EDTA bind 111In stably under physiological conditions. Available evidence indicates that the indium is cleared from the body in its original chelated form. Initial studies of a series of antibody-chelate conjugates joined by different molecular linkers show that the 111In biodistribution is strongly dependent on the nature of the linker. Linkers containing thiourea, thioether, peptide, ester, and disulfide groups were compared in healthy BALB/c mice. The disulfide linker led to particularly rapid clearance of 111In from the liver, and from the whole body. Results did not appear to be as favorable as those currently obtainable with reversible radiolabelling techniques, in which the 111In chelate is bound non-covalently to the antibody and a competing hapten is used to displace it when desired. However, the concept of a metabolically cleavable linker is sound. Further exploration is needed to produce a conjugate with the desired properties.

Animals↗
PubMed1988

The effects of levamisole on urinary enzyme measurements and proximal tubule cell inclusions in male rats.

A markedly increased incidence of large angular secondary lysosomes was observed in the proximal tubular cells of male Wistar rats dosed orally with levamisole, 75 mg/kg body weight for 15 days. These inclusions were similar in appearance to those previously observed in male rats treated with decahydronaphthalene. Urinary enzymes were measured throughout the study, and of these enzymes lactate dehydrogenase and N-acetyl-beta-D-glucosaminidase activities were higher on days 9 and 13 for rats dosed with levamisole in comparison with control animals. Urine volumes increased for the levamisole treatment group, but no treatment related changes of urine protein output were found.

Acetylglucosaminidase↗
PubMed1988

Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens.

A method of tumor imaging utilizing the nonspecific accumulation of antibody through leaky capillaries is described, in which the antibody and the radiolabel are administered separately. Nonradioactive antibody is given first (pre-targeted), and allowed adequate time to reach maximum tumor concentration. Depending on the antibody, this may take several days. At the time of maximum tumor concentration of nonradioactive antibody, the blood is quickly cleared of excess circulating nonradioactive antibody using a special i.v. "chase". The radiolabel then is given and imaging done in 1 to 3 hr. The use of short lived tracers (hours) to image antibodies that localize slowly (days) in-vivo is made possible by this method.

Animals↗
PubMed1986

Metabolizable 111In chelate conjugated anti-idiotype monoclonal antibody for radioimmunodetection of lymphoma in mice.

The relative biological properties of 111In-labeled monoclonal antibodies (MoAb) coupled with a conventional bifunctional chelate (BC) and a new, enzyme metabolizable, bifunctional chelate (BCM) were investigated. A rat IgG2a MoAb against idiotype from a mouse B-cell lymphoma was utilized. Mice bearing B-cell lymphomas in the subcutaneous tissues of the flank were given IV-injections of labeled MoAb and imaged or killed for organ counting at 24 h or 48 h. Rat anti-dinitrophenyl IgG2a MoAb and non-specific polyclonal mouse IgG were used as controls. Compared to BC, the use of BCM resulted in a substantial decrease in blood background activity, a shorter biological half-life and an increase in tumor to blood ratio at the expense of a moderate decrease in absolute tumor uptake. The versatile chemistry of these C-1 substituted bifunctional chelates provides a variety of possible enzyme cleavable moieties for further investigation.

Animals↗
PubMed1986

Monoclonal antibodies as reversible equilibrium carriers of radiopharmaceuticals.

We have prepared monoclonal antibodies (MoAbs) with the specific ability to bind metal chelates such as 111In benzyl EDTA. One, 10, 50 and 100 micrograms MoAb CHA255 Kb = 4 X 10E9 was complexed with 111In BLEDTA II, BLEDTA IV, and benzyl EDTA and injected i.v. in Balb/c mice with KHJJ tumor. The biological half-life by whole body counting was profoundly altered for all three compounds; from minutes to hours with 10 micrograms; to days with 100 micrograms. Tumor uptake increased 50 fold at 24 h with increasing MoAb but satisfactory tumor concentrations (3% per g) and tumor/blood ratios (1.8:1) were obtained with an amount equivalent to 7 mg for a human. Blood level and whole body activity were decreased 30-50% within 3 h or i.v. injection of a "flushing" dose of unlabeled indium benzyl EDTA, increasing tumor/blood ratios to 50:1.

Animals↗
PubMed1986

Monoclonal antibody hapten radiopharmaceutical delivery.

One hundred micrograms of monoclonal antibody (MoAb) CHA255 with a binding constant Kb of 4 X 10(9) was complexed with indium-111 labelled BLEDTA II, BLEDTA IV, benzyl EDTA, and an EDTA conjugate of Fab. The 24-h tumour and organ distribution of BALB/c mice bearing KHJJ tumours was studied for each compound alone, the antibody complex, and 3 h following a chelate chase of the antibody complex. Whole body biological half-life was measured for 7 days with and without a chelate chase for each antibody complex. The 24-h whole body counts dropped 20 to 60% and blood concentration fell over 89% within 3 h of administering the chelate chase. Theoretical equivalent human organ doses were calculated from the 24-h organ concentrations, effective half-life, and MIRD 11 S values (absorbed dose per cumulated activity). Liver and spleen were the target organs, with the dose ranging from 0.50 to 3.91 rads mCi-1. The reduction in organ radiation dose varied up to 95% following the chelate chase. Rapid selective renal clearance of chelate labelled radiopharmaceuticals by competitive inhibition (chelate chase) of their reversible binding to monoclonal antibodies enhances tumour imaging and improves the radiation dosimetry.

Animals↗
PubMed1986

Metal decomposition rates of 111In-DTPA and EDTA conjugates of monoclonal antibodies in vivo.

We have studied the metal chelate decomposition rates in vivo in both 111In-labelled benzyl EDTA and DTPA (bicyclic anhydride) conjugates of monoclonal anti-IAk IgG2a with identical Ka = 1 X 10(11)M-1 in both Ag+ve and Ag-ve mice. Twenty mu Ci was given i.v. and whole body counting done immediately and daily for 10 days, with six to eight mice in each group. Half the mice in each group received i.p. injections of 5.0 mg CaNa2 EDTA chase (Versenate) to facilitate urinary excretion of free 111In. 50% of control 111In-citrate remained at nine days but only 8% with chase. No significant loss of 111In with chase occurred with C1 substituted EDTA conjugates. A 19% increase in excretion was demonstrated with the chase in mice given DTPA conjugates (1.9% per day). While this will not interfere with radioimmunoimaging up to 24 h after injection, waiting periods of a week or longer will produce significant background of free 111In in the reticuloendothelial system, RES. 111In-EDTA stability was important in accurate metabolic rate measurements of anti-IAk; T1/2 = 7.0 days in Ag-ve mice, T1/2 = 9.3 days in Ag-ve mice. It will be important to measure the in vivo rates for each new metal complex, especially those intended for therapy such as Y-90.

Animals↗
PubMed1985

Human scanning with In-111 oxine labeled autologous lymphocytes.

Autologous lymphocytes were labeled with In-111 oxine in 26 patients with chronic inflammatory disease. Whole body gamma camera scans were performed at 24 and 48 hours post injection. Activity was normally seen in spleen, liver, bone marrow, and cervical and inguinal lymph nodes; any activity outside there areas was considered abnormal. Five out of 11 patients with proven or suspected chronic osteomyelitis had positive scans. Four out of five patients with chronic arthritic diseases had positive scans. Also, three patients had bladder uptake suggesting bladder inflammation on a chronic basis.

Adult↗
PubMed1985

An ultrastructural study of stored human platelets after washing using prostacyclin.

The morphology of washed human platelets stored at 4 degrees C has been examined over a period of 96 h. Platelets prepared using prostacyclin showed good preservation of their internal structure. These platelets showed no signs of activation when stirred in an aggregometer and only small reversible aggregates were formed during storage. In contrast, platelets prepared using a more conventional method, which does not use prostacyclin, showed poor preservation of internal structure. Storage and stirring of these platelets resulted in activation and morphological deterioration. These observations support our previous finding that prostacyclin prolongs the viability of washed human platelets in vitro.

Blood Platelets↗
PubMed1985

Faecal hydrogen production in vitro as an indicator for in vivo hydrogen producing capability in the breath hydrogen test.

In the assessment of carbohydrate malabsorption, it is important to determine if a flat breath hydrogen test is a false negative result. Currently, the only reliable way to do this is with a lactulose test. We determined the reliability of assessing faecal hydrogen production as an indicator of an adequate in vivo hydrogen producing colonic bacterial flora. Unfortunately, the results clearly show that the incidence of falsely positive and negative faecal hydrogen production, when compared with in vivo lactulose testing, is so high that the simple faeces screening test is unsuitable for routine use. Until a simpler alternative is found, centres using the breath hydrogen test to determine carbohydrate malabsorption must continue to rely on lactulose breath testing when it is necessary to exclude potential false negative results.

Breath Tests↗
PubMed1985

Chelate conjugates of monoclonal antibodies for imaging lymphoid structures in the mouse.

Radiolabeling of a mouse monoclonal antibody (MoAb) specific for the mouse histocompatibility alloantigen IAk expressed by the B lymphocytes of BALB/k and C3H mice but not BALB/c mice was performed by mixing the chelate-labeled anti (alpha) IAk MoAb with purified, no-carrier-added 111In citrate. Labeling efficiency was 85-95%, and the labeled alpha IAk MoAb retained its antigen binding properties in vitro and in vivo. The organ, spleen, and lymph node distribution of intravenously and subcutaneously administered 111In alpha IAk MoAb was compared in mice, two IAk positive and one IAk negative strains, and to 125I alpha IAk MoAb in one IAk positive strain. The 111In alpha IAk MoAb was more stable in vivo compared to 125I alpha IAk MoAb, as shown by a much slower excretion and a higher absolute uptake in lymph nodes and spleen. Lymph node to blood ratio was increased twofold by intravenous anti-EDTA MoAb. Subcutaneous injection permitted clear images of the tiny lymph nodes in the mouse. Potential clinical applications of 111In alpha lymphocyte MoAb include localization of normal lymph nodes and T & B cell leukemias and lymphomas, as well as detecting lymphatic metastases of other cancers. Therapy may also be possible using MoAbs labeled with beta-emitting metal ions such as yttrium-90.

Animals↗