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H Sands

Publications and source records attributed to H Sands.

At least 37 records · Page 2Linked to original sources
PubMed1988

Correlation of vascular permeability and blood flow with monoclonal antibody uptake by human Clouser and renal cell xenografts.

The specific uptake of 125I-A6H antibody by xenografts of the human renal cell carcinoma (RCC) TK177G in the athymic mouse was considerably greater than that seen for other human tumor xenografts and their associated antibodies (e.g., 125I-B6.2 uptake by the human breast carcinoma, Clouser). In addition the A6H-RCC model also demonstrated both greater localization indices and absolute amount of antibody bound than did the B6.2-Clouser model. Several physiological factors were studied to assess whether they might play a role in this greater specific uptake. Vascular volume was determined using the in situ labeling of red blood cells with 99mTc. Vascular permeability was determined by measuring the amount of 125I-labeled bovine serum albumin and 131I-labeled nonspecific IgG1 (anti-horseradish peroxidase) extravasated out of the tumor vasculature during 1 hr. Relative blood flow to the tumor was determined using the 86Rb method. Blood flow and vascular permeability were found to be significantly greater in the RCC tumor xenografts than in Clouser tumors. Differences in vascular permeability were especially dramatic, showing the vasculature of the RCC xenograft was twice as permeable as that of the Clouser tumor. Animals bearing either RCC or Clouser xenografts were injected with a monoclonal antibody to human major histocompatibility complexes (125I-labeled anti-human histocompatibility complex A, B, C). Tumor uptake of 125I-labeled anti-human histocompatibility complex A, B, C was found to be 5 times greater in RCC than Clouser xenografts. These results, therefore, suggest that the differences seen in the physiological factors studied can account for some of the greater specific 125I-A6H uptake by the RCC tumor than 125I-B6.2 uptake by the Clouser xenograft.

Animals↗
PubMed1987

Tumor-specific genetically engineered murine/human chimeric monoclonal antibody.

Murine variable and human constant region exons were fused to produce "chimeric" immunoglobulin gamma and kappa genes. These constructs were cotransfected into murine myeloma cells which then produced and secreted intact, functional antibody. Cells secreting the chimeric antibody were introduced into mice. The engineered immunoglobulin was subsequently harvested from ascites fluid and was purified by affinity chromatography. Its immunological properties were compared to those of the parental murine monoclonal (B6.2), which exhibits specificity for human breast, lung, and colon carcinoma cells. Competitive binding, immunofluorescent cell staining, and analysis of immunoprecipitated antigen gave similar results for the chimeric and murine B6.2. The biodistribution of chimeric and murine B6.2 after injection into mice bearing human tumors was found to be identical. These results suggest that murine/human chimeric antibodies may be viable clinical replacements for murine monoclonals with the potential for better immunological tolerance and pharmacological efficacy.

Animals↗
PubMed1987

Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labeled with either 125I or 111In.

A comparison of the pharmacokinetics of intact B72.3 (a murine monoclonal antibody specific for human breast and colon carcinoma) with F(ab')2 and Fab fragments labeled with 111In and 125I was done in athymic mice bearing target (LS174T) and non-target (HCT-15) tumors. IgG B72.3 labeled with either isotype imaged LS174T. Biodistributions of both labels were similar in all organs except liver. F(ab')2 also imaged the LS174T tumor, while Fab bearing either isotype did not. The blood clearance was Fab greater than F(ab')2 greater than immunoglobulin G B72.3 for both isotopes. 111In-labeled fragments yielded large accumulations in the kidneys which persisted for 2 days. The different patterns of biodistribution for the various forms of B72.3 labeled with the two isotopes suggest that the most desirable combination of fragment and isotope will depend on the intended use.

Animals↗
PubMed1987

Characterization of in vivo chemistry of cations in the heart.

A variety of laboratory procedures can be used to define the chemistry and pharmacokinetics of myocardial cationic imaging agents. These methods are utilized to define the in vivo chemistry of cationic heart agents, in order to understand the kinetics and mechanisms of: tissue and cellular transport, subcellular distribution, and intracellular localization. Transport across cell membranes can be active, passive or facilitated. Studies performed in erythrocytes, heart cells, slices and isolated perfused hearts using methods for separation of metabolites have shown a high degree of myocardial specificity for [99mTc]hexakis alkyl isonitrile by an uptake mechanism different from 201Tl. These studies demonstrate the importance of in vivo chemistry and pharmacokinetics in the development of new radiopharmaceuticals.

Animals↗
PubMed1987

Lymphoscintigraphy of human colorectal carcinoma metastases in athymic mice by use of radioiodinated B72.3 monoclonal antibody.

The potential of radioiodinated monoclonal antibody B72.3 for lymphoscintigraphy was evaluated, using suitable animal models of a human colorectal carcinoma. LS174T xenografts were grown at various sites in beta-estradiol-pretreated athymic mice, and the development of metastases in different organs was assessed histologically. After iv inoculation of the mice, 66% of the animals developed "metastases" to the axillary lymph nodes. Of these mice, 100% also developed multiple tumors on their backs and 79% had lung micrometastases. Livers, kidneys, and spleens showed no evidence of tumor growth. In 33% of the mice in which primary LS174T tumors had been removed from the hindfoot pad, metastases to the popliteal lymph nodes were observed 3 1/2 weeks after tumor implantation. BALB/c (nu/nu) female mice bearing axillary and popliteal lymph node metastases were used to test the potential of radiolabeled B72.3 antibody (an IgG1) as a lymphoscintigraphic agent. A monoclonal antibody against horseradish peroxidase (also an IgG1), which did not bind LS174T tumor cells in vitro, served as a control. Both normal and tumor-bearing axillary and popliteal lymph nodes imaged up to 6 hours after the sc injection of 20-40 mu Ci of 125I-labeled B72.3 into either the forefoot or hindfoot pads. The localization index (L.I.) (specific/nonspecific antibody in tumor divided by specific/nonspecific antibody in blood) for LS174T tumors in lymph nodes was approximately 1 during the first 6 hours after antibody injection, thus indicating no specific antibody accumulation. Twenty-four hours and later after sc injection, images of nodal metastases (14-477 mg) and specific antibody accumulations were observed. At these times the L.I.'s ranged 1.5-3.5. Tumor-negative nodes did not image at 24 hours after injection of 125I-labeled B72.3. The L.I.'s of the normal nodes and of other tissues from these mice were about 1.0 at 24 hours, indicating no specific antibody accumulation. Autoradiographic analysis of lymph nodes containing LS174T tumor showed heterogeneous antibody distribution of B72.3 within tumor sections with heavy patches of antibody accumulation in mucin globules. In lymph nodes the normal lymphocytes adjacent to the LS174T tumor cells showed no antibody accumulation. The lack of specific, early antibody accumulation by LS174T tumor-bearing nodes in mice suggests that B72.3 does not accumulate in nodal metastases to the degree necessary to consider it a potential agent for use in lymphoscintigraphy.

Animals↗
PubMed1987

Methods for the study of the metabolism of radiolabeled monoclonal antibodies by liver and tumor.

Methods for elucidating the mechanisms by which radiolabeled antibodies are taken up and accumulated in tumor and liver are reviewed. These include the use of isolated perfused rat livers, RES blockade using dextran sulfate, single and double labeled antibodies, micropore chambers for the accumulation of the interstitial fluid, and in vitro tissue culture studies of antibody metabolism. Each method has its utility, examples of which will be discussed along with the methods' limitations. All of the methods have value in furthering our understanding of the metabolism of monoclonal antibodies both in vivo and in vitro. Use of these procedures to create a greater understanding of radiolabeled antibody metabolism, hopefully, will result in improved clinically useful agents for diagnosis and therapy.

Animals↗
PubMed1986

Autoradiographic analysis of monoclonal antibody distribution in human colon and breast tumor xenografts.

The targeting of monoclonal antibodies to human tumor xenografts in nude mice was investigated by analysis of the cellular distribution of two radioiodinated monoclonal antibodies, B6.2 and B72.3, which recognize different tumor-associated antigens. The time course of distribution of each antibody within Clouser human mammary carcinoma (B6.2 positive, B72.3 negative) and LS174T human colorectal carcinoma (B6.2 positive, B72.3 positive) following i.v. injections was compared using autoradiographic techniques, which were also used to determine the pattern of binding after in vitro incubation with radiolabeled antibody. Both in vivo and in vitro localization of 125I-B72.3 in LS174T were characterized by the binding of antibody to antigen-rich mucin globules. In contrast, in vivo localization of B6.2 was restricted to groups of cells in well vascularized regions. Thus, the in vivo accumulations of B6.2 and B72.3 although quantitatively similar showed very different spatial distributions within LS174T tumors. The in vivo binding of B6.2 in Clouser tumors was restricted to small clusters of cells scattered fairly evenly throughout the tumor. There was no evidence for the presence of such antigen-rich foci after in vitro incubation of tumor sections with B6.2 suggesting that heterogeneity of regional uptake may be due to differences in antibody delivery. This type of information may provide a rational basis for the selection of appropriate therapeutic isotopes for radioimmunotherapy studies using these and other tumor models.

Animals↗
PubMed1986

Site-related differences in the localization of the monoclonal antibody OX7 in SL2 and SL1 lymphomas.

The uptake of a monoclonal antibody (OX7) by murine lymphomas (SL1, SL2) growing in two sites in the mouse were compared. SL2 tumors grown in the subrenal site showed greater specific antibody uptake than did the same tumor grown in the subcutaneous site. Major differences in membrane bound antibody, in vitro antibody binding patterns, and gamma scintillation camera imaging were also observed between the two sites. These differences may be due to the greater blood flow measured in tumors growing in the subrenal capsule than those growing at the subcutaneous site. The differences observed in antibody uptake of the same tumor growing in two different sites raises questions concerning the choice of animal model systems that can be used to predict clinical utility.

Animals↗
PubMed1986

Uptake of hexakis(t-butylisonitrile) technetium (I) and hexakis(isopropylisonitrile) technetium (I) by neonatal rat myocytes and human erythrocytes.

The uptake mechanism of two potential cardiac imaging agents [99mTc]hexakis(t-butylisonitrile) technetium (I) (TBI) and [99mTc]hexakis(isopropylisonitrile) technetium (I) (IPI) has been studied using neonatal rat myocytes and human erythrocytes. Uptake of these complexes was rapid, of greater magnitude than seen previously for 42K, and was unaffected by either 0.15 mM ouabain or 10 mM KCI. Both [99mTc]isonitrile complexes had a high affinity for the membranes of the myocytes and erythrocytes. The data suggest that the uptake is not dependent on the membrane Na+/K+ ATPase but may be related to the lipophilicity of these agents as evidenced by the rapidity, tenacity, and quantity of the binding observed.

Animals↗
PubMed1985

Comparison of the transport of 42K+, 22Na+, 201Tl+, and [99mTc(dmpe)2 X Cl2]+ using human erythrocytes.

The ability of isolated human erythrocytes to exchange Na+ for K+ via (Na+ + K+)-ATPase was used to study the characteristics and interactions of the transport of both alkali metal and synthetic monovalent cations. Both efflux and influx studies were carried out and the results showed that: (1) Efflux of 22Na+ from human erythrocytes was stimulated by the addition of either of K+, or Tl+ at 10 mM and inhibited by the addition of ouabain. Unlabeled K+ and the addition of [99Tc(dmpe)2 X Cl2]+ (dmpe, 1,2-bis(dimethylphosphino)ethane) at 5 mM had no effect on 22Na+ efflux. (2) Influx of 42K+ was inhibited by the addition of ouabain, unlabeled K+, or Tl+. 201Tl+ influx was more rapid and of a greater magnitude than 42K+ influx. [99Tc(dmpe)2 X Cl2]+ had no effect on 42K+ uptake. (3) Influx of 201Tl+ was inhibited by ouabain and by the addition of unlabeled Tl+. Addition of [99Tc(dmpe)2 X Cl2]+ at 5 mM resulted in an inhibition of 201Tl+ influx. (4) [99Tc(dmpe)2 X Cl2]+ influx resembled that of 42K+ with respect to rate and magnitude. Influx of [99mTc(dmpe)2 X Cl2]+ was shown to be unaffected by ouabain, unlabeled K+ or Tl+. Addition of 5 mM [99Tc(dmpe)2 X Cl2]+ initially had no effect on [99mTc(dmpe)2 X Cl2]+ influx, however, a time-dependent stimulation of the influx of the [99mTc(dmpe)2 X Cl2]+ was observed. We conclude that the influx of the various alkali, metal and synthetic monovalent cations into erythrocytes is mediated by different mechanisms. Most clearly, the influx of [99mTc(dmpe)2 X Cl2]+ is not by a mechanism similar to that of utilized by K+ or Tl+.

Erythrocytes↗
PubMed1985

Vascular volume and permeability of human and murine tumors grown in athymic mice.

99mTc-labeled red blood cells have been used to measure tumor vascular volume (VV). When combined with the use of 125I-labeled bovine serum albumin [( 125I]BSA) and 131I-labeled IgGs this method also provides the rapid simultaneous determination of tumor vascular permeability (VP). Using this technique the VV and VP of a human (Clouser) and a murine tumor (SL2) grown in athymic mice were determined. The relative VV were Clouser = SL2 greater than or equal to skin greater than muscle. The relative VP of BSA and IgG were Clouser greater than SL2 = skin greater than muscle. These results may explain the differences observed in the accumulation of monoclonal antibodies in human and murine tumors grown in the athymic mouse.

Animals↗
PubMed1985

Radioimmunodetection of small human tumor xenografts in spleen of athymic mice by monoclonal antibodies.

The ability of radiolabeled monoclonal antibodies to accumulate in and image small human tumors growing in the spleen of athymic mice was assessed. The antibodies B6.2 and B72.3, which reacted against human breast (Clouser) and colon (LS174T) tumor cells in vitro and in vivo, respectively, and the isotype matched anti-horseradish peroxidase antibody which did not bind to these tumors were used in pharmacokinetic and imaging experiments. Human melanoma cells and tumors (A375) which did not react with any of the three antibodies were used as additional controls. Radioiodinated "tumor specific" and non-specific antibodies were injected i.v. into athymic mice bearing intrasplenic tumors and the mice were sacrificed at various times to assess the specificity of uptake of these antibodies into tumor and normal host tissues. The accumulation of B6.2 in the Clouser tumor was maximal at 24 h as indicated by a localization index (specific/nonspecific antibody in tumor divided by the same ratio in blood) of about 4.0. The uptake of B72.3 in LS174T tumor increased with time with a localization index of about 12.0 observed at 50 h post-antibody injection. Localization indices for the control A375 tumor and for all normal mouse tissues, including the uninvolved portion of the tumor bearing spleen, were between 0.8 and 1.0, thus indicating no specific antibody accumulation. The relative blood flows of the Clouser and A375 tumors, as determined by the 86RbCl method, were similar. The results suggested that immunospecificity was a major factor in antibody localization in vivo. Specific images of approximately 100-mg Clouser tumors with radiolabeled B6.2 and of LS174T tumor with radiolabeled B72.3 were seen by 24 h after antibody injection. Images of smaller (about 20 mg) LS174T tumors were seen by 48 h following B72.3 injection. The control antibody, anti-horseradish peroxidase, did not image either Clouser or LS174T tumor. Also the control tumor was not imaged with any of the three antibodies tested. The data generated with this novel animal model support the concept of using radiolabeled monoclonal antibodies for detecting and possibly treating small metastatic visceral tumors in cancer patients.

Animals↗
PubMed1984

The imaging of small experimental murine tumors grown in the subrenal capsule using monoclonal antibodies.

The ability of a "tumor-specific', monoclonal antibody (OX7) and a subclass-matched, non-specific, control antibody (anti HRP) to localize in and image small (20-60 mg) murine lymphomas growing in the subrenal capsule of mice was tested. Due to the small tumor size, and its visceral location, the subrenal site of tumor growth represents a model of metastases which may be more clinically relevant to human cancer. The in vivo and in vitro quantitative data (as well as the gamma camera images) support the feasibility of the concept of using monoclonal antibodies for metastatic tumor detection and treatment.

Animals↗
PubMed1981

Effect of drug treatment and aerosoled antigen sensitization on cyclic AMP and beta adrenergic receptors of guinea pig lung.

The interaction between the number of beta adrenergic binding sites and the ability of a beta adrenergic agonist, isoproterenol, to increase cyclic AMP content of guinea pig lung slices was studied. A complex relationship was found. Chronic sensitization of the guinea pig to an aerosol of ovalbumin resulted in lung slices which were hyporesponsive to isoproterenol in vitro, yet possessed an unchanged number of beta adrenergic binding sites. Chronic exposure of guinea pigs to aerosoled isoproterenol or acute treatment with hydrocortisone did not change the number of beta adrenergic binding sites or the responsiveness of the tissue to isoproterenol in vitro. However, chronic hydrocortisone treatment increased the number of binding sites found on the lung slices by 44%, yet there was no change in the responsiveness of the tissue to isoproterenol in vitro. These data suggest that drugs and disease may change the relationship between the various components of the beta adrenergic binding-adenylate cyclase complex of lung.

Animals↗