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Biomedical subjects

F Searle

Publications and source records attributed to F Searle.

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

A cytotoxic agent can be generated selectively at cancer sites.

Attempts to improve the selectivity of anti-cancer agents by conjugating them to antibodies directed at tumour associated antigens have demonstrated tumour localisation but only limited therapeutic success. We report here the advantage of a 2-stage approach in which the first component combines the selective delivery of antibody with a capability to generate a cytotoxic agent from a second subsequently administered component. A bacterial enzyme, carboxypeptidase G2 (CPG2) was conjugated with F(ab')2 fragment of a monoclonal antibody directed at beta subunit of human chorionic gonadotrophin (beta-hCG) and injected into nude mice bearing hCG producing CC3 xenografts of human choriocarcinoma. Time was allowed for the conjugate to localise at tumour sites and clear from blood before injecting para-N-bis (2-chloroethyl) aminobenzoylglutamic acid. Cleavage of the glutamic acid moiety from this molecule by CPG2 released a benzoic acid mustard. Growth of the tumour which is resistant to conventional chemotherapy was markedly depressed by a single course of treatment. This demonstrates for the first time the potential of an antibody directed enzyme to activate an alkylating agent and to eradicate an established human cancer xenograft.

4-Aminobenzoic Acid↗
PubMed1987

The clinical value of imaging with antibody to human chorionic gonadotrophin in the detection of residual choriocarcinoma.

Choriocarcinoma can be imaged by external scintigraphy after intravenous administration of radiolabelled antibody directed against human chorionic gonadotrophin (HCG). The purpose of this study was to investigate whether antibody imaging was sufficiently sensitive and specific to improve the selection of patients for surgical resection of localised deposits of drug resistant or recurrent choriocarcinoma. Eighteen patients with raised serum HCG concentrations in whom the site of tumour was not known were investigated by antibody imaging and conventional imaging methods. When the tumour appeared localised, resection was attempted. Tumour was found at all sites in which both antibody imaging and conventional imaging methods were positive. Antibody imaging gave false positive results in 2 of 18 patients and false negatives in 5. Computerised tomography was false positive in one case and false negative in 2. In these patients, antibody imaging gave true negative and true positive results respectively. Of 8 patients with positive antibody imaging in whom resection was attempted, 5 achieved sustained complete response with up to five years follow up. It is concluded that antibody imaging is useful in selection of patients for surgery in drug resistant or recurrent choriocarcinoma.

Antibodies↗
PubMed1987

Use of second antibody in radioimmunotherapy.

In this study, a second antibody was directed against the first antitumor antibody to accelerate clearance of the 131I-labeled first antibody and improve tumor to normal tissue ratios of radioactivity. The value of this method in improving the therapeutic index of radioimmunotherapy with 131I-antibody to CEA has been investigated in nude mice bearing xenografts of human colon carcinoma and in 5 patients with colorectal cancer. The xenografts did not become saturated with anti-CEA as the administered dose was increased to therapeutic levels. At these high dose levels, the second antibody increased tumor to blood ratios to a maximum of 155:1, 48 times the level in controls that did not receive the second antibody. In 5 patients given 50 mCi of anti-CEA, there was no significant toxicity with the second antibody; clearance of radioactivity was accelerated; and tumor imaging was enhanced. The second antibody appears to have the potential to improve the therapeutic index of radioimmunotherapy.

Animals↗
PubMed1986

Radioimmunolocalization and selection for surgery in recurrent colorectal cancer.

The value of radioimmunolocalization (RIL) of cancer depends on its performance in situations where the result determines the choice of management. A rise in serum carcinoembryonic antigen (CEA) values after apparently curative resection of colorectal cancer implies localized, resectable recurrence in some patients and widespread unresectable tumour in others. This study investigated the ability of RIL with radiolabelled antibody to CEA and a novel numerical method for analysis of results to determine the extent of disease in 31 patients with raised serum CEA but no physical signs of recurrence. Surgical exploration or conventional radiology later confirmed the presence of tumour in 94 per cent of sites which were positive by RIL. Negative RIL predicted the absence of disease in 53 per cent of patients. The investigation could discriminate between localized and disseminated disease and often performed better than conventional radiology. RIL appears useful in selection of patients for second look laparotomy.

Carcinoembryonic Antigen↗
PubMed1986

Distribution of intact and Fab2(1) fragments of anti-human chorionic gonadotrophin antibodies in nude mice bearing human choriocarcinoma xenografts.

A direct comparative study of the distribution of intact and Fab2(1) fragments of mouse monoclonal anti-human chorionic gonadotrophin antibody, W14A, in nude mice bearing a human choriocarcinoma xenograft, indicates that the tumour:blood ratio is generally improved with fragments. Some parameters which may determine the distribution are outlined.

Animals↗
PubMed1986

A comparative distribution study of 111In-labeled DTPA and TTHA monoclonal antibody conjugates in a choriocarcinoma xenograft model.

Conjugates of the chelating agents DTPA and TTHA with a monoclonal anti-HCG were prepared. The tissue distribution of the 111In-labeled conjugates and also 111In-citrate was studied in mice bearing human choriocarcinoma xenografts. The antibody conjugates both gave high liver and spleen radionuclide accumulation. Elevated femur levels were observed for the TTHA conjugate and 111In-citrate. Generally the DTPA conjugate showed the highest tumor/tissue ratios, although its tumor/blood ratio was lower than the other two materials. The results infer that the DTPA conjugate has the greatest utility as an imaging agent but that it would require a background subtraction technique.

Animals↗
PubMed1986

The potential of carboxypeptidase G2-antibody conjugates as anti-tumour agents. I. Preparation of antihuman chorionic gonadotrophin-carboxypeptidase G2 and cytotoxicity of the conjugate against JAR choriocarcinoma cells in vitro.

Carboxypeptidase G2, a zinc metalloenzyme isolated from Pseudomonas sp. strain RS-16, which catalyses the hydrolytic cleavage of reduced and non-reduced folates to pteroates and L-glutamate, has been linked to a monoclonal antibody (W14A) raised to human chorionic gonadotrophin. The coupling efficiency and retention of antibody and enzymatic activities are compared for three separate methods of preparing 1:1 conjugates. Preliminary in vitro studies on the cytotoxicity of the free enzyme and the conjugated enzyme towards JAR choriocarcinoma cells are reported. Despite the limitations of the in vitro model, it could be demonstrated that a significant proportion of 10(6) choriocarcinoma cells lost viability when exposed to either free or conjugated enzyme for 72 hours at concentrations of carboxypeptidase G2 of 1-3 units ml-1 of medium.

Antibodies, Monoclonal↗
PubMed1984

Preparation and properties of mouse monoclonal antibody (W14A) to human chorionic gonadotropin.

A mouse monoclonal antibody, W14A, has been prepared which reacts with intact human chorionic gonadotropin and its beta-subunit, showing less than 2% cross-reactivity towards the alpha-subunit and 0.5% cross-reactivity towards the beta-subunit of luteinizing hormone. The reagent is suitable for the radioimmunolocalization of choriocarcinoma and trophoblastic teratoma in humans. A preliminary radioimmunoassay has been developed.

Animals↗
PubMed1984

An efficient method for labelling antibodies with 111In.

Using a new method, rabbit IgG and a monoclonal antibody have been conjugated with the chelating agent DTPA. This was accomplished with reaction conditions that should entail lower antibody damage than existing methods. Gel filtration of the 111In-labelled antibody conjugate indicated minimal damage to the antibody and radioimmunoassay showed no significant change in its immunological activity.

Antibodies↗
PubMed1984

Choriocarcinoma xenografts in the nude rat.

The transplantation of a human choriocarcinoma xenograft (CC3) in the nude rat is reported. The tumours grew progressively for up to 5 weeks but subsequently regressed. Our preliminary results suggest that regression of the tumours appears to be dependent on host age.

Age Factors↗
PubMed1984

The comparative distribution of monoclonal antibodies to CEA in colorectal xenografts.

The in vivo distribution of three different, parenterally administered, monoclonal antibodies to CEA was studied in MAWI human colorectal tumour xenografts. By the use of conventional autoradiography, more antibody was generally detected within necrotic areas, extracellular spaces and stromal connective tissue than within tumour cells. However, some peripheral tumour cell groups markedly accumulated anti-CEA. The number of such groups involved and the degree to which antibody was internalised varied widely with the antibody studied. Immunoperoxidase staining of the same preparations showed that antibody accumulation did not necessarily correspond to CEA-positivity. These findings are compared with results of previous work with polyclonal anti-CEA, and discussed in relation to the use of anti-CEA's as carriers to deliver cytotoxic agents into colorectal tumours.

Adenocarcinoma↗
PubMed1983

Improved radioimmunodetection of tumours using liposome-entrapped antibody.

The discrimination of radioimmunodetection of tumours is reduced by the presence of circulating radiolabelled antibody (primary antibody). We have prepared liposomes containing an antibody to the primary antibody (secondary antibody), with the intention of complexing and delivering to the liver primary antibody which is not associated with the tumour. In mice bearing xenografts of human tumours which secrete the marker carcinoembryonic antigen (CEA), liposomally entrapped secondary antibody was able to reduce the blood levels of 125I-labelled anti-CEA within 2 h, without reducing the amount of anti-CEA bound to the tumour. We therefore suggest that the use of liposomally entrapped secondary antibody would improve the diagnostic potential of radioimmunodetection of tumours and their metastases.

Animals↗
PubMed1983

Clearance of injected radioactively labelled antibodies to tumour products by liposome-bound second antibodies.

Liposomes containing anti-goat immunoglobulin were injected 24 h after administration of 125I-labelled goat antibody against the carcinoembryonic antigen (anti-CEA) to groups of nude mice bearing human tumour xenografts, and normal mice. Controls in each group received radioactively labelled anti-CEA only. In liposome-treated mice, blood 125I levels were lower than those of controls 30 min to 24 h after liposome administration, with corresponding accumulation of 125I activity in the liver and spleen for the first 2 h after liposome injection. [14C]Cholesterol or 99mTc labels in the bilayer were eliminated rapidly from the blood, with uptake in the liver and spleen. In xenograft-bearing mice, 125I activity detected in the tumours up to 6 h after liposome injection was identical to that detected in the tumours of controls. However, 24 h after liposome injection a reduction in the tumour concentration of 125I-labelled anti-CEA was obtained, but the tumour/blood radioactivity was still increased. In two mice given 27 mumol lipid, the blood radioactivity count after 24 h was only 5% of that in the controls. In rabbits, 2 h after administration of liposomes containing anti-goat second antibody, the circulating 125I activity had dropped by 28-40%. The results suggest that administration of liposome-entrapped second antibody approximately 2 h prior to external scintigraphy may clear circulating radioactively labelled primary antibody by up to 50%.

Animals↗
PubMed1982

Liposomally entrapped second antibody improves tumour imaging with radiolabelled (first) antitumour antibody.

The usefulness of antibodies directed against tumour products for localisation and therapy of cancer is limited by the large proportion of administered antibody which remains non-specifically in the circulation and extravascular space. Liposomally entrapped second antibody (LESA) directed against the first (antitumour) antibody has been used to accelerate clearance of non-tumour-bound first antibody without affecting its clearance from the tumour. Intravenously administered LESA binds the first antibody and LESA is cleared by the reticuloendothelial system. LESA accelerated clearance of radiolabelled antibody directed against carcinoembryonic antigen (CEA) from the circulation in four of five patients with gastrointestinal cancer, enhancing gamma-camera imaging of the tumour in three of them. These results suggest that LESA can improve the sensitivity and specificity of tumour imaging with radiolabelled antitumour antibody. This strategy may also have the potential to improve the therapeutic ratio of some toxic agents linked to antitumour antibody.

Adolescent↗
PubMed1981

A human choriocarcinoma xenograft in nude mice; a model for the study of antibody localization.

The successful development of the concept of linking cell-killing agents to tumour-specific antibodies will be largely determined by the extent to which the antibodies are preferentially localized in the malignant tissue. A xenograft of human choriocarcinoma (CC3) has been established in nude mice, and the relative distribution of affinity-purified specific antibodies to human chorionic gonadotrophin has been compared with that of nonspecific antibodies from the same species. Treatment of the nonspecific antibodies with ammonium thiocyanate appeared to be important to ensure that the distributions in normal nude mice were equivalent. Specificity indices, derived from the comparative distributions of isotope activity in the tumour and lung of labelled specific and nonspecific antibodies, ranged between 1.3 and 2.0.

Animals↗