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1.
Biochem J ; 346 Pt 2: 519-28, 2000 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10677374

RESUMO

MFE-23 is the first single-chain Fv antibody molecule to be used in patients and is used to target colorectal cancer through its high affinity for carcinoembryonic antigen (CEA), a cell-surface member of the immunoglobulin superfamily. MFE-23 contains an N-terminal variable heavy-chain domain joined by a (Gly(4)Ser)(3) linker to a variable light-chain (V(L)) domain (kappa chain) with an 11-residue C-terminal Myc-tag. Its crystal structure was determined at 2.4 A resolution by molecular replacement with an R(cryst) of 19.0%. Five of the six antigen-binding loops, L1, L2, L3, H1 and H2, conformed to known canonical structures. The sixth loop, H3, displayed a unique structure, with a beta-hairpin loop and a bifurcated apex characterized by a buried Thr residue. In the crystal lattice, two MFE-23 molecules were associated back-to-back in a manner not seen before. The antigen-binding site displayed a large acidic region located mainly within the H2 loop and a large hydrophobic region within the H3 loop. Even though this structure is unliganded within the crystal, there is an unusually large region of contact between the H1, H2 and H3 loops and the beta-sheet of the V(L) domain of an adjacent molecule (strands DEBA) as a result of intermolecular packing. These interactions exhibited remarkably high surface and electrostatic complementarity. Of seven MFE-23 residues predicted to make contact with antigen, five participated in these lattice contacts, and this model for antigen binding is consistent with previously reported site-specific mutagenesis of MFE-23 and its effect on CEA binding.


Assuntos
Anticorpos/química , Anticorpos/imunologia , Antígeno Carcinoembrionário/imunologia , Epitopos/química , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/imunologia , Camundongos , Dados de Sequência Molecular , Conformação Proteica
3.
Nat Med ; 2(9): 979-84, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8782454

RESUMO

We present a system for cancer targeting based on single-chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)-producing cancers using an iodine-123 labeled scFv anti-CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.


Assuntos
Anticorpos Antineoplásicos/metabolismo , Neoplasias da Mama/metabolismo , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/metabolismo , Fragmentos de Imunoglobulinas/metabolismo , Adulto , Idoso , Anticorpos Antineoplásicos/genética , Anticorpos Antineoplásicos/imunologia , Sistemas de Liberação de Medicamentos , Humanos , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/imunologia , Pessoa de Meia-Idade , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Tomógrafos Computadorizados
4.
Cancer Res ; 56(14): 3293-300, 1996 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-8764124

RESUMO

Radioimmunotherapy (RIT) does not readily eradicate common solid tumors and therefore requires augmentation by complementary therapies that do not increase normal tissue damage. We have examined the efficacy of RIT combined with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a drug which induces immunomodulation and cytokine production and preferentially reduces tumor blood flow, using a colorectal xenograft model in nude mice. Although an optimal i.p. dose (27.5 mg/kg) of drug alone induced massive hemorrhagic necrosis of all but a thin peripheral rim of viable tumor cells, survival was unaffected. However, when combined with i.v. 18.5 MBq 131I-labeled anti-carcinoembryonic antigen IgG, DMXAA significantly potentiated the RIT without increased toxicity, with five of six mice showing complete cures. Scheduling was critical because the antibody must be allowed to reach maximum tumor accumulation before initiation of drug-induced blood flow inhibition. Subsequently, the antibody was retained preferentially in the tumor, reaching approximately twice control levels by 5 days after drug delivery. In combined studies, the drug had a narrow therapeutic window, 30 mg/kg being toxic to two of six mice, whereas 20 mg/kg were ineffective. However, the addition of a second vasoactive agent, serotonin, to RIT plus 20 mg/kg DMXAA enhanced therapy without increasing systemic toxicity. Tumor histology and phosphor image plate analysis reflected these results. When given without RIT, the two drugs combined, although not alone, also significantly inhibited tumor growth. Drug-induced tumor necrosis and tumor retention of radioantibody may both contribute to the enhanced RIT produced by this combined complementary therapy.


Assuntos
Neoplasias Colorretais/terapia , Radioimunoterapia/métodos , Xantonas , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/metabolismo , Anticorpos Antineoplásicos/uso terapêutico , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/irrigação sanguínea , Terapia Combinada , Flavonoides/administração & dosagem , Humanos , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Fluxo Sanguíneo Regional/efeitos dos fármacos , Serotonina/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Transplante Heterólogo , Xantenos/administração & dosagem
5.
J Mol Biol ; 259(4): 718-36, 1996 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-8683578

RESUMO

Carcinoembryonic antigen (CEA) is one of the most widely used cell-surface tumour markers for tumour monitoring and for targeting by antibodies. It is heavily glycosylated (50% carbohydrate) and a monomer is constructed from one V-type and six C2-type fold domains of the immunoglobulin superfamily. The solution arrangement at low resolution of the seven domains in CEA cleaved from its membrane anchor was determined by X-ray and neutron scattering. Guinier analyses showed that the X-ray radius of gyration RG of CEA was 8.0 nm. The length of CEA was 27 to 33 nm, and is consistent with an extended arrangement of seven domains. The X-ray cross-sectional radius of gyration RXS was 2.1 nm, and is consistent with extended carbohydrate structures in CEA. The neutron data gave CEA a relative molecular mass of 150,000, in agreement with a value of 152,500 from composition data, and validated the X-ray analyses. The CEA scattering curves were analysed using an automated computer modelling procedure based on the crystal structure of CD2. The V-type and C2-type domains in CD2 were separated, and the C2-type domain was duplicated five times to create a linear seven-domain starting model for CEA. A total of 28 complex-type oligosaccharide chains in extended conformations were added to this model. By fixing the six interdomain orientations to be the same, three-parameter searches of the rotational orientations between the seven domains gave 4056 possible CEA models. The best curve fits from these corresponded to a family of zig-zag models. The long axis of each domain was set at 160(+/-25) degrees relative to its neighbour, and the two perpendicular axes were orientated at 10(+/-30) degrees and -5(+/-35) degrees. Interestingly, the curve fit from this model is within error of that calculated from a CEA model generated directly from the CD2 crystal structure by the superposition of adjacent domains. Zig-zag models of this type imply that the protein face of the GFCC' beta-sheet in neighbouring CEA domains lie on alternate sides of the CEA structure. Such a model has implications for the adhesion interactions between CEA molecules on adjacent cells or for the antibody targeting of CEA.


Assuntos
Antígeno Carcinoembrionário/química , Oligossacarídeos/química , Sequência de Aminoácidos , Configuração de Carboidratos , Sequência de Carboidratos , Humanos , Imunoglobulinas/química , Modelos Moleculares , Dados de Sequência Molecular , Nêutrons , Conformação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Espalhamento de Radiação , Alinhamento de Sequência , Ultracentrifugação , Raios X
6.
J Nucl Med ; 37(5): 868-72, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8965166

RESUMO

UNLABELLED: Single-chain Fv (scFv) antibody fragments have potential for clinical imaging because of their rapid tumor penetration and high tumor-to-tissue ratios at early time points. ScFvs clear rapidly from the circulation so radiolabels such as 99mTc which have short half-lives are desirable, but the free thiol groups necessary for labeling with 99mTc are not normally found on these molecules. METHODS: We constructed a vector which enabled a free cysteine to be linked to the C-terminus of scFvs. MFE-23, a scFv directed against carcinoembryonic antigen (CEA), was cloned into this vector and cys-tagged MFE-23 was labeled with 99mTc using a D-glucarate transfer method. RESULTS: The radiolabeled product was stable in vivo and in vitro and showed favorable tumor-to-blood ratios in vivo at early time points (4:1 at 24 hr and 8:1 at 48 hr), although high kidney levels were also detected. CONCLUSION: Our study demonstrates an effective method to enable scFvs radiolabeling with 99mTc and also shows the potential of using a 99mTc-labeled scFv for clinical imaging studies.


Assuntos
Fragmentos de Imunoglobulinas , Radioimunodetecção , Tecnécio , Adenocarcinoma/diagnóstico por imagem , Animais , Neoplasias do Colo/diagnóstico por imagem , Humanos , Marcação por Isótopo , Camundongos , Transplante de Neoplasias , Distribuição Tecidual , Transplante Heterólogo , Células Tumorais Cultivadas
7.
Br J Cancer ; 73(2): 175-82, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8546903

RESUMO

Polyethylene glycol (PEG) modification of a chimeric Fab' fragment (F9) of A5B7 (alpha-CEA), using an improved coupling method, increases its specificity for subcutaneous LS174T tumours. PEGylation increased the area under the concentration-time curve (AUC0-144) in all tissues but there were significant differences (variance ratio test, F = 27.95, P < 0.001) between the proportional increases in AUC0-144, with the tumour showing the greatest increase. The increase in AUCtumour from F9 to PEG-F9 was similar to the reported increase from Fab' to F(ab')2 while the increase in AUCblood by PEGylation of F9 was only 21% of the reported increase from Fab' to whole IgG. A two sample t-test showed no significant differences between maximal tumour/tissue ratios for PEG-F9 and F9 while the tumour/tissue ratios for PEG-F9 remained high over a longer period, with tumour levels at least double those for F9. PEG-F9 emerges as a new generation antibody with potential advantages for both radioimmunotherapy and tumour imaging. Since there was a reduction in antigen binding, optimisation of PEGylation might further improve tumour specificity. The latter resulted from complex effects on both the entry into and exit rates from tumour and normal tissues in a tissue-specific fashion.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Antineoplásicos/metabolismo , Especificidade de Anticorpos/efeitos dos fármacos , Antígeno Carcinoembrionário/imunologia , Fragmentos Fab das Imunoglobulinas/metabolismo , Polietilenoglicóis/química , Sulfonas/química , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Animais , Anticorpos Antineoplásicos/efeitos dos fármacos , Sítios de Ligação de Anticorpos , Disponibilidade Biológica , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/imunologia , Modelos Lineares , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteínas Recombinantes de Fusão , Sulfonas/farmacologia , Distribuição Tecidual
8.
Int J Cancer ; 61(4): 497-501, 1995 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-7759155

RESUMO

Single-chain antibodies (scFvs) can be derived from a monoclonal antibody (MAb) or produced directly using filamentous phage technology, where antibodies with desired binding and purification characteristics can be readily selected from libraries. To test the hypothesis that the latter approach is more useful, we compared 2 anti-carcinoembryonic antigen (CEA) scFvs produced by these 2 different approaches. Our study showed that, both in the purification process and in the biodistribution pattern, MFE-23, produced by filamentous phage technology, gave favourable results compared to A5-SC, which is derived from the A5B7 MAb. This indicates the value of the filamentous phage approach for obtaining tumour-targeting scFvs.


Assuntos
Anticorpos Antivirais/isolamento & purificação , Anticorpos Antivirais/metabolismo , Bacteriófagos/metabolismo , Hibridomas/metabolismo , Região Variável de Imunoglobulina/biossíntese , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Bacteriófagos/imunologia , Antígeno Carcinoembrionário/imunologia , Cromatografia de Afinidade , Cromatografia em Gel , Clonagem Molecular , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Estabilidade de Medicamentos , Humanos , Hibridomas/imunologia , Iodo/farmacocinética , Radioisótopos do Iodo , Ponto Isoelétrico , Camundongos , Camundongos Nus , Cintilografia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Distribuição Tecidual , Transplante Heterólogo
9.
J Immunol Methods ; 179(1): 105-16, 1995 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-7868918

RESUMO

A new procedure is described for the purification of an anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), referred to as MFE-23, from bacterial supernatant. A simple insertion of a hexa-histidine tail fused at the C-terminus (MFE-23 His) provides an affinity tag which selectively binds to transition metal ions immobilised on an iminodiacetic acid (IDA) derivitised solid phase matrix. This method proved to be superior to standard CEA antigen affinity chromatography in the following ways. (1) A higher yield was produced (10 mg/l as opposed to 2.2 mg/l of bacterial supernatant). The latter figure was largely affected by the limited availability (size of the column) of immobilised CEA antigen. (2) Scale-up was relatively simple and less costly. (3) The risk of tumour derived antigen leaching from the column is eliminated. Results showed that immobilised Cu2+ ions were more effective than Ni2+ and Zn2+ ions in retaining the His tagged product giving a 90% pure product on elution. Clinical grade material was generated using size exclusion chromatography to remove aggregated material, and Detoxi gel to remove bacterial endotoxins. Validation assays to measure DNA, copper and endotoxins were performed to assess the levels of contaminants. MFE-23 His retained 84% antigen binding after 6 months storage at 4 degrees C and > 75% after radiolabelling. Further experiments confirmed that the His tail did not affect biodistribution and tumour localisation in nude mice bearing human colorectal tumour xenografts.


Assuntos
Cromatografia de Afinidade/métodos , Região Variável de Imunoglobulina/isolamento & purificação , Sequência de Aminoácidos , Animais , Sequência de Bases , Quelantes , Histidina/genética , Humanos , Região Variável de Imunoglobulina/química , Região Variável de Imunoglobulina/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação
10.
Br J Cancer ; 70(3): 521-5, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8080740

RESUMO

Studies in animal tumour models of colorectal cancer suggest that F(ab')2 antibody fragments to carcinoembryonic antigen (CEA) labelled with iodine-131 give superior therapy compared with intact anti-CEA antibody. The purpose of this study was to investigate this hypothesis in patients. Ten patients received intact A5B7 IgG1 mouse monoclonal antibody (MAb) to CEA and nine patients received the F(ab')2 fragment of the same antibody. The biodistribution for each molecule was compared using quantitative single-photon emission computerised tomographic (SPECT) gamma-camera imaging. Tumour responses were seen in both groups and myelosuppression was the limiting toxicity. F(ab')2 localised more rapidly than intact antibody in tumour, giving a mean percentage injected activity per kg at 4.25 h after injection of 8.2% for F(ab')2 compared with 4.4% for intact antibody (P < 0.05). No significant difference in antibody clearance from, or cumulative dose per unit administered activity (cGy MBq-1) to, tumour was seen. Distribution in blood was similar for both the intact and fragment antibody. These findings are consistent with more rapid penetration of the smaller F(ab')2 into tumour masses. More efficient early uptake will give higher maximum dose rates to the tumour which is valuable for radioimmunotherapy (RIT) when low dose rates may limit effectiveness of treatment. F(ab')2 fragments may provide a substantially enhanced method of delivering RIT.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/radioterapia , Imunotoxinas/metabolismo , Imunotoxinas/uso terapêutico , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Radioimunoterapia , Adulto , Idoso , Antígeno Carcinoembrionário/metabolismo , Antígeno Carcinoembrionário/uso terapêutico , Antígeno Carcinoembrionário/toxicidade , Feminino , Meia-Vida , Humanos , Fragmentos de Imunoglobulinas/metabolismo , Fragmentos de Imunoglobulinas/uso terapêutico , Fragmentos de Imunoglobulinas/toxicidade , Imunotoxinas/toxicidade , Radioisótopos do Iodo/toxicidade , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual
11.
Int J Cancer ; 57(6): 830-5, 1994 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-8206678

RESUMO

Radioimmunotherapy (RIT) is hampered clinically by poor tumour localization of antibody. In order to enhance localization we have investigated the concomitant use of RIT with 2 drugs, flavone-8-acetic acid (FAA) and its analogue 5,6-dimethylxanthenone-4-acetic acid (XAA), which both reduce tumour blood flow and induce immunomodulation. A single i.v. dose of 0.5 mCi (18.5 MBq) intact 131I anti-CEA antibody significantly delayed growth and prolonged survival over that of untreated controls, in an established LS174T colon xenograft model in nude mice. The adjuvant use of a single i.p. dose of either FAA or XAA, given 24 or 48 hr after 131I-A5B7 to allow maximum tumour levels of antibody to be attained before drug-induced blood-flow inhibition, significantly enhanced the RIT. FAA caused entrapment of antibody within the tumour in relation to the time allowed for localization before drug administration. Repeated doses of FAA prolonged tumour growth inhibition but did not enhance the therapy achieved after a single dose. Although both drugs alone induced massive tumour necrosis of all but a thin peripheral rim of viable cells, tumour regrowth was inhibited for a few days only, with no effect on survival. Drug-induced tumour necrosis, immunomodulation and retention of higher doses of 131I-A5B7 within the tumour may contribute to the enhanced RIT produced by this combined therapy.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Neoplasias do Colo/terapia , Flavonoides/uso terapêutico , Animais , Neoplasias do Colo/irrigação sanguínea , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fluxo Sanguíneo Regional/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Células Tumorais Cultivadas
12.
Int J Cancer ; 57(1): 67-72, 1994 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-8150543

RESUMO

A recombinant chimeric Fab (rcFab), with Fv derived from the monoclonal A5B7 antibody to carcinoembryonic antigen (CEA), and with human CHI and C kappa was cloned into pUC 19 and expressed in Escherichia coli. rcFab (10 to 12 mg per litre) was produced in bacterial culture fluid, and functional purified rcFab was isolated by affinity chromatography (using antibody to human C kappa) and size-exclusion gel filtration. The rcFab did not show reduced affinity for CEA, and reacted with human colorectal tumours showing a typical anti-CEA pattern by immunocytochemistry; it was also stable after iodination. Biodistribution studies in nude mice bearing human tumour xenografts showed no toxicity and good tumour localization. Therapeutic ratios at early time points were better than those obtained with whole murine antibody. The results demonstrate that bacterially produced anti-CEA Fab is of use for tumour targeting.


Assuntos
Adenocarcinoma/metabolismo , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Expressão Gênica/genética , Humanos , Regiões Constantes de Imunoglobulina/biossíntese , Regiões Constantes de Imunoglobulina/genética , Regiões Constantes de Imunoglobulina/metabolismo , Fragmentos de Imunoglobulinas/biossíntese , Região Variável de Imunoglobulina/biossíntese , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/metabolismo , Camundongos , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/biossíntese , Distribuição Tecidual , Transplante Heterólogo
13.
Int J Clin Pharmacol Ther Toxicol ; 29(10): 412-7, 1991 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-1748541

RESUMO

The first therapeutic trials to evaluate the treatment of climacteric symptoms by the administration of ovarian tissue were reported in 1896, i.e. before the endocrine function of the ovary was known or estrogens had been discovered. These were followed by investigations using various ovarian, placental and urine extracts, implantation of ovarian tissue and by oral treatment with dried ovarian tissue. However, reasonably acceptable hormonal drugs did not become available until the third decade of this century, while drugs meeting modern requirements, including that of oral activity, have been available only since the 1940s. It took at least 20 more years before publications for lay people and intensive endocrinological research convinced both the affected women and the medical profession of the value and even the necessity of hormonal treatment for ovarian-deficiency sequelae. Nowadays the treatment of climacteric and post-climacteric symptoms with estrogens and progestogens is a highly effective and indeed common practice. However, their use is of less value for the therapy of post-climacteric cardiovascular diseases and osteoporosis. As regards the latter, it may be said that androgenic-anabolic steroids and Org OD 14, a steroid related to norethynodrel, have usefully extended the available therapeutic armamentarium. Estrogens and progestogens are widely used for the prophylaxis of post-climacteric osteoporosis and cardiovascular diseases because their exceptional efficacy is well proven. Intensive research has resulted in the development of highly effective and virtually harmless hormonal drugs that are available in a great variety of formulations for all possible modes of administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Terapia de Reposição de Estrogênios , Anabolizantes/uso terapêutico , Androgênios/uso terapêutico , Climatério/efeitos dos fármacos , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Humanos , Menopausa/efeitos dos fármacos , Norpregnenos/uso terapêutico , Progestinas/uso terapêutico
14.
Maturitas ; 12(3): 163-70, 1990 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-2215268

RESUMO

Robert Wilson rendered women aged over 45 a great service. He provoked a line of research which has in 25 years resulted in a sensible approach towards the use of medication in treating the climacteric and post-menopausal oestrogen deficiency. The history of hormone replacement therapy (HRT) is described, as is the current approach to rational HRT. Some ideas are outlined for future development.


Assuntos
Terapia de Reposição de Estrogênios , Climatério/efeitos dos fármacos , Terapia de Reposição de Estrogênios/história , Feminino , História do Século XX , Humanos , Pessoa de Meia-Idade
15.
Clin Exp Immunol ; 78(2): 307-13, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12412766

RESUMO

When anti-tumour antibodies are given systematically for tumour imaging or therapy, second antibody directed against the first (anti-tumour) antibody can be used to accelerate clearance of first antibody, thus improving discrimination between tumour and normal tissues. Liposome-entrapped, and free second antibodies (LESA and FSA, respectively) have been compared in an animal tumour model system and in patients with cancer. Nude mice bearing xenografts of human colon carcinoma were given goat antibody to carcino-embryonic antigen (CEA) as first antibody and horse anti-goat second antibody. Patients with gastrointestinal carcinomas received i.v. 131I-labelled goat anti-CEA or mouse monoclonal 17-1A first antibody and unlabelled horse angi-goat or rabbit anti-mouse second antibody, respectively. Antibody distribution was studied by serial gamma camera imaging. The effectiveness of LESA and FSA depended on dose. Tumour-to-blood ratios were increased up to eight-fold by either method in animals. Tumour imaging was enhanced among 15 patients with gastrointestinal cancer and tumour was correctly identified at five sites where it was not seen by a background subtraction method. No significant toxicity occurred in patients nor in rabbits studied for evidence of immune complex mediated disease. LESA and FSA appear to be equally effective.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Antineoplásicos , Radioimunodetecção/métodos , Animais , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Antineoplásicos/efeitos adversos , Neoplasias Gastrointestinais/diagnóstico por imagem , Cabras , Cavalos , Humanos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Coelhos , Radioimunodetecção/efeitos adversos
16.
Br J Cancer ; 60(3): 406-12, 1989 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-2789951

RESUMO

The distribution of iodine-131 (131I) labelled antibody to carcinoembryonic antigen (CEA) has been studied in 16 patients with colorectal cancer. Levels of tumour and normal tissue radioactivity were measured by serial gamma-camera imaging and counting of blood and urine. Maximum concentrations were found in tumour 8 h after administration and varied up to 9-fold in different patients. Higher levels were found on average in tumour than in any other tissue. Liver, lung and blood were the other tissues in which antibody was concentrated relative to the rest of the body. Antibody cleared from all these tissues over 1 week. Second antibody directed against the antitumour (first) antibody was given 24 h after first antibody in order to accelerate clearance from the blood. This increased the tumour to blood ratio but had little effect on other tissues. Cumulative radiation dose to tumour and normal tissue was estimated. In patients with the most efficient localisation the tumour to body ratio was 20:1 and tumour to blood ratio 5:1. This may be sufficient for effective therapy of cancer in patients selected for efficient antibody localisation. The data may be used to estimate the effect of different therapeutic strategies. For instance, in the time after second antibody administration the average tumour to blood ratio of radiation dose was 11:1, suggesting that two phase systems in which the therapeutic modality is given after a good tumour to normal tissue ratio is obtained may be effective for the majority of patients.


Assuntos
Anticorpos Antineoplásicos/análise , Neoplasias do Colo/radioterapia , Radioisótopos do Iodo/uso terapêutico , Neoplasias Retais/radioterapia , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/diagnóstico por imagem , Humanos , Cintilografia , Dosagem Radioterapêutica , Neoplasias Retais/diagnóstico por imagem
17.
Int J Cancer ; 43(4): 713-8, 1989 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-2539334

RESUMO

Radioimmunotherapy in humans is limited by toxicity to normal tissues, caused by circulating radio-antibody. Second antibody directed against the first (anti-tumor) antibody accelerates clearance of first antibody from normal tissues, and may thus improve the therapeutic ratio. The effect of second antibody both on anti-tumor antibody distribution and on tumor and normal tissue radiation doses, has been investigated in nude mice bearing colonic tumor xenografts. Second antibody, given either 6 or 24 hr after the first, rapidly cleared circulating activity and reduced the calculated radiation dose to all tissues except the spleen, where it rose by 11 and 43% respectively. The dose received by the blood fell by 87% and 71%, while that to the tumor was reduced by 81% and 58%, after 6 or 24 hr second antibody. Administration of second antibody therefore improved the tumor to blood ratios. Tumor identification by gamma camera was greatly facilitated by the use of second antibody, and required no background subtraction. Results obtained from this system demonstrate the utility of second antibody in protecting normal tissues from prolonged circulating radioactivity during radioimmunotherapy.


Assuntos
Adenocarcinoma Mucinoso/terapia , Anticorpos Antineoplásicos/administração & dosagem , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/terapia , Modelos Animais de Doenças , Radioisótopos do Iodo/uso terapêutico , Adenocarcinoma Mucinoso/imunologia , Animais , Neoplasias do Colo/imunologia , Terapia Combinada , Relação Dose-Resposta Imunológica , Relação Dose-Resposta à Radiação , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fatores de Tempo , Transplante Heterólogo
19.
Maturitas ; Suppl 1: 39-49, 1988.
Artigo em Inglês | MEDLINE | ID: mdl-3237110

RESUMO

PIP: In Belgium, the contraceptive choices and views on completed family size were studied. The study involved a 2-page questionnaire; the 1st part was self-administered while the 2nd half of the questionnaire allowed for the physician to interview the respondents. The survey studied the demographic characteristics of the respondents and the relationship of these characteristics to contraceptive choice, family size and possible future choice in contraception. Demographic information assayed included age and occupation and religion of the respondent and the number of unplanned children. 235 of the 359 respondents (2/3) considered their family complete. 70% of those surveyed used some form of contraception with oral contraceptives and female sterilization being the most popular currently used methods and oral contraceptives and condoms being the most popular ever used method. Motivations for contraceptive choice were also evaluated (family health, age, socioeconomic conditions, etc). Although a large number of unplanned pregnancies were reported, they were not necessarily unwanted. The failure a contraceptive method may account for this. Over 80% of those surveyed had used oral contraceptives at some time. Although the couples agreed on family size, the reasoning behind their decision was obtuse and not well planned. Sterilization created mixed emotions among both partners. Its popularity stems from the standard recommendation of discontinued use of oral contraceptives after age 35. However, doctors need to be considerate of the ambivalent feelings of their patients and recommend choices that leave options open without presenting health risks.^ieng


Assuntos
Comportamento de Escolha , Anticoncepção , Características da Família , Adulto , Bélgica , Feminino , Humanos , Masculino
20.
NCI Monogr ; (3): 59-61, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3493442

RESUMO

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.


Assuntos
Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/radioterapia , Neoplasias Retais/radioterapia , Animais , Humanos , Radioisótopos do Iodo/sangue , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/urina , Camundongos , Camundongos Nus , Transplante de Neoplasias , Radioterapia/métodos
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