Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
J Clin Oncol ; 19(6): 1658-63, 2001 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11250994

RESUMO

PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.


Assuntos
Antineoplásicos/efeitos adversos , Quimioprevenção , Surdez/induzido quimicamente , Adulto , Fatores Etários , Idoso , Animais , Audiometria , Surdez/prevenção & controle , Humanos , Pessoa de Meia-Idade , Monitorização Fisiológica , Neoplasias/prevenção & controle , Seleção de Pacientes , Guias de Prática Clínica como Assunto
4.
Ann N Y Acad Sci ; 952: 88-108, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11795446

RESUMO

Chemoprevention science is in flux owing to rapid advances in postgenomic technology. We have witnessed enormous advances in the areas of early detection and molecular profiling of colorectal carcinogenesis; however, unique interpretive and technologic challenges persist. Neoplastic hallmarks must be iteratively tested and validated as markers of risk, targets for intervention, and/or markers of response in order to expedite the development of preventive interventions. In this review, we highlight several of the technologies that are revolutionizing our understanding of carcinogenesis and our approach to colorectal cancer prevention.


Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Adenocarcinoma/diagnóstico , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Adenoma/etiologia , Adenoma/genética , Adenoma/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores , Cálcio/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/uso terapêutico , Diagnóstico por Imagem , Progressão da Doença , Desenho de Fármacos , Sinergismo Farmacológico , Eflornitina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Ácido Fólico/uso terapêutico , Previsões , Genes APC , Humanos , Isoenzimas/antagonistas & inibidores , Proteínas de Membrana , Camundongos , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Inibidores da Ornitina Descarboxilase , Prostaglandina-Endoperóxido Sintases , Proteoma , Risco
5.
Curr Oncol Rep ; 2(3): 242-50, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-11122849

RESUMO

Biomarkers are routinely applied in the management of chronic diseases to reduce morbidity and mortality through early diagnosis, as well as to assess the necessity for, and responsiveness to, applied interventions. Biomarkers yield mechanistic insights into layers of biologic organization from molecule to organelle, to cell, and finally to cellular organization and tissue. A step-wise approach to the development of tissue-based biomarkers is presented. These biomarkers may serve as molecular targets for scientific inquiry and intervention, as well as approvable endpoints for clinical trials.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias/diagnóstico , Neoplasias/prevenção & controle , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Prevenção Primária/métodos , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade
6.
Int J Oncol ; 17(4): 643-51, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10995873

RESUMO

We determined the efficacy of HB21(Fv)PE40, a single-chain immunotoxin made by fusing the variable regions of a monoclonal antibody directed at the human transferrin receptor (TfR) with a truncated mutant of Pseudomonas exotoxin (PE), against metastatic human colon carcinoma KM12L4 cells growing in the liver or subcutis of nude mice. Organ-specific modulation of TfR expression was examined by immunohistochemistry and flow cytometry using anti-human CD71 antibody. KM12L4 cells expressed human TfR and were lysed in vitro by HB21(Fv)PE40 but not LMB-7 (a control immunotoxin specific for a Lewis Y-related carbohydrate antigen). KM12L4 cells growing in the liver expressed higher levels of TfR than cells growing s.c. Systemic administration of HB21(Fv)PE40 eliminated KM12L4 liver metastasis, whereas administration of LMB-7 did not. Treatment of mice with HB21(Fv)PE40 only delayed the growth of s.c. tumors. KM12L4 cells recovered from liver metastases, expressed higher levels of TfR, and were more sensitive to lysis by HB21(Fv)PE40 than KM12L4 cells recovered from s.c. tumors. Indeed, collectively, the data show that the expression level of the TfR by human colon cancer cells is modulated by the organ microenvironment which can be advantageous for the use of therapeutic immunotoxins.


Assuntos
Neoplasias do Colo/metabolismo , Imunotoxinas/uso terapêutico , Neoplasias Experimentais/prevenção & controle , Receptores da Transferrina/biossíntese , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos B/análise , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Humanos , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/imunologia , Imuno-Histoquímica , Imunotoxinas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores da Transferrina/genética , Receptores da Transferrina/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Transplante Heterólogo , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Immunother ; 23(4): 473-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10916757

RESUMO

Mesothelin, a differentiation antigen, is a 40-kD glycosylphosphatidylinositol-linked cell-surface glycoprotein, that is present on the surface of normal mesothelium and is overexpressed in many patients with epithelial ovarian cancer and malignant mesotheliomas. Monoclonal antibody K1 is a murine immunoglobulin G1 that recognizes mesothelin. LysPE38QQR is a truncated form of Pseudomonas exotoxin that lacks the cell-binding domain, but retains the translocation and adenosine diphosphate-ribosylation domains. It has a single lysine residue near the amino terminus that is available for conjugation to antibodies. To prevent chemical conjugation of the antibody to lysine residues at the C-terminus of Pseudomonas exotoxin, the two lysine residues at positions 590 and 606 were mutated to glutamine, and the lysine residue at position 613 was mutated to arginine. Monoclonal antibody K1 was chemically conjugated with LysPE38QQR, by modifying the antibody with sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate and coupling it with SPDP N-succinimidyl 3-(2-pyridyldithio)propionate-modified LysPE38QQR. The resulting immunotoxin K1-LysPE38QQR was highly toxic to A431-K5 cells (a human epidermoid carcinoma cell line transfected with a mesothelin expression plasmid) with a half-maximal inhibitory concentration of 3-6 ng/mL. The immunotoxin had negligible activity against A431 cells, which do not express mesothelin (median inhibitory concentration > 100 ng/mL). This immunotoxin also caused complete regression of tumors in nude mice that received xenografts of mesothelin-positive human carcinomas. These results show that immunotoxins directed against mesothelin are a therapeutic option that merits further investigation for the treatment of ovarian cancer and malignant mesotheliomas.


Assuntos
ADP Ribose Transferases , Toxinas Bacterianas , Exotoxinas/imunologia , Exotoxinas/uso terapêutico , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/uso terapêutico , Mesotelioma/imunologia , Mesotelioma/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Fatores de Virulência , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/isolamento & purificação , Antígenos de Neoplasias/uso terapêutico , Exotoxinas/genética , Exotoxinas/isolamento & purificação , Feminino , Proteínas Ligadas por GPI , Humanos , Imunotoxinas/imunologia , Imunotoxinas/isolamento & purificação , Imunotoxinas/uso terapêutico , Glicoproteínas de Membrana/isolamento & purificação , Mesotelina , Camundongos , Camundongos Nus , Mutação , Células Tumorais Cultivadas , Exotoxina A de Pseudomonas aeruginosa
8.
J Nutr ; 130(2S Suppl): 467S-471S, 2000 02.
Artigo em Inglês | MEDLINE | ID: mdl-10721931

RESUMO

Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention.


Assuntos
Quimioprevenção/tendências , Dieta , Neoplasias/prevenção & controle , Biomarcadores , Humanos , Farmacocinética
9.
Ann N Y Acad Sci ; 889: 1-13, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10668477

RESUMO

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/patologia , Neoplasias/prevenção & controle , Animais , Humanos , Camundongos , Metástase Neoplásica/prevenção & controle , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle
10.
Proc Natl Acad Sci U S A ; 95(2): 669-74, 1998 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-9435250

RESUMO

Mesothelin is a differentiation antigen present on the surface of ovarian cancers, mesotheliomas, and several other types of human cancers. Because among normal tissues, mesothelin is present only on mesothelial cells, it represents a good target for antibody-mediated delivery of cytotoxic agents. In the present study mice were immunized with an eukaryotic expression vector coding for mesothelin. When high serum antibody titers were obtained, a phage display library was made from the splenic mRNA of these mice. After three rounds of panning on recombinant mesothelin, a single-chain Fv (scFv)-displaying phage was selected that bound specifically to recombinant mesothelin and mesothelin-positive cells. The scFv was used to construct an immunotoxin by genetically fusing it with a truncated mutant of Pseudomonas exotoxin A. The purified immunotoxin binds mesothelin with high affinity (Kd 11 nm), is stable for over 40 hr at 37 degrees C and is very cytotoxic to cells expressing mesothelin. It also produces regressions of tumors expressing mesothelin. This combination of selective cytotoxicity, high activity, and stability makes the immunotoxin a good candidate for development as a therapeutic agent. This work also shows that DNA immunization can be used to isolate and clone antibodies against epitopes present on human proteins in their native conformation.


Assuntos
Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , DNA/imunologia , Exotoxinas , Região Variável de Imunoglobulina/imunologia , Imunotoxinas/imunologia , Glicoproteínas de Membrana/imunologia , Animais , Antígenos de Neoplasias/genética , Feminino , Proteínas Ligadas por GPI , Biblioteca Gênica , Humanos , Imunização , Região Variável de Imunoglobulina/genética , Glicoproteínas de Membrana/genética , Mesotelina , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...