RESUMEN
Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor alpha accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor alpha pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/antagonistas & inhibidores , Bencenosulfonatos/uso terapéutico , Investigación Biomédica/tendencias , Inhibidores Enzimáticos/química , Everolimus , Humanos , Indoles/uso terapéutico , Modelos Biológicos , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Transducción de Señal , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/fisiologíaRESUMEN
Metastatic renal cell carcinoma (RCC) has historically been refractory to cytotoxic and hormonal agents; only interleukin 2 and interferon alpha provide response in a minority of patients. We reviewed RCC biology and explored the ways in which this understanding led to development of novel, effective targeted therapies. Small molecule tyrosine kinase inhibitors, monoclonal antibodies and novel agents are all being studied, and phase II studies show promising activity of sunitinib, sorafenib and bevacizumab. The results of phase III studies will determine the role of these agents in metastatic RCC.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados , Bencenosulfonatos/uso terapéutico , Bevacizumab , Carcinoma de Células Renales/secundario , Ensayos Clínicos como Asunto , Humanos , Indoles/uso terapéutico , Neoplasias Renales/patología , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Sorafenib , SunitinibRESUMEN
The BCL6 gene codes for a zinc-finger transcription factor and is involved in chromosomal rearrangements in 30-40% of diffuse large-cell lymphoma (DLCL). These rearrangements cluster within the 5' regulatory region of BCL6 spanning its first non-coding exon. To determine the functional consequences of these alterations, we have analyzed the structure of the rearranged BCL6 alleles and their corresponding RNA and protein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobulin heavy-chain (IgH) loci. In all three cases, the breakpoints were mapped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons. An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL6 transcripts which initiated from IgH germline transcript promoters (I mu or I gamma 3), but retain a normal BCL6 coding domain. In the tumor cell line, the chimeric I gamma 3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 protein. These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 protein.
Asunto(s)
Proteínas de Unión al ADN/genética , Linfoma de Células B/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Translocación Genética , Alelos , Secuencia de Bases , Quimera/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 3/genética , Clonación Molecular , Cartilla de ADN/genética , ADN Complementario/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Genes de Inmunoglobulinas , Humanos , Linfoma de Células B Grandes Difuso/genética , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-bcl-6 , Células Tumorales CultivadasRESUMEN
The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.
Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Proto-Oncogenes/genética , Dedos de Zinc/genética , Secuencia de Aminoácidos , Línea Celular , Cromosomas Humanos Par 3 , ADN Complementario , Proteínas de Unión al ADN/genética , Exones , Reordenamiento Génico , Humanos , Intrones , Datos de Secuencia Molecular , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Homología de Secuencia de Aminoácido , Factores de Transcripción/genética , Translocación GenéticaRESUMEN
Literature pertaining to genetic epidemiological studies of familial cancer has been reviewed from a historical perspective. Although interest in the question of heritability of cancer was extant at least as early as the beginning of the nineteenth century, early investigators were unable to produce consistent and meaningful evidence pertaining to the issue because of unsystematic methods of data collection and inadequate methods of data analysis. During the early twentieth century, developments in the fields of genetics, statistics, and epidemiology provided concepts and methods that permitted investigators to recognize important deficiencies in past studies, and to design others in which the critical comparisons could be made between patient groups and control groups. Registries of cancer incidence in large populations became available in several countries in the middle twentieth century, providing a standard "control group" for comparison. Large surveys of site-specific cancer experience in families, rigorously designed and analyzed, found for most kinds of cancers a two- to threefold increased risk for close relatives of propositi. These studies also reemphasized the great difficulty in obtaining even minimally complete family health history information, and the importance of verifying all reported cases with medical or vital records. Although clinical and laboratory investigation will be necessary to understand the mechanisms by which human genes may predispose to cancer, epidemiological approaches can estimate the extent to which genetic etiological factors may be present in a population, whether a general population or one defined by other factors under investigation. Population-based studies are already of practical significance to the clinical geneticist in the estimation of risk of eventual cancer development in unaffected family members, and can be expected to continue to identify specific groups and characteristics associated with genetic cancer predisposition. Finally, segregation and linkage analysis and their present applications to family studies of cancer were reviewed. As a result of the increasing number of DNA polymorphisms that are becoming available due to developments in molecular biology, the human gene map can be expected to be well defined in the near future, and investigation of families using segregation and linkage analysis will then be instrumental in defining the role of heredity in the development of cancer in human populations.