RESUMEN
Anthracyclines are frequently used in the adjuvant setting for breast cancer treatment since it is considered that anthracycline-based chemotherapy treatment benefits breast cancer patients. Nonetheless, these drugs are associated with severe side effects and predictive factors, for sensitivity to anthracyclines, are warranted in clinical practice. Topoisomerase 2 alpha (TOP2A) is considered to be the molecular target of these drugs. The potential predictive value of TOP2A amplification and overexpression has been extensively studied in breast cancer patients treated with anthracyclines. However, results are not conclusive. In this paper, we review some of the published studies addressing the predictive value of TOP2A as well as the cellular functions of this enzyme and its status in breast cancer tissue.
Asunto(s)
Antraciclinas/uso terapéutico , Antígenos de Neoplasias/fisiología , ADN-Topoisomerasas de Tipo II/fisiología , Proteínas de Unión al ADN/fisiología , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/uso terapéutico , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/fisiología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/diagnóstico , Carcinoma/tratamiento farmacológico , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Modelos Biológicos , Proteínas de Unión a Poli-ADP-Ribosa , Valor Predictivo de las Pruebas , Pronóstico , Resultado del TratamientoRESUMEN
Therapy-related leukaemias are becoming an increasing healthcare problem as more patients survive their primary cancers. The nature of the causative agent has an important bearing upon the characteristics, biology, time to onset and prognosis of the resultant leukaemia. Agents targeting topoisomerase II induce acute leukaemias with balanced translocations that generally arise within 3 years, often involving the MLL, RUNX1 and RARA loci at 11q23, 21q22 and 17q21 respectively. Chromosomal breakpoints have been found to be preferential sites of topoisomerase II cleavage, which are believed to be repaired by the nonhomologous end-joining DNA repair pathway to generate chimaeric oncoproteins that underlie the resultant leukaemias. Therapy-related acute myeloid leukaemias occurring after exposure to antimetabolites and/or alkylating agents are biologically distinct with a longer latency period, being characterised by more complex karyotypes and loss of p53. Although treatment of therapy-related leukaemias represents a considerable challenge due to prior therapy and comorbidities, curative therapy is possible, particularly in those with favourable karyotypic features.
Asunto(s)
Leucemia Mieloide Aguda/genética , Neoplasias Primarias Secundarias/genética , Animales , Antineoplásicos Alquilantes/efectos adversos , Rotura Cromosómica/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo II/fisiología , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Modelos Biológicos , Biología Molecular , Neoplasias Primarias Secundarias/inducido químicamenteRESUMEN
The importance of the DNA structure for the expression of the osmotic response (osmotolerance) was investigated in Bacillus subtilis 168. Plasmid pUB110 DNA was used as a reporter of the chromosomal DNA topology, and analyses were performed in chloroquine agarose gels. Plasmidic DNA obtained from cultures in Schaeffer medium (D) taken in those periods in which B. subtilis is able to express osmotolerance (early stationary phase or from germinating spores) or from adapted cultures to hyperosmotic medium (DN) presented a higher level of negative supercoiling than DNA samples from vegetative cultures, normally refractory to induction of osmotolerance. The involvement of the DNA gyrase was investigated through the sensitivity to novobiocin, an antibiotic inhibitor of its activity and the behavior of a gyrB1 mutant strain (RG1). In the wild-type strain, the addition of a sublethal concentration of novobiocin (0.5 microg/ml) to the hyperosmotic medium relaxed DNA and inhibited growth. Moreover, already growing cultures in DN medium and later submitted to the same antibiotic presented a relaxed DNA and stopped growing. The RG1 mutant strain submitted to similar novobiocin treatments displayed normal growth in DN novobiocin medium. These results pointed to the requirement of a highly negative supercoiled DNA structure involving the gyrase activity in osmotic response.