RESUMEN
For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments reveal that AdRGD-PGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGD-PGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel thus avoiding leukopenia, yet still showed potent anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma.
Asunto(s)
Genes p53/genética , Neoplasias de la Próstata/terapia , Taxoides/farmacología , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia sin Enfermedad , Quimioterapia Combinada/métodos , Regulación Neoplásica de la Expresión Génica/genética , Genes p53/inmunología , Terapia Genética/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Taxoides/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Trichomonas gallinae and Tritrichomonas foetus are flagellated parasitic protozoa of the upper digestive tract of birds and the urogenital tract of cattle, respectively. Both of these species are important in the veterinary field, due to the fact that they cause significant economic losses. Therefore, we investigated the morphology of these parasites by studying microtubule cytoskeleton organization. FLUTAX-2, an active fluorescent derivative of Taxol, was used in this study. This fluorescent taxoid binds to polymerized alphabeta-tubulin dimers. Our results showed that FLUTAX-2 was able to bind to and stabilize microtubules of intact T. gallinae and T. foetus trophozoites, allowing the microtubular cytoskeleton to be easily observed by fluorescence microscopy. T. foetus and T. gallinae had no differences in their FLUTAX-2 binding profiles. Further studies may allow this technique to be improved, and it may possibly be used as a routine laboratory method for the diagnosis of avian and bovine trichomonosis.