RESUMEN
PURPOSE: MicroRNAs (miRNAs) are small, noncoding RNA molecules that can be down- or upregulated in colorectal cancer and have been associated to prognosis and response to treatment. We studied miRNA expression in tumor biopsies of patients with rectal cancer to identify a specific "signature" correlating with pathological complete response (pCR) after neoadjuvant chemoradiotherapy. METHODS AND MATERIALS: A total of 38 T3-4/N+ rectal cancer patients received capecitabine-oxaliplatin and radiotherapy followed by surgery. Pathologic response was scored according to the Mandard TRG scale. MiRNA expression was analyzed by microarray and confirmed by real-time Reverse Transcription Polymerase Chain Reaction (qRT-PCR) on frozen biopsies obtained before treatment. The correlation between miRNA expression and TRG, coded as TRG1 (pCR) vs. TRG >1 (no pCR), was assessed by methods specifically designed for this study. RESULTS: Microarray analysis selected 14 miRNAs as being differentially expressed in TRG1 patients, and 13 were confirmed by qRT-PCR: 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909∗, miR-630, miR-765) were significantly upregulated in TRG1 patients, 2 (miR-1274b, miR-720) were downexpressed. MiR-622 and miR-630 had a 100% sensitivity and specificity in selecting TRG1 cases. CONCLUSIONS: A set of 13 miRNAs is strongly associated with pCR and may represent a specific predictor of response to chemoradiotherapy in rectal cancer patients.
Asunto(s)
Quimioradioterapia Adyuvante/métodos , MicroARNs/análisis , Terapia Neoadyuvante/métodos , ARN Neoplásico/análisis , Neoplasias del Recto/genética , Neoplasias del Recto/terapia , Adulto , Anciano , Antineoplásicos/uso terapéutico , Biopsia , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias del Recto/patología , Recto/química , Recto/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sensibilidad y EspecificidadRESUMEN
Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Brostallicin has a peculiar mechanism of action involving activation upon binding to glutathione (GSH) catalyzed by glutathione-S-transferase (GST). As a consequence, cells expressing relatively high GST/GSH levels are more susceptible to treatment with brostallicin. Considering that increased levels of GST/GSH are often found in human tumors, this could represent an advantage for the drug in the clinic. Initial clinical studies indicate the tolerability of the drug and allow the determination of the optimal dose for subsequent studies. Some partial response were obtained in these initial phase I studies. Altogether, the results suggest brostallicin to be a new promising anticancer agent with a new mechanism of action. It also raises the possibility to use it in combination with other anticancer drugs currently used.
Asunto(s)
Alquilantes/uso terapéutico , Antineoplásicos/uso terapéutico , Distamicinas/uso terapéutico , Alquilantes/farmacocinética , Alquilantes/toxicidad , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Ensayos Clínicos Fase I como Asunto , ADN/efectos de los fármacos , Distamicinas/farmacocinética , Distamicinas/toxicidad , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Glutatión/química , Glutatión/metabolismo , Glutatión Transferasa/química , Glutatión Transferasa/metabolismo , Guanidinas/administración & dosificación , Guanidinas/farmacocinética , Guanidinas/uso terapéutico , Guanidinas/toxicidad , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Pirroles/administración & dosificación , Pirroles/farmacocinética , Pirroles/uso terapéutico , Pirroles/toxicidadRESUMEN
Brazil. Iron deficiency and ferropenic anemia are, certainly, the most prevalent and specific nutritional problems in Brazil. The Ribeirao Preto region is no exception to it. A large prevalence of iron deficiency/anemia is found, mainly in the age group 6-24 months. In spite of the fact that several aspects of its physiopathology are known is a very difficult problem to be solved. Many approaches and alternatives for thheir prevention have been tried but we are far from controlling the situation. Several studies carried out at the Medical School of Ribeirao Preto, University of Sao Paulo, Brazil have shown this high incidence of iron deficiency and iron anemia among infants and preshool children. The importance of iron supplementation to preterm, premature and normal infants was pointed out. The possibility of use of iron complexes to prevent iron deficiency, besides the usual ferrous sulfate, was shown. Several community studies proved the feasibility of distribution and intake of iron as supplements or carriers as alternatives to prevent iron deficiency