RESUMEN
Recently, it has been demonstrated that the Arg399Gln substitution in the XRCC1 gene is associated with increased levels of markers of DNA damage. Deficiency in DNA repair pathways has been shown to confer to resistance to several drugs, including platinum compounds. Here we have studied whether this polymorphism of the XRCCI gene will predict response and survival of patients with metastatic colorectal cancer treated with oxaliplatin and 5-FU. Sixty-one patients received a combination of 130 mg/m2 oxaliplatin and continuous infusion 5-FU. The XRCC1 polymorphism was evaluated using a RFLP method. We found 73% (8/11) of responders had an Arg/Arg genotype and three were heterozygous, but 66% (33/50) of non-responders showed a Gln/Gln or Gln/Arg genotype (p=0.038). Patients carrying at least one Gln mutant allele were at a 5.2 (95%CI: 1.21,22.07) fold increased risk to fail the 5-FU/oxaliplatin chemotherapy. The data suggest that the polymorphism in exon 10 of the XRCC1 gene may be associated with resistance to oxaliplatin/5-FU chemotherapy in advanced colorectal cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Polimorfismo Genético , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Camptotecina/administración & dosificación , Codón/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Femenino , Fluorouracilo/administración & dosificación , Genotipo , Humanos , Irinotecán , Tablas de Vida , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Supervivencia , Resultado del Tratamiento , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.