RESUMO
Various studies suggested that cytotoxicity induced by 5-fluorouracil (5-FU) is an apoptotic mechanism possibly mediated by the Fas/FasL system. In this preliminary work, we studied retrospectively the role the Fas/FasL expression as a predictive response factor with fluoropyrimidine-based chemotherapies. We developed a real-time PCR method for measuring Fas and FasL expression in various biopsies from patients treated with a FUFOL-like protocol. No correlation was found between Fas or FasL expression and overall survival or partial response. However, the PCR assay was simple and convenient to use for quantitation of Fas/FasL in tumor biopsies.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Glicoproteínas de Membrana/metabolismo , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , DNA Complementar/genética , Proteína Ligante Fas , Feminino , Fluoruracila/efeitos adversos , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Estudos RetrospectivosRESUMO
We report the first mutational study of thymidine kinase 1 (TK1) performed in human solid tumors. We sequenced cDNAs representing the complete coding region of TK1 in human breast (n=22) and colorectal (n=26) cancer. Codon 106 near the ATP binding site constantly differed (ATG --> GTG; Met --> Val) from the one deposited by Bradshaw and Deininger in the Genbank database (Accession number NM_003258). Silent polymorphisms at codon 11 (CCC --> CCT; Pro --> Pro) and codon 75 (GCG --> GCA; Ala --> Ala) were frequently detected in tumors as well as in normal tissues. In breast cancer the two polymorphisms were observed in 63.6% of the samples analyzed. No significant association could be found between polymorphisms and TK activity. In colorectal cancer the incidence of the two changes was 73.1% and 69.2%, respectively. Interestingly, one colon cancer with high cytosolic TK activity displayed two missense mutations located in and near the putative phosphorylation site by tyrosine kinase (s) (TAT --> CAT; Tyr --> His) and by cAMP-, cGMP-dependent protein kinase (TAC --> TGC; Tyr --> Cys), respectively; adjacent normal mucosa showed no mutation. This may open new avenues that imply TK1 activity in tumor cell proliferation.