Avaliação das proteínas reguladoras do ciclo celular e apoptose nos Linfomas não-Hodgkin agressivos e influência na resposta ao tratamento / Evaluation of cell cycle and apoptosis-regulating proteins in aggressive non-Hodgkin's lymphomas and influence in response to treatment

RESUMO

Os linfomas não-Hodgkin (LNH) agressivos constituemum grupo heterogêneo de neoplasias hematológicas.Os LNH difusos de grandes células B compreendem cercade 20-25% dos LNH. O tratamento quimioterápico podecurar apenas 40%-50% dos pacientes adultos com linfomasagressivos. São considerados indicadores prognósticos:idade, número de sítios extranodais, LDH, performancestatus e estadiamento clínico.Além desses fatores, anormalidades das proteínasreguladoras do ciclo celular e da apoptose parecem ser umimportante mecanismo de desenvolvimento de neoplasiase podem ter um papel no prognóstico dos linfomas agressivos.A expressão das proteínas reguladoras do ciclo celular,p...Avaliamos também a expressão de proteínas reguladorasda apoptose (p53, Bcl-2, Bax, Bak e Mcl-1) de 33pacientes com LNH difusos de grandes células B e analisamosa relação entre a expressão dessas proteínas comdados clínicos e resposta à quimioterapia.Nossos resultados mostraram que a expressão dap53 foi considerada um parâmetro imunohistoquímico independenterelacionado a um pior prognóstico nesseslinfomas. Apesar da alta expressão observada das proteínasBcl-2, Bax, Bak e Mcl-1, não foi encontrado associaçãocom prognóstico ou resposta ao tratamento.

ABSTRACT

Aggressive non-Hodgkin’s lymphomas (NHL) forma heterogeneous group in terms of clinical presentation,histology, immunophenotype, response to treatment andprognosis. Diffuse large B-cell NHL (DLCL) constitute upto 20-25% of NHL in many series. Combinationchemotherapy may cure 40-50% of adult patients. Severalclinical prognostic factors have been described to predictclinical outcome, as age, LDH, performance status andstage and are useful for identifying high-risk patients, whowould benefit from a more intensive approach.Abnormalities of cell cycle and apoptosis regulatingproteins seem to be an important mechanism oftumorigenesis and may play a role in the prognosis ofaggressive NHL.The expression of p53, p21/WAF-1, Mdm2 , c-Mycand proliferating cell nuclear antigen (PCNA) proteins wereexamined by the immunohistochemistry of paraffinembedded samples of 113 high grade non-Hodgkin’slymphomas (NHL) and in 62 patients with aggressive NHLcorrelated to clinical data. Expression of p53, ....NHL patients with a hyper-expression of p53 protein(n=17). DNA extraction was performed in 15 patients andPCR amplification of exons 5-9 was possible in 7 cases.We found a point mutation in exon 6 (Val→Glu;T→A), ina patient with a p53 hyper-expression and p21 negativeexpression.We also evaluated the expression of apoptosisregulatingproteins (p53, Bcl-2, Bax, Bak and Mcl-1) ofparaffin-embedded samples of 33 patients with diffuse largeB-cell NHL, and assessed the relationship of these proteinsto clinical outcome and response to chemotherapy.Our results showed that p53 expression was anindependent immunohistochemical parameter related to apoor prognosis in these lymphomas. Bcl-2, Bax, Bak andMcl-1 proteins, though highly expressed in almost all caseswere not associated with prognosis or response totreatment.