RESUMEN
Epirubicin is a cytotoxic drug used in the treatment of different types of cancer and increasing evidence suggests that its target is cell membranes. In order to gain insight on its toxic effects, intact red blood cells (RBC), human erythrocyte membranes and molecular models were used. The latter consisted in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes found mainly in the outer and inner monolayers of the human erythrocyte membrane, respectively. The results obtained by X-ray diffraction displayed that epirubicin induced structural perturbations in multilayers of DMPC. Differential scanning calorimetry (DSC) showed that epirubicin disturbed the thermotropic behavior of both DMPC and DMPE vesicles, whereas fluorescence spectroscopy demonstrated alterations in the fluidity of DMPC vesicles and the erythrocyte membrane. Scanning electron microscopy (SEM) revealed that epirubicin changed the normal discoid form of RBC to echinocytes and stomatocytes. Electron paramagnetic resonance (EPR) disclosed that this drug induced conformational changes in the erythrocyte membrane proteins. These findings demonstrate that epirubicin interacts with lipids and proteins of the human erythrocyte membrane, effects that might compromise the integrity and function of cell membranes. This is the first time that its toxic effects on the human erythrocyte membrane have been described.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Epirrubicina/toxicidad , Eritrocitos/efectos de los fármacos , Rastreo Diferencial de Calorimetría , Células Cultivadas , Dimiristoilfosfatidilcolina , Eritrocitos/patología , Eritrocitos/ultraestructura , Humanos , Liposomas , Microscopía Electrónica de Rastreo , Fosfatidiletanolaminas , Difracción de Rayos XRESUMEN
The genotoxic effects of the anthracycline doxorubicin (DOX) and two of its analogues, epirubicin (EPI) and pirarubicin (THP) were studied using the wing Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. These compounds are classified as topoisomerase II (topo II) poisons, acting by stabilizing a topoisomerase II-cleaved DNA complex. Using the standard version of the SMART test it was possible to estimate the quantitative and qualitative genotoxic effects of these compounds, comparing the wing spot frequencies in marker- and balancer-heterozygous flies. The results obtained indicate that all three compounds induce a high frequency of spots related to homologous recombination (HR), which is the major event responsible for their genetic toxicity. Pirarubicin was the most genotoxic anthracycline, inducing approximately 21 times more genetic lesions than doxorubicin, probably due to the presence of a second sugar ring in the amino sugar moiety in its chemical structure. Although the only difference between epirubicin and doxorubicin is the steric position of the amino sugar 4'-OH in the molecule, epirubicin is approximately 1.6 times as genotoxic as doxorubicin.
Asunto(s)
Doxorrubicina/análogos & derivados , Doxorrubicina/toxicidad , Epirrubicina/toxicidad , Mutágenos/toxicidad , Animales , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Pruebas de Mutagenicidad , Recombinación Genética/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Com o objetivo de avaliar a eficácia e a toxicidade da 4'-epirubicina em poliquimioterapia no tratamento de linfomas näo-Hodgkin de alto grau, foram estudados 14 pacientes, sendo nove do sexo masculino e cinco do sexo feminino. A idade mediana dos homens foi de 52 anos e das mulheres, 32 anos. Linfoma histiocítico difuso foi o diagnóstico mais freqüente, representando 50 por cento dos casos. Nove oacientes haviam sido submetidos à cirurga antes do tratamento e um paciente foi submetido à radioerapia antes do início da quimioterapia. Dos 14 pacientes avaliáveis, 10 apresentaram resposta completa (91 por cento) e um apresentou resposta parcial (9 por cento). Dois pacientes faleceram durante o tratamento quimioterápico e um abandonou o tratamento por toxicidade. A duraçäo mediana da resposta foi de 17 meses após o início do tratamento. Com relaçäo à toxicidade, mucosite foi o sintoma mais freqüente, sendo observada em oito pacientes (73 por cento); náuseas e vômitos foram observados em três pacientese diarréia e alopecia, cada uma, em dois pacientes. Quatro pacientes apresentaram contagem plaquetária inferior a 150.000 plaquetas/mm3; nenhum paciente apresentou contagem leucocitária inferior a 2.000 leucócitos/mm3. Concluímos que este protocolo 4'epi é altamente eficaz no tratamento dos L.N.H. de alto grau, embora apresente expressiva toxicidade