RESUMEN
BACKGROUND: Topotecan, a topoisomerase I inhibitor, acts by stabilizing the topoisomerase DNA cleavage complex. Etoposide, a topoisomerase II inhibitor, mediates antitumor activity by stabilizing cleavage complex formed between topoisomerase II and DNA. These two agents have therapeutic activity in non-Hodgkin lymphoma. The authors report Phase I data of topotecan and etoposide combination for patients with recurrent or refractory non-Hodgkin lymphoma and correlation of topoisomerase-DNA complex formation to clinical response. METHODS: Twenty-two patients with recurrent or refractory aggressive non-Hodgkin lymphoma were treated at four dose levels of topotecan (1 mg/m(2)/day to 2.5 mg/m(2)/day). Topotecan was given at a 30-minute infusion daily with etoposide 150 mg/m(2)/day, both for 5 days. Topoisomerase-DNA covalent complex formation was measured using in vivo link assay, whereas topoisomerase I, IIalpha, and IIbeta in RNA expression levels were determined by reverse transcription-polymerase chain reaction in blood samples. The relation of these levels to clinical response was studied. RESULTS: The maximum tolerated dose of topotecan was 2.0 mg/m(2)/day for 5 days. Oropharyngeal mucositis was dose-limiting. Of 21 examinable patients, 3 patients achieved complete remission, and 5 patients achieved partial remission. Of six untreated patients who experienced a recurrence, three had complete remission, and the other three had partial remission. Drug-induced topoisomerase-DNA complex formation was observed throughout the treatment in blood samples of all the patients who responded. However, only 4 of 13 patients, who did not respond, formed covalent complex at all time points. This was statistically significant (P = 0.024). In all patients, expression levels of topoisomerase I and IIbeta mRNA remained similar to pretreatment levels, whereas topoisomerase IIalpha mRNA levels decreased dramatically by the third day. CONCLUSION: The recommended Phase II dose of topotecan with etoposide of 150 mg/m(2)/day for 5 days was 2.0 mg/m(2)/day for 5 days. Topoisomerase-DNA complex formation correlated with response to treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN-Topoisomerasas de Tipo II , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Neoplasias/metabolismo , Etopósido/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Topotecan/uso terapéutico , Adulto , Anciano , Antígenos de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , ADN-Topoisomerasas de Tipo I/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/genética , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN de Neoplasias/efectos de los fármacos , Proteínas de Unión al ADN , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Isoenzimas/efectos de los fármacos , Isoenzimas/genética , Isoenzimas/metabolismo , Linfoma no Hodgkin/enzimología , Masculino , Persona de Mediana Edad , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Topotecan/administración & dosificación , Topotecan/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: To compare the laboratory and clinical outcome of patients who received solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS: A randomized, double-blinded study to assess the ability of SDP and FFP to reduce a prolonged prothrombin time (PT) to