RESUMO
The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/microL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16, 000 to 110,000/microL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses =200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.
Assuntos
Amifostina/administração & dosagem , Hematopoese/efeitos dos fármacos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Idoso , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
Northern blots with poly(A)-selected RNAs were prepared from four primary human breast carcinomas and hybridized with a SIS/PDGF-B gene probe. High expression of a normal-sized 3.7 kb SIS/PDGF-B transcript was observed in three samples. These three carcinomas were all T3 (greater than 5 cm) lesions and were histologically infiltrating ductal carcinomas accompanied by moderate to marked desmoplasia. Furthermore in situ hybridization with photobiotinylated probes was performed and demonstrated that the SIS/PDGF-B expression was localized within the epithelial cells of malignant as well as benign lesions. It is possible that SIS/PDGFB expression within the epithelial cell components of nonmalignant as well as malignant breast lesions may be in part responsible for the stromal reaction.