Print Email Facebook Twitter Acetyldinaline: A new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells - Preclinical studies in a relevant rat model for human acute myelocytic leukemia Title Acetyldinaline: A new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells - Preclinical studies in a relevant rat model for human acute myelocytic leukemia Author El-Beltagi, H.M. Martens, A.C.M. Lelieveld, P. Haroun, E.A. Hagenbeek, A. Instituut voor Toegepaste Radiobiologie en Immunologie TNO Publication year 1993 Abstract Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'- aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a 'full dose' of 23.7 mg/kg once daily (first group), a twice daily 'half dose' of 11.85 mg/kg with an interval of 8 h (second group), or a 'half dose' of 11.85 mg/kg once daily (third group). The drug- free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval inbetween, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or >8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro- intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies. Chemicals/CAS: acetyldinaline, 112522-64-2; Antineoplastic Agents; dinaline, 58338-59-3; Phenylenediamines Subject Administration, OralAnimalAntineoplastic AgentsBone MarrowBone Marrow CellsCell DifferentiationCell SurvivalClone CellsComparative StudyDisease Models, AnimalDose-Response Relationship, DrugDrug Administration ScheduleDrug EvaluationDrug Screening Assays, AntitumorHematopoietic Stem CellsLeukemia, Myelocytic, AcuteMalePhenylenediaminesRatsRats, Inbred BNSupport, Non-U.S. Gov'tTumor Cells, Cultured To reference this document use: http://resolver.tudelft.nl/uuid:412f7b7c-3b12-4223-abeb-8f463c706819 TNO identifier 280613 ISSN 0008-5472 Source Cancer Research, 53 (13), 3008-3014 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.