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, Oral
Animal
Antineoplastic Agents
Bone Marrow
Bone Marrow Cells
Cell Differentiation
Cell Survival
Clone Cells
Comparative Study
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Evaluation
Drug Screening Assays, Antitumor
Hematopoietic Stem Cells
Leukemia, Myelocytic, Acute
Male
Phenylenediamines
Rats
Rats, Inbred BN
Support, Non-U.S. Gov't
Tumor Cells, Cultured
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TNO identifier
280613
ISSN
0008-5472
Source
Cancer Research, 53 (13), 3008-3014
Document type
article