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.
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 in between, 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.
el-Beltagi
H M
HM
Department of Hemato-Oncology TNO, Erasmus University Rotterdam, The Netherlands.
Martens
A C
AC
Lelieveld
P
P
Haroun
E A
EA
Hagenbeek
A
A
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004354:Drug Screening Assays, Antitumor; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; C045838:dinaline; C081895:tacedinaline