title: Potential antitumor agents. 40. Orally active 4,5-disubstituted derivatives of amsacrine.
abstract: The DNA-intercalating agent amsacrine is an effective drug for the treatment of human leukemias and lymphomas but has minimal solid tumor activity. As a first step in identifying analogues with a wider spectrum of activity, a comparison was made of the in vivo antileukemic (P-388) activity of amsacrine analogues given by oral (po) and intraperitoneal (ip) routes. A series of 4-substituted and 4,5-disubstituted derivatives all showed high activity when administered ip against ip-implanted P-388, but activity varied widely when the compounds were given orally. 4-Methoxy and 4-carbamoyl derivatives proved essentially inactive, whereas 4-methyl and 4-methylcarbamoyl derivatives retained activity. Exceptional oral activity was shown by the 4-methyl-5-methylcarbamoyl derivative, making this amsacrine derivative worthy of further testing.
mesh_terms: D000284:Administration, Oral; D000609:Aminoacridines / Q000008:administration & dosage / Q000627:therapeutic use*; D000677:Amsacrine; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D004247:DNA / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D000677:Amsacrine; D004247:DNA