title: In vitro and in vivo activity of 1-aryl-3-(2-chloroethyl) urea derivatives as new antineoplastic agents.
abstract: A few 1-aryl 3-(2-chloroethyl)ureas (CEU) were synthesized and screened in vitro for their cytotoxicity. Some of these derivatives were assayed for their mutagenicity, their in vivo toxicity and their antineoplastic activity. Methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tertbutyl (3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tert-butyl (3-(2-chloroethyl) ureido) benzene had an ID50 of 28, 20 and 4 microM respectively when tested on LoVo cells, while chlorambucil (CBL) and CCNU had an ID50 of 21 and 45 microM. These 3 chloroethyl urea derivatives were not toxic when injected i.p. at doses up to 220 mg/kg, whereas chlorambucil was already toxic at 18.5 mg/kg. The survival time of BDF1 mice bearing L1210 leukemia tumors was significantly enhanced by intraperitoneal injections of CBL and CEU. The most cytotoxic derivative (tert-butyl derivative) gave the best antineoplastic activity with a median survival time 1.77 times that of the control at 10 mg/kg/day and was not toxic, whereas CBL at this concentration enhanced survival time by a factor of 1.6 and presented important side effects. The 4-tert-butyl (3-(2-chloroethyl) ureido) benzene and the methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate showed no mutagenicity when assayed on TA-97, TA-98, TA-100 and TA-102, four strains of S. thyphimurium, while CBL had a weak effect on TA-102 and CCNU was highly mutagenic on TA-100 and TA-102.
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008130:Lomustine / Q000494:pharmacology; D051379:Mice; D009152:Mutagenicity Tests; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D010671:Phenylurea Compounds; D002699:Chlorambucil; D008130:Lomustine