Pharmacokinetic studies of chloroethylnitrosocarbamoyl-amino acid derivatives in vivo and in vitro.
The in vitro chemosensitivity of MAC 15A ascites cells to CNC-alanylalanine and CNC-glycinemethylamide was assessed using a clonogenic assay system. In vitro stability studies and in vivo pharmacokinetics were performed using a reversed-phase HPLC technique. Initial concentrations of CNC-alanylalanine and CNC-glycinemethylamide of 5.2 micrograms ml-1 and 3.2 micrograms ml-1 respectively, were required for a 70% reduction in colony formation of MAC 15A cells in vitro. The concentrations of active alkylating species generated were calculated from the drug half-lives in tissue culture medium. On this basis, a 70% cell kill was achieved by equivalent concentrations of 10.8 microM CNC-alanylalanine and 10.6 microM CNC-glycinemethylamide. Analysis of drug levels following intraperitoneal administration revealed that CNC-alanylalanine was cleared more slowly from the peritoneal cavity producing a greater drug concentration at the site of the ascitic MAC 15A tumour. These results suggested that the superior activity of CNC-alanylalanine over CNC-glycinemethylamide against MAC 15A in vivo could be attributed mainly to differences in the pharmacokinetic behaviour of the two drugs following intraperitoneal administration and that CNC-alanylalanine might have a role in the treatment of local peritoneal disease.
Matthew
A M
AM
Clinical Oncology Unit, University of Bradford, West Yorkshire, U.K.
Bibby
M C
MC
Eisenbrand
G
G
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004151:Dipeptides / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010529:Peritoneal Cavity / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004151:Dipeptides; C080772:chloroethylnitrosocarbamoyl-glycinemethylamide; C080770:chloroethylnitrosocarbamoyl-alanyl-alanine; D005038:Ethylnitrosourea; D005998:Glycine