Pharmacokinetic studies of chloroethylnitrosocarbamoyl-amino acid derivatives in vivo and in vitro.

Abstract

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.

• Authors: A M Matthew, M C Bibby, G Eisenbrand
• Journal: Anticancer research (Anticancer Res) 1993 Jan-Feb Vol. 13 Issue 1 Pg. 81-6 ISSN: 0250-7005 [Print] Greece
• PMID: 8476230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dipeptides
• chloroethylnitrosocarbamoyl-glycinemethylamide
• chloroethylnitrosocarbamoyl-alanyl-alanine
• Ethylnitrosourea
• Glycine

Topics

• Adenocarcinoma (drug therapy, metabolism)
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, toxicity)
• Cell Survival (drug effects)
• Chromatography, High Pressure Liquid
• Colonic Neoplasms (drug therapy, metabolism)
• Dipeptides (pharmacokinetics, pharmacology, toxicity)
• Drug Screening Assays, Antitumor
• Drug Stability
• Ethylnitrosourea (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
• Glycine (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
• Injections, Intraperitoneal
• Male
• Mice
• Mice, Inbred Strains
• Peritoneal Cavity (physiology)
• Structure-Activity Relationship
• Tumor Cells, Cultured (drug effects)