The effect of phenobarbital on cyclophosphamide antitumor activity

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was...

Full description

Saved in:
Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 36; no. 8; p. 2785
Main Authors Alberts, D S, van Daalen Wetters, T
Format Journal Article
LanguageEnglish
Published United States 01.08.1976
Subjects
Animals
Bone Marrow - drug effects
Bone Marrow Cells
Cyclophosphamide - adverse effects
Cyclophosphamide - metabolism
Cyclophosphamide - therapeutic use
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Induction
Leukemia, Experimental - drug therapy
Leukemia, Lymphoid - enzymology
Leukemia, Lymphoid - metabolism
Male
Mice
Mice, Inbred DBA
Phenobarbital - pharmacology
Proadifen - pharmacology
Online AccessGet full text

Cover

More Information
Summary:We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily phenobarbital intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without phenobarbital pretreatment showed a constant 90% (1-log) reduction in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas enzyme induction had no effect on the toxicity of the drug to normal bone marrow colony-forming units. Parallel survival studies confirmed the 1-log diminution in the antileukemic activity of cyclophosphamide in phenobarbital-pretreated mice. This phenobarbital-induced change in the antitumor activity of cyclophosphamide appears explainable on a pharmacokinetic basis. The Friedman and Boger assay for plasma alkylating metabolites showed that the reduction in the area under the plasma metabolite curve caused by enzyme induction exactly predicted the observed reduction in cyclophosphamide antitumor effect.
ISSN:0008-5472