Albumin inhibition of the antileukemic activity of hydroxylated phenothiazines.
Trifluoperazine (TFP) shows cytotoxic activity against human acute lymphatic leukemia (ALL) in vitro. This activity is inhibited by increasing serum concentration and by albumin. Despite its in vitro activity, the drug is inactive in vivo. To determine if increased phenothiazine hydrophilicity could protect against albumin inhibition of antileukemic activity, we compared ALL cytotoxic median effective dose concentrations of a series of hydroxylated phenothiazines in 5% fetal bovine serum (FBS) and in 5% FBS supplemented with albumin. Albumin inhibits the activity of all drugs. A representative derivative 7,8-dihydroxychlorpromazine, although active in vitro, is inactive against L1210 and P388 murine leukemias in vivo.
Slater
L M
LM
Department of Medicine, College of Medicine, University of California, Irvine 92717.
Sweet
P M
PM
Stupecky
M M
MM
Murray
S L
SL
Wetzel
M W
MW
D000418:Albumins / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007938:Leukemia / Q000188:drug therapy*; D010640:Phenothiazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000418:Albumins; D002147:Calmodulin; D010640:Phenothiazines