Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels.
A marked inhibition of the growth of solid tumor adenocarcinoma 755 was achieved by the combination of 5-fluorouracil (5-FU) with bromovinyldeoxyuridine (BVDU). The therapeutic index (LD50/ED50) for the combination of BVDU plus 5-FU was 8.1 and 3.9 upon intraperitoneal (i.p.) or oral (p.o.) administration, respectively. The therapeutic index of i.p. 5-FU given alone was 2.3, whereas for p.o. 5-FU given alone no therapeutic index could be established because of insufficient activity of the compound. Thus, the therapeutic index of 5-FU increased significantly when combined with BVDU. Pharmacokinetic studies revealed that upon i.p. or p.o. 5-FU administration plasma 5-FU levels rapidly declined, but that, in the combination with BVDU, the plasma clearance of 5-FU, especially following p.o. administration, was slowed down considerably. Antitumor activity of 5-FU correlated with AUC (area under the concentration x time curve), within the plasma 5-FU concentration range from 0.02 to 0.4 microgram/ml.
Iigo
M
M
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Araki
E
E
Nakajima
Y
Y
Hoshi
A
A
De Clercq
E
E
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D051379:Mice
C020235:brivudine; D001973:Bromodeoxyuridine; D005472:Fluorouracil