High-dose 5-Fluorouracil with uridine-diphosphoglucose rescue increases thymidylate synthase inhibition but not 5-Fluorouracil incorporation into RNA in murine tumors.
5-Fluorouracil (5FU) shows a steep dose response curve in several experimental systems, but the clinical use of high doses is hampered by the toxic side effects of this drug. Uridine diphosphoglucose (UDPG) rescue allows an increase in the maximum tolerated dose of 5FU in mice from 100 (FU(100)) to 150 mg/kg (5FU(150)+UDPG) and the higher dose is more effective than the standard treatment against several tumors. In the present paper we report on the effect of high-dose 5FU on thymidylate synthase (TS) levels and on 5FU incorporation into RNA. In the resistant murine tumor (Colon 26A) high-dose 5FU inhibited TS catalytic activity 8 h after treatment (4-fold; p = 0.00041) and the inhibition persisted until day 3 (p < 10(-4)). Standard-dose 5FU did not significantly inhibit TS activity. In a relatively sensitive tumor (Colon 26-10), there was no difference in the initial extent of TS inhibition by the two 5FU doses, but TS was still inhibited (2-fold) on day 3 after (5FU(150)+UDPG) while it was within the normal range after 5FU(100). In both tumor types TS activity showed an impressive rebound (3-fold) on days 3-7, and this occurred after both 5FU doses. In Colon 26A, however, a new 5FU injection on day 7 was still able to inhibit TS but not as effectively as the first dose. 5FU incorporation into RNA reached similar peak values (8 pmol/microg RNA) after the two 5FU doses, but the clearance was faster in mice receiving UDPG rescue. We conclude that UDPG does not interfere with the extent of TS inhibition by 5FU, but UDPG allows the use of a higher dose of 5FU resulting in enhanced TS inhibition. UDPG, however, increases 5FU clearance from RNA. In this experimental system the inhibition of TS seems essential in order to obtain a good antitumor activity, while 5FU incorporation into RNA does not seem to play a role in the antitumor activity of 5FU. Since preliminary results indicate that UDPG is well tolerated by patients, the use of higher 5FU doses may improve the response rate of human tumors.
Codacci-Pisanelli
Giovanni
G
Department of Internal Medicine, University La Sapienza, Rome, Italy.
Van der Wilt
Clasina L
CL
Smid
Kees
K
Noordhuis
Paul
P
Voorn
Daphne
D
Pinedo
Herbert M
HM
Peters
Godefridus J
GJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D012334:RNA, Neoplasm / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014532:Uridine Diphosphate Glucose / Q000008:administration & dosage*
D000964:Antimetabolites, Antineoplastic; D012334:RNA, Neoplasm; D013940:Thymidylate Synthase; D005472:Fluorouracil; D014532:Uridine Diphosphate Glucose