Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA.
Two strategies for modulation of 5-fluorouracil (FUra) activity were compared in vivo in advanced murine CD8F1 breast tumors with regard to three parameters: chemotherapeutic activity, inhibition of thymidylate synthase (TSase) activity, and incorporation of FUra into RNA, (FU)RNA. Inhibition of TSase by FUra was modulated by leucovorin (LV), and the incorporation of FUra into RNA was increased by the administration of otherwise lethal doses of FUra followed by uridine "rescue". Thymidylate synthase activity was inhibited substantially (49%) by low-dose FUra at 25 mg/kg, but was not further enhanced (48%) by repeated daily treatments at the same dose (FUra25 x 4). Inhibition of TSase was somewhat enhanced (55%) by the addition of LV to FUra25 x 4, and a greater therapeutic effect was obtained with FUra25 x 4 + LV over FUra25 x 4 alone. FUra as a single agent at the maximum tolerated weekly dose of 100 mg/kg inhibited TSase activity 66-73%. This inhibition was further enhanced slightly by the addition of LV (71-82%), and its therapeutic efficacy was greater than with FUra25 x 4 with or without LV. However, in contrast to low dose FUra25 x 4, the antitumor effect of FUra100 was not enhanced by LV. (FU)RNA increased with FUra dose from 0.4 (FUra25) to 2.2 nmol/mg DNA (FUra100). At a very-high-dose of FUra (200-225 mg/kg) followed by uridine "rescue", TSase inhibition was not further enhanced, but both (FU)RNA (4.8 nmol/mg DNA) and the therapeutic efficacy were increased. Since TSase could not be further inhibited at doses above FUra100, the increased chemotherapeutic efficacy correlated with increased (FU)RNA.
Nord
L D
LD
Department of Cancer Research, Catholic Medical Center, Woodhaven, NY 11421.
Stolfi
R L
RL
Martin
D S
DS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D012313:RNA / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014529:Uridine / Q000378:metabolism*
D012313:RNA; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; D014529:Uridine