Effect of folinic acid on fluorouracil activity and expression of thymidylate synthase.
Folinic acid (leucovorin, [LV]) can potentiate the growth inhibitory effects of fluorouracil (5-FU) in vitro and in vivo. LV is a precursor for 5,10-methylene-tetrahydrofolate (CH2-THF). Sufficient levels of CH2-THF enhance the inhibition of the enzyme thymidylate synthase by the 5-FU metabolite FdUMP. This study describes the effects of 5-FU and LV in two murine (C26-10, C38-1) and two human (WiDr, HT-29) colon carcinoma cell lines and in two murine tumors (Colon 26 and Colon 38). In vitro, only C38-1 was more sensitive for the combination of LV/5-FU compared with 5-FU alone. This effect was not dose or schedule dependent. l-LV, a purified stereo-isomere of LV, is thought to be the biological active form. Tests with this compound in vitro did not show a better effect than the mixture of d- and l-LV. In vivo, dl-LV could potentiate 5-FU antitumor effect in two murine colon tumors (Colon 26, Colon 38). This effect was clearly schedule dependent. dl-LV administered 1 hour before and together with 5-FU was much better than only simultaneous or posttreatment, but there was no dose dependency, while like in vitro l-LV effect was comparable to dl-LV. TdR was used to study the role of TS inhibition in the growth inhibitory effect of 5-FU with and without LV. TdR can reverse growth inhibition caused by TS inhibition due to 5-FU. In vitro, a partial reversal of growth inhibition of 5-FU and 5-FU/LV was observed, but in vivo there was no reversal. In vivo, TdR combinations led to high toxicity. Measurements of TS amounts in cells and tumors showed that those of human origin had much lower TS than the murine. C38-1 and Colon 38 with low TS were more sensitive to 5-FU than Colon 26 with higher TS amounts. TS inhibition was studied in the two murine colon tumors at several time points after weekly 5-FU or LV and 5-FU administration. LV did not increase the extent or retention of TS inhibition due to 5-FU during the first week. After three courses of treatment a fourfold increase of TS levels was seen in Colon 26 after 5-FU therapy. This resulted in a less effective TS inhibition after this treatment. Tumors treated with 5-FU and LV also showed an increase of TS, but to a lower extent, while the effect on TS inhibition remained the same.(ABSTRACT TRUNCATED AT 400 WORDS)
van der Wilt
C L
CL
Free University Hospital, Department of Oncology, Amsterdam, The Netherlands.
Pinedo
H M
HM
Smid
K
K
Cloos
J
J
Noordhuis
P
P
Peters
G J
GJ
D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014542:Uridine Monophosphate / Q000378:metabolism
D005467:Floxuridine; D014542:Uridine Monophosphate; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; C025034:doxifluridine; D013936:Thymidine