Effects of a fluorinated pyrimidinedione anti-cancer drug, 5-fluoro-1-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FT), and related compounds on nigro-striatal dopaminergic neurons in the central nervous system.
The cause of the side effects of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FT) on the central nervous system (CNS), and especially the extrapyramidal system were investigated by examining the effects of FT on pre- and post-synaptic functions of the dopaminergic system in comparison with the effects of 5-fluoro-2,4-pyrimidinedione (5-FU) and UFT. FT caused a significant decrease of spontaneous motor activity (SMA), significant increases in the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), an increase in dopamine (DA) turnover induced by alpha-methyl-p-tyrosine and an inhibition of presynaptic dopamine receptors. FT also slightly inhibited [3H] spiperone binding to rat striatal membranes (10-15%) in vitro at doses of 10(-6)-5 X 10(-4) M. 5-FU slightly decreased SMA, significantly increased the levels of DOPAC and HVA, and significantly inhibited (P less than 0.05) [3H]spiperone binding (about 30% at 5 X 10(-4) M). The effects of UFT on the CNS were almost the same as those of FT, but uracil had no effect on the CNS. These results suggest that the side effects of FT on the CNS, especially its action on dopaminergic neurons, may result from blockade of pre- and post-synaptic dopamine receptors, and may be mediated by its main metabolite 5-FU in the brain.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D005641:Tegafur / Q000494:pharmacology*; D013997:Time Factors; D014498:Uracil / Q000494:pharmacology; D019805:alpha-Methyltyrosine
D000970:Antineoplastic Agents; D008781:Methyltyrosines; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D005641:Tegafur; D013134:Spiperone; D014498:Uracil; D019805:alpha-Methyltyrosine; D006220:Haloperidol; D005472:Fluorouracil; D004298:Dopamine; D006719:Homovanillic Acid