PubMed · 647321
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M Soukop, J G McVie, K C Calman. 1978-05-27. Fluorouracil cardiotoxicity.. https://doi.org/10.1136/bmj.1.6124.1422
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We have recently shown that 5-Fluorouracil (5-FU) suppresses the transcription factor NF-kappaB in human salivary gland cancer cells (cl-1) by mediating upregulation of IkappaB-alpha expression. However, the precise mechanism involved in this action has not yet been elucidated. IkappaB kinases (IKK-alpha and IKK-beta) are the key components of the IKK complex that mediates activation of NF-kappaB in response to external stimuli such as cytokines. In addition, NF-kappaB-inducing kinase (NIK) and mitogen-activated protein kinase kinase kinase 1 (MEKK-1), both of which are the upstream kinases for the IKKs, interact with and activate the IKKs. Thus, we investigated the molecular mechanisms involved in the suppression of NF-kappaB by 5-FU. Although 5-FU did not affect the expression levels of IKKs, NIK, or MEKK-1, IKK activity in cl-1 cells was suppressed at both 6 h and 12 h after treatment with 2 microgram/ml 5-FU. Moreover, when cells were treated with various concentrations of 5-FU for 12 h, the concentration of 2 microgram/ml efficiently inhibited the IKK activity as compared to 1, 5, or 10 microgram/ml. The expression of Fas-associated death domain-like interleukin 1-converting enzyme-inhibitory protein (FLIP), which acts as an inhibitor of an initiator caspase (caspase-8), was down-regulated by 5-FU treatment in cl-1 cells. Apoptosis, as evidenced by cleavage of poly(ADP-ribose) polymerase through the action of an executioner caspase (caspase-3), was also clearly observed. Thus, these results suggest that 5-FU induction of apoptosis in cl-1 cells may be mediated by suppression of NF-kappaB via inhibition of IKK activity.
Multiple regression analysis of fluxes from suspensions in isopropyl myristate (J(M)) as a function of molecular weights (MW) and solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) were performed on a data set of 41 compounds (n = 41) comprising 39 prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP), in addition to 5-FU and Th, using four models. Two series/parallel models have been developed that allow an aqueous-only path in parallel with a lipid-only path and with a lipid-aqueous series path for the permeation of solutes through skin: log J(M) = log ¿1/[1/(aS(LIPID) 10(PhiMW)) + 1/(bS(AQ)/MW(1/2))] + cS(LIPID)10(PhiMW) + dS(AQ)/MW(1/2)¿ where a, b, c, and d are coefficients for flux through the lipid and aqueous portions of the series path, the lipid-only path, and the aqueous-only path, respectively, and Phi is the dependence of diffusivity in lipid on MW. In the first series/parallel model, S(LIPID) was predicted by S(IPM), and in the second, solvatochromic series/parallel model, S(LIPID) was predicted by S(IPM)(k MW + Omegai) where Omega(i) is the sum of the solvatochromic terms alpha, beta, pi, and R(2), and k is the coefficient for the dependence of partitioning on MW. Using the n = 41 solutions, the coefficients for the aqueous-only path were very small or not different from zero in the two series/parallel models, so only two-path series/parallel models were compared with the solvatochromic and transformed Potts-Guy models where a homogeneous barrier to permeation was assumed. For each model, one compound at a time was omitted from the data set and new parameter estimates were obtained for these 41-1 solutions and used to predict log J(M) for the omitted compound. The average errors of prediction of log J(M) (experimental log J(M) - predicted log J(M)) for the four models were 0.134 for the series/parallel (r(2) = 0.937), 0.127 for the solvatochromic series/parallel (r(2) = 0.967), 0.150 for the solvatochromic (r(2) = 0.950), and 0.134 log units for the transformed Potts-Guy model (r(2) = 0.944). Thus, the solvatochromic series/parallel model provides fit and predictive ability comparable to or slightly superior to previous models that assumed homogeneity of the diffusional barrier to flux in the rate-determining step, provides further theoretical support against the existence of a high capacity aqueous-only path, and provides further insight into the physicochemical properties that should be incorporated into solutes to optimize their flux. Using the solvatochromic series/parallel model, the parameter estimates for the n = 41 solution were used to calculate the flux of each compound through the two paths. For compounds with log partition coefficients (K(IPM:AQ)) of <0.8, permeation was mostly by the lipid-aqueous series path; for compounds with log K(IPM:AQ) >1.0, permeation was mostly by the lipid-only path; the lipid-aqueous series path exhibited the higher carrying capacity. (c) 2000 Wiley-Liss, Inc.
tRNA pseudouridine synthase I (PsiSI) catalyzes the conversion of uridine to Psi at positions 38, 39, and/or 40 in the anticodon loop of tRNAs. PsiSI forms a covalent adduct with 5-fluorouracil (FUra)-tRNA (tRNA(Phe) containing FUra in place of Ura) to form a putative analog of a steady-state intermediate in the normal reaction pathway. Previously, we proposed that a conserved aspartate of the enzyme serves as a nucleophilic catalyst in both the normal enzyme reaction and in the formation of a covalent complex with FUra-tRNA. The covalent adduct between FUra-tRNA and PsiSI was isolated and disrupted by hydrolysis and the FUra-tRNA was recovered. The target FU39 of the recovered FUra-tRNA was modified by the addition of water across the 5,6-double bond of the pyrimidine base to form 5,6-dihydro-6-hydroxy-5-fluorouridine. We deduced that the conserved aspartate of the enzyme adds to the 6-position of the target FUra to form a stable covalent adduct, which can undergo O-acyl hydrolytic cleavage to form the observed product. Assuming that an analogous covalent complex is formed in the normal reaction, we have deduced a complete mechanism for PsiS.