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UFT: Mechanism of Drug ActionReview Article [1] | October 01, 2000By Claus Henning Köhne, MD [2] and Godefridus J. Peters, PhD [3]

The mechanism of action of fluorouracil (5-FU) and the oral fluoropyrimidines and the importance ofbiochemical modulation and inhibition of dihydropyrimidine dehydrogenase for oral application of theprodrugs of 5-FU are discussed.

Introduction

Fluoropyrimidines are among the most widely used antineoplastic agents with activity againstbreast, gastrointestinal, and head and neck malignancies. Since their synthesis by Heidelberger[1]during the 1950s, fluoropyrimidines have undergone extensive preclinical and clinical evaluation.The antineoplastic activity of fluorouracil (5-FU) is improved by biochemical modulation[2,3] andwhen administered as a continuous infusion.[4] Although the oral absorption of 5-FU is erratic andresults in unpredictable and variable plasma levels in patients,[5] 5-FU prodrugs arepharmacologically more predictable. These compounds are being evaluated clinically and will likelybecome important drugs in the care of patients.

Prodrugs of 5-FU

Fluorouracil and its analogs tegafur and capecitabine (Xeloda) are shown in Figure 1. Afteradministration, 5-FU is rapidly catabolyzed by the rate-limiting enzyme dihydropyrimidinedehydrogenase (DPD), which has its highest level of activity in the liver. This accounts for the highclearance of the drug, with only 5% to 10% entering anabolism into active compounds.[6,7] Inaddition, approximately 2% to 4% of the population is DPD-deficient due to genetic polymorphism inDPD activity.[8]The oral fluoropyrimidines may be divided into two categories: those administered in combinationwith a DPD inhibitor and those administered without. Inhibition of DPD activity may be competitivewith 5-FU, as in the case of uracil and 5-chloro-dihydropyridine; 5-ethynyluracil acts as a suicideinhibitor by inactivating DPD.Capecitabine, a non-DPD 5-FU prodrug, becomes cytotoxic only after conversion to 5-FU. Followingoral administration, capecitabine is metabolized in the liver by carboxyl esterase into5-deoxy-5-fluorocytidine and by cytidine deaminase into 5´-deoxy-5-fluorouridine (Figure 2). The laststep of conversion occurs with pyrimidine phosphorylase, which is shown to be at a higherconcentration in the tumor than in normal tissue, with the potential advantage of greater tumorselectivity.[9]Tegafur is a prodrug that slowly metabolizes into 5-FU through the activity of hepatic cytochromeP450 and systemic soluble enzymes;[10,11] 5-FU is the end product of this reaction. In order toincrease the concentration of 5-FU, and prevent degradation of 5-FU by DPD, uracil is added at amolar concentration of 1:4 (5-FU:uracil). In preclinical models,[12] this molar combination has beenidentified as the most efficient.S1 is a combination of tegafur and two modulators that prevent degradation. Tegafur, potassiumoxonate, and 5-chloro-2,4-dihydropyridine (CDHP), are combined in a molar ratio of 1:0.4:1.[13,14]CDHP is a competitive, reversible DPD inhibitor that prolongs the half-life of 5-FU. Oxonic acid is apyrimidine phosphoribosyltransferase inhibitor that is added to prevent the phosphorylation of 5-FUin the digestive tract with the aim of reducing 5-FU�related gastrointestinal toxicity.[15]The intravenous (IV) formulation of 5-FU may be given as an oral drug when it is combined with theoral DPD inhibitor ethynyluracil. Pretreatment with ethynyluracil results in 100% oral bioavailabilityand extends the half-life of 5-FU from less than 10 minutes to over 100 minutes.[16] In thesecircumstances, 5-FU has linear pharmacokinetics and clearance is primarily renal. Complete DPDinhibition might last for several weeks after ethynyluracil is discontinued,[17,18] thus preventingfurther conventional dosing of 5-FU for several weeks or even months.

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5-FU Mechanism of Action

All 5-FU prodrugs and 5-FU combined with DPD inhibitors exert their antineoplastic activity in asimilar manner. The biochemical modulation of 5-FU is reviewed in Figure 3. 5-FU may act viathymidylate synthase (TS) inhibition through its active anabolites such as fluorodeoxyuridinemonophosphate (FdUMP). This reaction is facilitated by the formation of a ternary complex consistingof FdUMP, TS, and 5,10-methylene tetrahydrofolate (5,10-MTHF). The intracellular concentration of5,10-MTHF can be increased through the addition of other reduced folates such as leucovorin, thuspromoting a greater stability of the ternary complex. Thymidylate synthase catalyzes the conversionof dUMP to TMP, which is a precursor of TTP, one of the four deoxyribonucleotides required for DNAsynthesis. Also, incorporation of the anabolites of 5-FU into RNA and DNA contributes to theantineoplastic activity of 5-FU.[19,20] In preclinical models, interferon demonstrated the ability toenhance the cytotoxicity of 5-FU by several potential mechanisms, including affecting thymidinekinase activity, depleting intracellular thymidine concentration,[21] and most likely, enhancing DNAdamage.[22,23]Pretreatment StrategiesPretreatment with methotrexate results in an increased intracellular concentration of phosphoribosylpyrophosphate (PRPP), the cofactor for conversion of 5-FU into fluorouridine monophosphate (FUMP)and, subsequently, into 5-fluorouridine 5´-tri-phosphate (FUTP).[24,25] The administration of high-dose methotrexate is usually accompanied byleucovorin rescue, which can lead to a dual effect. Leucovorin will not only protect againstmethotrexate-induced toxicity, but can also interfere with methotrexate uptake, thereby abolishingits effect. In addition, administration of leucovorin will result in direct modulation of 5-FU.[26,27] Thenet effect seems to be a leucovorin-mediated modulation. Therefore, methotrexate was substitutedwith trimetrexate, which, due to its lipophilicity, does not require the reduced folate carrier. Thiscombination was very effective in vitro, and is currently being evaluated in the clinic.Phosphonacetyl-L-aspartate (PALA) is an inhibitor of aspartate transcarbamylase,[28] an importantenzyme in the de novo synthesis of uridine and cytidine nucleotides. Pretreatment with PALA canyield a higher incorporation of 5-FU nucleotides into cellular RNA,[29] and a depletion of dUMP,leading to enhanced inhibition of TS.After transport of preformed extracellular thymidine into cells, it is anabolyzed by thymidine kinaseto thymidine triphosphate (dTTP) and replete dTTP pools, thereby bypassing the 5-FU�induceddepletion of dTTP.[30] Dipyridamole interferes with the cellular uptake of nucleosides. In tumor cells,in which the inhibition of TS is critical, dipyridamole results in depletion of dTTP pools by blocking thefacilitated transport of exogenous thymidine. Unfortunately, in vivo application of dipyr-idamole ishampered by its high protein binding, thus preventing a dipyridamole-induced inhibition ofnucleoside transport.All of these biochemical strategies have been extensively studied in clinical trials.[31,32]Methotrexate, PALA, alpha-interferon, DP have all been investigated as biochemical modulators, butthe biochemical modulation by leucovorin appears to be most efficient�resulting in a doubling of theresponse rate.[3]The rationale for combining UFT (uracil and tegafur) plus oral leucovorin (a combination beingdeveloped under the trade name Orzel) derives from extensive evaluation of leucovorin modulationof 5-FU. As outlined in Figure 4, UFT plus leucovorin produces a double 5-FU modulation. A 1:4 molarcombination of the 5-FU prodrug tegafur with uracil as a DPD inhibitor was developed two decadesago in Asia. Preclinical studies demonstrated that tegafur plus uracil resulted in higher tumor/bloodratios and greater tumor activity.[33,34]In addition, tegafur plus uracil was associated with lower central nervous system and gastrointestinaltoxicity compared to tegafur alone.[35] As uracil is added to tegafur, the half-life of 5-FU is prolongeddue to the inhibited ability of DPD to degradate 5-FU into alpha-fluoro-beta-alanine.

5-FU Resistance and Downstream Events

Only about 20% of patients with advanced colorectal cancer respond to the combination of 5-FU andleucovorin via bolus administration, leaving approximately 80% who fail to respond. Additionally,responses usually last for a short time, with most patients failing to respond later due to possiblesecondary resistance. Resistance to fluoropyrimidines is multifactorial and may be related to theirantipyrimidine or antifolate properties (Table 1).[36] A general form of fluoropyrimidine resistance isthe induction of TS activity at the initiation of 5-FU treatment (Figure 5).[37-40] This phenomenon

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has been observed in a number of model systems both in vivo and in vitro.Using an in vivo murine colon tumor model, Van der Wilt and coworkers[39,41] observed thedevelopment of resistance following weekly bolus injections and after continuous administration of5-FU for 10 to 21 days in tumors that were initially sensitive to such treatment. This resistance wasassociated with a rapid increase in TS levels, while plasma 5-FU levels under these conditions werecomparable to the levels that had been achieved during the first days of infusion. Interestingly,pretreatment with leucovorin depressed this 5-FU�induced TS increase after the bolus injections.Sobrero and coworkers observed that low-dose, continuous exposure of 5-FU almost immediatelyresulted in resistant clones of the HCT-8 colon tumor cell line, whereas short-term exposure to 5-FUrequired a longer period to induce resistance.[42] Cells resistant to intermittent short exposure weresensitive to continuous exposure, but cells resistant to continuous exposure were also resistant toshort-term exposure. The observation that the increase in TS was less pronounced if cells werepretreated with leucovorin[39] may serve as an explanation for the higher response rate observedwith 5-FU therapy when modulated by leucovorin. Other investigators observed a similar increase inTS levels after treatment with 5-FU in a tumor cell model.[43,44] In this experiment,gamma-interferon was able to significantly reduce TS induction.Deregulation of Thymidylate Synthase Protein SynthesisThe increase in TS levels is most likely explained by a deregulation of the normal TS proteinsynthesis. Under certain physiologic conditions, TS protein synthesis is related to the cell cycle, withhigh activity associated with the S-phase.[45] The translation of TS mRNA appears to be controlledby its end product, the TS protein, in an autoregulatory manner. However, when TS is bound to aternary complex, the protein can no longer regulate its synthesis, leading to the observed increase.Expression of TS appears to be managed by a translational regulatory process during the cell cycleas well as in response to cytotoxic agents.The capacity of TS as an RNA-binding protein was demonstrated by Chu and coworkers.[46] Ninedifferent cellular RNAs were shown to form a ribonucleoprotein complex with TS in intact coloncancer H630 cells. Several of these isolated RNA sequences display a high degree of homology tothose encoding the human p53 tumor suppressor protein, the c-myc and l-myc family of transcriptionfactors, and the human zinc finger 8 transcription factor. p53 and c-myc encode for nuclearphospho-proteins that play central roles in the regulation of cell cycle progression, DNA synthesis,and apoptosis.[47,48]Apoptosis RegulationInteresting insights into the more downstream events of 5-FU antineoplastic activity have beenreported by Houghton and coworkers,[49] who used a TS-negative (TS-) human GC3I TS- cell clonethat was deficient in TS-mRNA and TS protein and studied the regulation of apoptosis followingthymineless stress. Protection from apoptosis induced by thymidine deprivation was achieved by themonoclonal antibody NOK-1, which inhibits Fas and binds to the Fas ligand.Fas is one of several cell surface death-receptors, a type I integral membrane protein characterizedby cysteine-rich residues.[50] It belongs to the tumor necrosis factor receptor superfamily with anintracellular domain required for downstream signaling. FasL is a type II transmembrane proteinhomologous to tumor necrosis factor and related cytokines.[51] Fas interacts with FADD, and thedeath effector domain of FADD interacts with a similar domain of proteases (FLICE, FLICE-2). Thesecaspases then degrade other proteins within the nucleus and activate endonucleases.The work by Houghton[52,53] indicates that the Fas/FasL apoptotic system may be involved in thecytotoxicity induced by 5-FU. In further experiments, the functional significance of a transfected K-ras oncogene in influencing apoptosis following thymidine deprivation was examined in aTS-deficient cell line.[49] Interestingly, survival was conferred in TS- but K-ras+ clones.No difference in Fas expression was detected among the cell lines after thymidine deprivation,indicating that K-ras does not interfere with Fas expression. Apoptosis in the presence of wild-typeRas correlated with upregulated expression of Bak and was not observed in TS- K-ras+ clones,whereas survival in these clones correlated with upregulated expression of BCL-XL. Therefore,induction of cell death after TS inhibition may be regulated in part by Fas and FasL and otherproteins involved in the apoptosis regulation.Work by Pritchard and coworkers[54] further highlights the role of p53 as a promoter of cell deathafter 5-FU application in p53 knock-out mice, and that of BCL-2 as a death inhibitor delaying celldeath and inhibiting cell proliferation in murine intestinal epithelia.

UFT as an Inhibitor of Angiogenesis?

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Recently, inhibition of angiogenesis by UFT and its metabolites has been reported.[55] A murinerenal cell carcinoma (RENCA) cell line was studied as an angiogenesis model using a dorsal air skinassay. Blood vessels are formed by an angiogenic factor released from these malignant tumor cells.UFT showed a strong angiogenesis inhibitory effect whereas 5-FU and doxifluridine did not. Theangiogenesis was apparently mediated by the degradation products of tegafur,gamma-hydroxybutyric acid, and gamma-butyrolactone. The inhibitory effect was amplified evenwhen these compounds were administered by continuous infusion. While the clinical relevance ofthis observation remains to be determined, it is important to note that, in addition to its cytotoxiceffects, UFT may have the potential to inhibit angiogenesis. This might be of special interest in theadjuvant setting.

Conclusions

Oral fluoropyrimidines are interesting compounds in the treatment of patients with solid tumors. Asthey are metabolized into 5-FU, their mechanism of action is basically similar to that reported with IVadministration of 5-FU. Biochemical modulation also may apply to oral fluoropyrimidines, such as thecombination of UFT plus oral leucovorin. Evidence is emerging that further downstream effects offluoro- pyrimidines are related to proteins involved in the regulation of apoptosis. The effect of UFTon angiogenesis deserves further exploration. References: 1. Heidelberger C, Chaudhuri NK, Danneberg P, et al: Fluorinated pyrimidines, a new class oftumor-inhibitory compounds. Nature 179:663-666, 1957.

2. Advanced Colorectal Cancer Meta-Analysis Project: Meta-analysis of randomized trials testing thebiochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol12:960-969, 1994.

3. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin inpatients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol10:896-903, 1992.

4. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracilcompared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.

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19. Rustum YM, Trave F, Zakrzewski SF, et al: Biochemical and pharmacologic basis for potentiationof 5- fluorouracil action by leucovorin. NCI Monogr 5:165-170, 1987.

20. Peters GJ, Hoekman K, van Groeningen CJ, et al: Potentiation of 5-fluorouracil induced inhibitionof thymidylate synthase in human colon tumors by leucovorin is dose dependent. Adv Exp Med Biol338:613-616, 1993.

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22. Houghton JA, Morton CL, Adkins DA, et al: Locus of the interaction among 5-fluorouracil,leucovorin, and interferon-alpha 2a in colon carcinoma cells. Cancer Res 53:4243-4250, 1993.

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25. Cadman E, Heimer R, Davis L: Enhanced 5-fluorouracil nucleotide formation after methotrexateadministration: Explanation of drug synergism. Science 205:1135-1137, 1979.

26. van der Wilt CL, Braakhuis BJ, Pinedo HM, et al: Addition of leucovorin in modulation of5-fluorouracil with methotrexate: Potentiating or reversing effect? Int J Cancer 61:672-678, 1995.

27. Romanini A, Li WW, Colofiore JR, et al: Leucovorin enhances cytotoxicity oftrimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells. J Natl Cancer Inst84:1033-1038, 1992.

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29. Martin DS, Kemeny NE: Overview of N-(phosphonacetyl)-aspartate + fluorouracil in clinical Trials.Semin Oncol 19(2 suppl 3):228-233, 1992.

30. Grem JL, Fischer PH: Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells bydipyridamole. Cancer Res 45:2967-2972, 1985.

31. Köhne-Wömpner CH, Schmoll HJ, Harstrick A, et al: Chemotherapeutic strategies in metastaticcolorectal cancer: An overview of current clinical trials. Semin Oncol 19:105-125, 1992.

32. Köhne CH, Kretzschmar A, Wils J: First-line chemotherapy for colorectal carcinoma�we aremaking progress. Onkologie 21:280-289, 1998.

33. Fujii M, Murakami N, Matsuka Y, et al: Chemotherapy of gastrointestinal cancer in elderlypatients�evaluation of combination therapy with mitomycin C and 5- fluorouracil [in Japanese]. GanNo Rinsho 29:A-8, 129-32, 1983.

34. Fujii S, Kitano S, Ikenaka K, et al: Effect of coadministration of uracil or cytosine on the anti-tumoractivity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents.Gann 70:209-214, 1979.

35. Yamamoto J, Haruno A, Yoshimura Y, et al: Effect of coadministration of uracil on the toxicity oftegafur. J Pharm Sci 73:212-214, 1984.

36. Pinedo HM, Peters GJ: Fluorouracil: Biochemistry and pharmacology. J Clin Oncol 6:1653-1664,1988.

37. Peters GJ, van der Wilt CL, van Groeningen CJ: Predictive value of thymidylate synthase anddihydropyrimidine dehydrogenase. Eur J Cancer 30A:1408-1411, 1994.

38. Priest DG, Ledford BE, Doig MT: Increased thymidylate synthetase in 5-fluorodeoxyuridineresistant cultured hepatoma cells. Biochem Pharmacol 29:1549-1553, 1980.

39. Van der Wilt CL, Pinedo HM, Smid K, et al: Elevation of thymidylate synthase following5-fluorouracil treatment is prevented by the addition of leucovorin in murine colon tumors. CancerRes 52:4922-4928, 1992.

40. Peters GJ, Köhne CH: Fluoropyrimidines as antifolate drugs, in Jackman AL (ed): Antifolate Drugsin Cancer Therapy, pp 101-145. Totowa, NJ, Humana Press Inc, 1999.

41. Codacci-Pisanelli G, van der Wilt CL, Pinedo HM, et al: Antitumour activity, toxicity, and inhibitionof thymidylate synthase of prolonged administration of 5-fluorouracil in mice. Eur J Cancer31A:1517-1525, 1995.

42. Sobrero AF, Aschele C, Guglielmi AP, et al: Synergism and lack of cross-resistance betweenshort-term and continuous exposure to fluorouracil in human colon adenocarcinoma cells. J NatlCancer Inst 85:1937-1944, 1993.

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44. Chu E, Koeller DM, Johnston PG, et al: Regulation of thymidylate synthase in human colon cancercells treated with 5-fluorouracil and interferon-gamma. Mol Pharmacol 43:527-533, 1993.

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47. Chu E, Takechi T, Jones KL, et al: Thymidylate synthase binds to c-myc RNA in human coloncancer cells and in vitro. Mol Cell Biol 15:179-185, 1995.

48. Chu E, Copur S, Jones KL, et al: Thymidylate synthase regulates the translation of p53 mRNA(abstract). Proc Am Assoc Cancer Res 36:563, 1995.

49. Houghton JA, Ebanks R, Harwood FG, et al: Inhibition of apoptosis after thymineless stress isconferred by oncogenic K-Ras in colon carcinoma cells. Clin Cancer Res 4:2841-2848, 1998.

50. Krammer PH: CD95(APO-1/Fas)-mediated apoptosis: Live and let die. Adv Immunol 71:163-210,1999.

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53. Houghton JA, Harwood FG, Gibson AA, et al: The fas signaling pathway is functional in coloncarcinoma cells and induces apoptosis. Clin Cancer Res 3:2205-2209, 1997.

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55. Yonekura K, Basaki Y, Chikahisa L, et al: UFT and its metabolites inhibit the angiogenesis inducedby murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res5:2185-2191, 1999.

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