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5-Fluoro Uracil

Figure. Structure 5-Fluorouracil (left) and thymine (right)

5-Fluorouracil (5-FU) is a main chemotherapy agent that used for colon cancer therapy. 5-FU is anti-metabolite that work antagonist with thymine against thymidylate synthetic (TS) enzyme activity.  5-FU is a pro-drug, metabolism of 5-FU produce fluoridin-5′-trifosfat (FUTP) that combines in RNA and affect its function, and fluorodeoxiuridilat (FdUMP) that inhibit DNA replication.

5-Fluorouracil (5-FU) was conversed become 3 main active metabolite namely : (1) fluoro-deoxyuridine monophosphate (FdUMP), (2) fluorodeoxyuridine triphosphate (FdUTP), and (3) fluorouridine triphosphate (FUTP). Main mechanism of 5-FU activation is conversion become fluorouridine monophosphate (FUMP) also directly by orotate phosphoribosyl transferase (OPRT), or un-directly via fluorouridine (FUR) through sequence action  from uridine phosphorylase (UP) and uridine kinase (UK). FUMP then phosphorylated become fluorouridine diphosphate (FUDP), that also phosphorylated further become active metabolite fluorouridine triphosphate (FUTP), or conversed become fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase (RR). In the other side, FdUMP also phosphorylated or dephosphorylated become active metabolite among others FdUTP and FdUMP. Other alternative activation track involve thymidine phosphorylase that catalyzing 5-FU conversion become fluorodeoxyuridine (FUDR), then phosphorylated by thymidine kinase (TK) and become thymidylate synthase (TS) inhibitor, FdUMP. There is also Dihydropyrimidine dehydrogenase (DPD) enzyme that conversing 5-FU become inactive dihydrofluorouracil. (DHFU) is a rate-limiting step catabolism 5-FU in normal cell and tumor cell, and proprsi from destruction become inactive metabolite 80% (Longley and Johnston, 2007).

 

This will cause apoptosis induction because inhibition of DNA synthesis that caused by lacked cell of deoksitimidin trifosfat (dTTP). TS expression increment in cancer cell is cell response that cause resistance against 5-FU (Giovanetti et al., 2007).

 

In relation to the cell recycle, 5-FU cannot work in cell that be out of cell cycle (G0). 5-FU just work in cell that active undergo cell cycle where require TS activity for constituent bases of DNA synthesis. TS expressed high in G1 phase through intermediary transcription activity from E2F. After expresses, TS synthesizing directly dUMP precursor that requird in synthesis phase. Treatment with 5-FU in cancer cell can cause cell accumulation in G1 phase and early synthesis phase (G1/S arrest) (Liu et al., 2006). But, however cell cycle inhibit activity by 5-FU depend in cancer cell type.

 

In colon cancer cell HCT-15 and HT-29, 5-FU show inhabitation in G2/M phase. 5-FU increasing expression of cyclin A, cyclin B, and CDC2 that include regulator protein in G2/M phase (Lim et al., 2007). Mechanism that mediating activity in that phase require to further explored. In Lovo cell and WiDr, Backus et al. (2001) reported that 5-FU cause inhabitation of cell cycle in S phase. This show that 5-FU activity not forever about TS inhabitation activity and required research for 5-FU activity confirmation in cell cycle if used another cell.

 

5-FU can induct the happen of cell cycle stop and apoptosis acceleration without involve p53 role, but involve expression increament of p21 and pRb. Both protein have important role in checkpoint system in G1 phase. High pRb expression will inhibit E2F activity thus causing cell inhibition to exceed R. p21 expression will inhibit activity of cyclin E/CDK2 and cyclin A/CDK2 thus cause inhibition of cell cycle in G1 and S phase. Cell that include in G1 phase will be stop in G1 phase, whereas cells that are in S phase will be stopped in that phase. Resistance that caused by 5-FU happen through mediator of cell cycle inhibition. Cancer cell with p21 mutant cannot touch up cell cycle stop so that it touch up apoptosis directly but cell with normal p21  that touch up cell cycle stop will trigger resistance cell. 5-FU activity in apoptosis accelerator can through p53 track or not (dependent or independent p53) (Levrero et al., 2000). This is evidenced that 5-FU can inducting apoptosis in cancer cell that deficiency p53 or have p53 mutant.

Side effect from 5-FU that found in patient among others neutropenia, stomatitis, diarrhea, and hand-food syndrome. Each effect related with giving method that applied in patients (Meyerhardt and Mayer, 2005).   In the most severe 5-FU side effect case was cardio-toxicity although seldom found (Thomas et al., 2004). Compared with other chemotherapy agent, 5-FU has a high selectivity in TS activity and the side effect that caused is easier. Although thus, 5-FU effectiveness as chemotherapy agent still reach 15% so that required development of chemoprevention agent for increasing effectiveness of 5-FU therapy (Meyerhardt and Mayer, 2005).


References

Backus, H.H.J., Pinedo, H.M., Wouters, D., Kuiper, C.M., Jansen, G. and van Groeningen, C.J., 2001, Differences in the Induction of DNA Damage, Cell Cycle Arrest, and Cell Death by 5-Fluorouracil and Antifolates, Oncol. Res. Featuring Preclinal and Clinical Cancer Therapy, 12(5):231-239.

Giovannetti, E., Backus, H.H.J., Wouters, D., Ferreira, C.G., van Houten, V.M.M., Brakenhoff, R.H., Poupon, M-F., Azzarello, A., Pinedo, H.M. and Peters, G.J., 2007, Changes in the Status of p53 Affect Drug Sensitivity to Thymidylate Synthase (TS) Inhibitors by Altering TS Levels, British J. Can., 96:769-775.

Levrero, M., Laurenzi, V. De, Constanzo, A., Sabatini, S., Gong, J., Wang, J.Y.J. and Melino, G., 2000, The p53/p63/p73 Family of Transcription Factors: Overlapping and Distinct Functions, J. of Cell Science, 113:1661-1670.

Lim, Y.J.L., Rhee, J.C., Bae, Y.M. and Chun, W.J., 2007, Celecoxib Attenuates 5-Fluorouracil-Induced Apoptosis in HCT-15 and HT-29 Human Colon Cancer Cells, World J. Gastroenterol., 13(13):1947-1952.

Liu, H.C., Chen, G.G., Vlantis, A.C., Leung, B.C.S., Tong, M.C.E. and van Hasselt, C.A., 2006, 5-Fluorouracil Mediates Apoptosis and G1/S Arrest in Laryngeal Squamous Cell Carcinoma via a p53-Independent Pathway, The Cancer J., 12(6):482-493.

Longley, D.B. and Johnston, P.G., 2007, 5-Fluorouracil Molecular Mechanisms of Cell Death in Srivastava R., Apoptosis, Cell Signaling, and Human Diseases, Humana Press.

Meyerhardt, J.A., and Mayer, R.J., 2005, Systemic Therapy for Colorectal Cancer, N. Engl. J. Med., 352(5):476-487.

Thomas, J.B.D., Sharker, A. and Glenne-Jones, R., 2004, Chest Pain Induced by 5-Fluorouracil, Br. J., Cardiol, 11:483-485.

Contributors: Muthi Ikawati dan Sarmoko