Biomedical Engineering Reference
In-Depth Information
23.2.1 X
ELODA
The classic antineoblastic agent 5-Fluorouracil, 5-FU (Figure 23.2A), is a l uorinated analog of
uracil. 5-FU exhibits its main activity via two known biochemical mechanisms originating from the
5-FU metabolites 5-l uoro-2¢-deoxyuridine monophosphate (FdUMP) and 5-l uorouridine triphos-
phate (FUTP) (Figure 23.2A). FdUMP and the folate cofactor
N
5
,
N
10
-methylene-tetrahydrofolate
bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhib-
its the formation of thymidylate from 2¢-deoxyuridylate. Since thymidylate is a necessary precursor
of thymidine triphosphate, which is essential for the synthesis of DNA, its inhibition causes inhibi-
tion of cancer cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate
O
F
HN
O
F
O
O
N
HN
O
P
O
R1
O
H
OH
O
5-FU
HO
R2
FdUMP: R1 = H, R2 = H
O
O
,
FUTP: R1 =
HO
P
O
P
R2 = OH
(A)
OH
OH
O
O
HN
O
NH
2
F
F
F
HN
N
N
O
O
O
O
N
N
N
F
HN
O
O
O
O
H
HO
OH
HO
OH
HO
OH
Xeloda
5'-DFCR
5'-DFUR
5-FU
5'-DFCR
CyD
Xeloda
Xeloda
CE
5'-DFUR
TP
5'-DFCR
CyD
5'-DFUR
5-FU
(B)
Intestine
Liver
Cancer cell
FIGURE 23.2
(A) Chemical structures of 5-FU and its bioactive metabolites. (B) Bioreactive pathways
leading to the generation of 5-FU from Xeloda. The relevant enzymes and their compartments are shown.
