Biomedical Engineering Reference
In-Depth Information
FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error
can interfere with RNA processing and protein synthesis and consequently with cell growth. It has
been suggested that while inhibition of TS is primarily responsible for the anticancer activity of
5-FU, its effect on RNA synthesis may be the main cause of its toxicity.
Even though 5-FU is an efi cient drug that has been used for many years in the treatment of solid
tumors, such as breast and colorectal cancers, there has been a wish to develop an orally available
l uoropyrimidine with improved efi cacy and safety proi le. The goal was to design derivatives
of 5-FU that could specii cally be converted to the parent drug (5-FU) by enzymes preferentially
located in tumor tissue. Several attempts have been made to make orally active prodrugs of 5-FU,
the most advanced version being a 5¢-deoxy-5-l uorouridine (5¢-DFUR) derivative (Figure 23.2B),
which is transformed by pyrimidine nucleoside phosphorylase (PyNPase) enzymes, which are pref-
erentially found not only in tumor tissue but unfortunately also in the intestine. Consequently, even
though there is some selective targeting of cancer cell with this compound, 5¢-DFUR also releases
5-FU in the intestine causing dose limiting toxicological effects there.
To get around the unwanted effects in the intestine, another strategy was developed. The chemi-
cal starting point for 5-FU prodrugs was the 5¢-deoxy-5-l uorocytidine (5¢-DFCR) described above
(Figure 23.2B), which was known to be effectively transformed to 5-FU by cytidine deaminase
(CyD), particularly in tumor tissue where it is highly expressed. This in combination with a low
activity of the same enzyme in human bone marrow cells indicated that selective killing of tumor
cells could be obtained. The strategy was now to i nd a l uoropyrimidine carbamate that was stable
in the intestinal tract but efi ciently hydrolyzed to 5¢-DFCR by carboxylesterase (CE) located in
the liver, where 5¢-DFCR could be further transformed to 5¢-deoxy-5-l uorouridine (5¢-DFUR), and
i nally to 5-FU by thymidine phosphorylase (TP) (Figure 23.2B).
Among the many prodrugs prepared to achieve this activity pattern, through extensively testing
for (1) selectivity for hepatic CE, (2) oral bioavailability, and (3) activity in human cancer xenograft
models in vivo, Capecitabine (
N
4
-pentyloxycarbonyl-5¢-deoxy-5-l uorocytidine, Xeloda
Ô
), devel-
oped and marketed by Roche, was found to have the most favorable characteristics resulting in
substantially higher 5-FU concentrations within tumors than observed in plasma and in normal
tissue (muscle) (Figure 23.2B). Additionally, the tumor 5-FU levels were much higher than those
that could be achieved by the intraperitoneal administration of 5-FU at equitoxic doses. This tumor
selective delivery of 5-FU ensures a greater efi cacy and a more favorable safety proi le than can
be obtained by other l uoropyrimidines. Xeloda is now approved in the United States, Canada, and
other countries for the treatment of metastatic breast cancer.
23.2.2 A
LIMTA
The discovery of Alimta has its chemical origin in the early i ndings of the antimetabolites amin-
opteridines and thereafter methotrexate and both inhibit folate metabolism (Figure 23.3C). The
impressive anticancer effects found for methotrexate validated folate antimetabolites early on as
antiproliferative agents. For decades, researchers have worked on the task to i nd inhibitors of
folate-dependent enzymes such as TS, dihydrofolate reductase (DHFR), and glycinamide ribonucle-
otide formyltransferase (GARFT), which take part in the folic acid activation (Figure 23.3A). The
active form of folate is the reduced form tetrahydrofolate (Figure 23.3B), which plays an important
role in the biochemical pathways to donate one carbon unit in the form of methyl, methylene, or
formyl groups. These metabolic reactions are essential for the formation of DNA, RNA, ATP, and
the catabolism of certain amino acids. Consequently, inhibiting this metabolic pathway abrogates
cancer cell proliferation because cancer cells have high demands for ATP, and because they require
high levels of nucleic acid precursors for DNA synthesis.
The pathway leading to the formation of tetrahydrofolate (THF) begins when folate (F) is
reduced to dihydrofolate (DHF), which is then reduced to THF, DHFR catalyses both steps (Figure
23.4). Methylene tetrahydrofolate (CH
2
THF) is formed from tetrahydrofolate by the addition of
