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Chapter: Biochemical Pharmacology : Some principles of cancer pharmacotherapy


Cell cycle-selective agents comprise antimetabolites (of DNA synthesis) and inhibitors of mitosis .


Cell cycle-selective agents comprise antimetabolites (of DNA synthesis) and inhibitors of mitosis (cell division; see below). A widely used example of an antimetabolite is 5-fluorouracil (5-FU; Figure 13.11). Before this drug ac-tually does something interesting, it needs to be converted to the nucleotide analog 5-fluoro-deoxyuridinemonophos-phate (5-FdUMP), which occurs in the same way as with normal uracil.

5-FdUMP is an analog of dUMP, which is the substrate for dTMP synthesis by thymidylate synthase; it is this reaction that is inhibited by dUMP (Figure 13.12a). The catalyt-ic mechanism of thymidylate synthase is depicted in Fig-ure 13.12b. The enzyme (thymidylate synthase) requires N,N'-methylene-tetrahydrofolic acid as a cosubstrate. The reaction is initiated by a cysteine residue in the active site of the enzyme and involves an intermediate in which the enzyme, the substrate (dUMP), and the cosubstrate are all covalently bound (bottom center in Figure 13.12b). This complex is resolved in the second step, which involves ab-straction of the hydrogen in position 5 of the uracil by a basic residue in the active site. The trick with 5-FU is that this abstraction doesn't happen, since position 5 is occupied by fluorine, which is very tightly bound to the ring. There-fore, the enzyme remains covalently locked up – 5-FU is a covalent and thus very efficient inhibitor of thymidylate synthase.

Another intriguing consequence of the fluorine substitution is its promotion of the tautomeric form of the ring, which has base-pairing properties resembling those of cytosine. Incorporation of 5-FU (subsequent to further phosphory-lation of 5-FdUMP to 5-FdUTP) therefore induces muta-tions due to misincorporation of guanine instead of adenine (Figure 13.11c)11. The same behaviour is observed with the bromine analog of 5-FU (5-bromouracil). Bromine is sim-ilar in size to a methyl group, so that 5-BU sterically re-sembles thymidine and therefore is efficiently incorporated into the DNA (more so than 5-FU). It is not used in cancer therapy but is commonly used (in the form of a pro-drug, 5-bromouracil-deoxyriboside) as a mutagen in experimen-tal research.

We have just seen that folic acid functions as a coenzyme in the synthesis of dTMP. It also donates methyl groups in the synthesis of purine bases, so that it is actually quite impor tant in DNA synthesis. After transfer of the methyl group by N,N'-methylene-tetrahydrofolate, the remainder (dihy-drofolate) is regenerated in two steps, the first of which is the reduction to tetrahydrofolate by dihydrofolate reductase. This enzyme is inhibited by methotrexate (Figure 13.13). Note that with this antimetabolite there is no possibility of introducing mutagenic base analogs into the DNA. It there-fore has less carcinogenic potential than most other drugs discussed here and is also sometimes used as an immuno-suppressive agent in diseases other than cancer.

A quite unusual antimetabolite is the enzyme L-asparagi-nase, isolated from E. coli, commonly used in the treatment of leukemia. Asparagine is a precursor of purine synthe-sis (Voet & Voet have all the details), and depletion of this amino acid seems to slow down tumour cells. One could speculate at length why this would have a preferential ef-fect on tumour cells, but it may be better not. Of note, this drug can be used for extended periods of time without inducing a neutralizing immune response (which it nor-mally should) because the immune system will be quite knocked out under the prevailing conditions of disease and treatment.


A nucleotide antimetabolite that carries the modification in the sugar rather than in the base is cytosine arabinoside (araC; Figure 13.14). In this molecule, there is an OH group in position 2 of the ribose, pointing in the `wrong' direction (as compared to ribose). AraC gets incorporated into DNA but then apparently interferes with further DNA synthesis. This may affect different DNA polymerases to different extents; in fact, araC reportedly inhibits DNA repair more strongly than DNA replication (the two processes involve different DNA polymerases).

Another aspect of antimetabolite therapy exemplified by araC is the emergence of resistance in tumours that are ini-tially susceptible. How come? Like 5-FU and many oth-er antimetabolites, araC requires metabolic activation; on the other hand, the activated metabolites are also subject to degradation (Figure 13.14c). In the beginning, we noticed that tumour cells are quite instable genetically. Chromoso-mal deletions or duplications may easily result either in a re-duced drug activation or in accelerated degradation, by way of changing the copy numbers of the genes encoding the re-spective enzymes. Similarly, translocation may cause trans-fer of these genes into foreign regulatory contexts with con-comitant over- or under-expression. Such causes of cancer cell drug resistance have been experimentally confirmed.

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