Anticancer drugs enzyme inhibitors

Relling, M.V., Evans, W.E., Fonne-Pfister, R., et al. (1989) Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49, 68-71. 

The protected E-ring moiety of (S)-camptothecin has been prepared in enantio-merically enriched form by the enzymatic resolution of a triester with PLE in a pH 7 phosphate buffer-acetonitrile (5 1) solution (Figure 6.7). The alkaloid camptothecin is an inhibitor of the enzyme topoisomerase and some of its derivatives are anticancer drugs [52]. 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

It should be noted that all these enzymes are targets for inhibitors that act as antitumour (anticancer) drugs (Chapter 21). 

Inhibitors. Aside from its role in providing reduced folate coenzymes for cells, this enzyme has attracted a great deal of attention because it appears to be a site of action of the important anticancer drugs methotrexate (amethopterin) and aminopterin.293 364 365 These compounds inhibit dihydrofolate reductase in concentrations as low as 10 8 to 10 9 M. Methotrexate is also widely used as an immunosuppresant drug and in the treatment of parasitic infections. 

During the course of clinical development, it is often important to identify the structures of metabolites. This information provides an opportunity to better understand interpatient variability in pharmacokinetics and toxicity. Clinical studies performed by Lokiec and coworkers, 1996 on a semisynthetic derivative of 20(S)-camptothecin, CPT-11, demonstrate the use of LC/MS to investigate the in vivo metabolic pathways. CPT-11 is a potent inhibitor of topoisomerase II, which is an enzyme involved in DNA duplication, and exhibits significant activity against various types of tumors in clinical studies. The understanding and control of the main biotransformation pathways are particularly important for anticancer drugs because therapeutic doses are often close to the maximum tolerated dose. 

The chemical structures of four commonly used anticancer drugs are shown in Fig. 15-17. Methotrexate was the first "true anticancer drug, synthesized in 1949, and has been in clinical use for treatment of a variety of cancers since the early 1950s. Methotrexate is a potent inhibitor of dihydrofolate reductase with an inhibition constant (Kt) for interaction with the enzyme of 10 9Af. Inhibition of this enzyme in a cell leads to major accumulation of DHF to concentrations of 2.5 fiM, and minor decreases in THF. Marked decreases in THF may not be seen due to the release of bound THF in methotrexate-treated cells. The high levels of DHF are toxic to the cell, inhibiting the reaction catalyzed by thymidylate synthase,... 

Most drugs produce a reversible pharmacological response. However, some antibiotics, irreversible enzyme inhibitors, and anticancer agents incorporate irreversibly or covalently into a cell s metabolic pathway. This results in an irreversible effect—cell death. Complex kinetic models are used to explain the relationship of dose-chemotherapeutic effects for some drugs, such as methotrexate, cyclophosphamide, and arabinosylcytosine.f ... 

Inhibitors of topoisomerase I and topoisomerase II are the most commonly used anticancer drugs. The camp-tothecins—topotecan and rrinotecan (CPT-11)—interact with the enzyme topoisomerase I the podophyllotoxins— etoposide and teniposide—target topoisomerase II. They cause various forms of single- and double-strand breaks in DNA (1-7). Other drugs inhibit both enzymes simultaneously (8) (see below). 

Another approach is the inhibition of the TNF-converting enzyme (TACE), which converts proTNF into its mature, proinflammatory form. Also, numerous inhibitors of P38 and Erk-MAP kinases have been synthesized and some have reached the clinical trial stage. MAP-p38 kinase occupies a central role in the signaling network responsible for the up-regulation of proinflammatory cytokines like interleukin 1 and TNFa. The pathway of Erk-MAP kinase is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. ... 

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