Enzyme inhibition/inhibitors anticancer

All things considered, then, folic acid (or one of its derivatives) should be further studied as an anticancer agent, especially as it has been listed as an inhibitor for the same enzymes inhibited by the usual cytotoxic chemo agents. It is a substance natural to the body, and not some mysterious chemical or questionable plant or animal extract. Effective dosage levels and the best method of administration would have to be determined and the side effects established. If most doctors are reluctant to give even B12 or B-complex shots, megadoses of folic acid may not be on the cards. As with other cancer treatment alternatives, the patient may have to look at avenues other than medical orthodoxy. 

The objective is that the enzyme-inhibiting substance should be selective only against cancerous cells and not normal cells. In other words, it should not have any adverse side effects, that is, it should not act as an inhibitor for other enzymes involved in the vital functions of normal cells. In particular, these substances should neither impair respiration or cardiac activity nor act against the heart, liver, or other life-sustaining organs. These qualifiers are the rationale for seeking out certain foods or food components that are reputed to be normally nontoxic but which naturally contain anticancer agents, such as traces of bioactive alkaloids. 

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. 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

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. 

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,... 

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