Selective drugs, activity toward

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

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]. 

Although CsA and FK506 are extremely selective inhibitors of calcineurin, some of the studies above indicate that these drugs could possibly have calcineurin-independent elfects. Moreover, calcineurin shows phosphatase activity towards a wide variety of phosphoprotein substrates, and inhibition of calcineurin by immunosuppressant-immunophilin complexes blocks phosphatase activity toward a broad spectrum of phos-phoproteins. Inhibitors that blocked calcineurin mediated dephosphorylation of a specific substrate (such as NF-AT, or specific isoforms of NF-AT) without affecting the dephosphorylation of other substrates would be of great therapeutic as well as academic interest. The search for... 

Figure 7. Basis for selectivity of action towards hypoxic cells of bioreductively-activated drugs which involve oxygen-reactive intermediates.

---