Fluoropyrimidine mechanisms

Thymidylate synthase (TS) is the rate-limiting enzyme in the DNA synthetic pathway and the target for 5-FU and folate analogs (Figure 14.3). Compared to normal tissues, TS is often overexpressed in tumor cells, probably as a result of tumor suppression loss of function, gene amplification or other mechanisms. Acute induction of TS protein as well as stable amplification of TS-specific genes may be associated with resistance to fluoropyrimidine derivatives [118, 119], and an inverse correlation between tumor TS expression and clinical response was found [120-122]. 

The aminodefluorination occurs to a considerably lesser extent according to the Sn(ANRORC) mechanism (40%) apparently, the competitive addition on C-2, leading to the Sn(AE) substitution, is more favored. This preference for Sn(AE) reactions is characteristic of the fluoro atom it has been also observed in aminodefluorinations of 2-fluoropyrimidines (Section II,C,l,c). 

Fluoro-5-phenyl-l,2,4-triazine (109, X = F) reacts much faster than the 3-chloro-, 3-bromo-, or 3-iodo-compound. Moreover, the reaction mixture obtained is cleaner than that from the corresponding 3-chloro- or 3-bromo compounds 3-amino-5-phenyl-l,2,4-triazine (110) is formed in good yield. This conversion takes place to only a small extent (18%) via the ANRORC process the main part of the aminodefluorination seems to involve the Sn(AE) mechanism. This result is consistent with the observation that the aminodefluorination of 4,6-diphenyl-2-fluoropyrimidine follows the Sn(AE) process, whereas 2-fluoro-4-phenylpyrimidine (position 6 is vacant for addition of the nucleophile) reacts for the most part according to the Sn(ANRORC) mechanism (see Section II,C,l,c). 

Fluoropyrimidine-Radiation Interactions Mechanisms of Radiosensitization by Fluoropyrimidines Pharmacological and Scheduling Requirements for Obtaining Effective Radiosensitization with Fluoropyrimidines... 

The fluoropyrimidines as a group can affect the synthesis and function of both deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and both of these two mechanisms... 

The DNA-mediated effects of fluropyrimidines can be modulated by a number of agents, such as leucovorin (LV), levamisole, and interferon-alpha (IFN-alpha). LV prolongs TS inhibition by increasing the availability of the reduced folate cofactor necessary for formation of the inactive TS-FdUMP complex (21) (Fig. 4). Studies show alpha-interferon can potentiate 5-FU-mediated cyotoxicity, but the mechanisms are not yet defined (22,23). Another approach to modulate the activity of fluoropyrimidines is the use of the nucleoside transport inhibitor dipyridamole. Dipyridamole probably permits... 

Fluoropyrimidine-radiation interactions can best be understood in terms of the fundamental mechanisms by which fluoropyrimidines lead to DNA damage and ultimately cell death. Two such mechanisms have been described as ... 

Mechanism of action Capecitabine, fluoropyrimidine carbamate, is a prodrug of fluorouracil. It undergoes three-step enzymatic... 

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