Fluoropyrimidine radiosensitization

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

Fluoropyrimidines do radiosensitize by causing redistribution of cells into a relatively sensitive phase of the cell cycle (early S). 

One hypothesis for fluoropyrimidine-induced radiosensitization is that fluoropyrimidines induce changes in nucleotide pools including the ability of polymerases to... 

Another proposal is that radiosensitization embarks from 5-FU-induced cell cycle redistribution. Both 5-FU and FdUrd result in arrest of S phase cells and block cells that are notinS phase at the Gl/S interface. Studies in rodent (31) and HeLa cells (32) have revealed that early S phase is a relatively sensitive phase of the cell cycle, thereby suggesting that fluoropyrimidine-mediated radiosensitization may result from redistribution into a more radiosensitization phase of the cell cycle. Investigators also tried to evaluate dependence on the timing of exposure to fluoropyrimidines in relation to radiation on the resultant radiosensitization, such as to correlate the enhancement ratio with the fraction of cells in early S phase (12) (Fig. 5). 

It has been postulated that radiation may act as a potentiator of fluoropyrimidine-medi-cated cytotoxicity. This possibility is borne out of the observation that fluoropyrimidine-induced radiosensitization of human colon cancer cells tends to occur under conditions that produce at least some cytotoxicity by the drug alone (15,33,36,37). This hypothesis is further supported by the data employing FdUrd treatment in HT29 cells, which showed that enhancement ratio was significantly greater when surviving fraction was <0.7 than when the surviving fraction was >0.7 (p < 0.05 by t test) (Fig. 6). 

PHARMACOLOGICAL AND SCHEDULING REQUIREMENTS FOR OBTAINING EFFECTIVE RADIOSENSITIZATION WITH FLUOROPYRIMIDINES... 

The recent availability of oral formulations of 5-FU involving the ability to modulate the anabolic and catabolic metabolism of 5-FU with LV and dihydropyrimidine dehydrogenase (DPD) inhibitors has provided a substantial improvement in the ease of administration and may probably improve the efficacy of fluoropyrimidine-induced radiosensitization. Such oral fluoropyrimidines include UFT (uracil tegafur) plus oral LV (Orzel ), an oral DPD-inhibitory fluoropyrimidine (DIF), and capecitabine (Xeloda Roche). 

Lawrence TS, Davis MA, LoneyTL (1996b) Fluoropyrimidine-mediated radiosensitization depends on cyclin E-depen-dent kinase activation. Cancer Res 56 3203-3206 Lawrence TS, Chang EY, Hahn TM (1996c) Radiosensitization of pancreatic cancer cells by 2, 2 -dilluoro-2 -deoxycyti-dine. Int J Radiat Oncol Biol Phys 34 867-872 Lawrence TS, Chang EY, Hahn TM, Shewach DS (1997) Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2, 2 -difluoro-2 -deoxycytidine (gemcitabine). Clin Cancer Res 3 777-782... 

Naida JD, Davis MA, Lawrence TS (1998) The effect of activation of wild-type p53 function on fluoropyrimidine-mediated radiosensitization. Int J Radiat Oncol Biol Phys... 

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