Gemcitabine radiosensitizer

Table 1 Summary of the Available Preclinical Data on Gemcitabine s Radiosensitizing Potential ...

In addition to the above-outlined cytotoxic effects of gemcitabine, it also serves to act as a radiation sensitizer in many cell lines (see Table 1). Depending on the cell line tested, the drug concentration, the schedule of administration, and the cell proliferative status (e.g., plateau vs exponential growth), relative enhancement ratios (RERs) in the range of 1.1-2.5 have been reported. There is no evidence that preferential radiosensitization occurs in more radioresistant cell lines. 

These same authors also report a dose-dependent increase in the apoptotic rate after the administration of gemcitabine (33), which they believe correlates with the elimination of the more radioresistant S phase population of cells and redistribution of the remaining cells into more radiosensitive compartments of the cell cycle. They also report in another study that reoxygenation of the resistant hypoxic fraction of tumor cells is also a mechanism for the action of gemcitabine (34). Therefore, elimination of these S phase tumor cells may aid the radiation response by not only causing cell cycle synchronization but also by leading to reoxygenation of hypoxic cells. 

Gregoire V, Beauduin M, Bruniaux M, et al. Radiosensitization of mouse sarcoma cells by fludarabine (F-ara-A) or gemcitabine (dFdC), two nucleoside analogues, is not mediated by an increased induction or a repair inhibition of DNA double-strand breaks as measured by pulsed-field gel electrophoresis. Int JRadiat Biol 1998 73(5) 511-520. 

Lawrence TS, Chang EY, Hahn TM, Shewach DS. Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2, 2 -difluoro-2 -deoxycytidine (Gemcitabine). Clin Cancer Res 1997 3(5) 777-782. 

Latz D, Fleckenstein K, Eble M, Blatter J, Wannenmacher M, Weber KJ. Radiosensitizing potential of gemcitabine (2, 2 -difluoro-2 -deoxycy tidine) within the cell cycle in vitro. Int JRadiat Oncol Biol Phys 1998 41(4) 875-882. 

Rosier JF, Beauduin M, Bruniaux M, et al. The effect of 2 -2 difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity. Int J Radiat Biol 1999 75(2) 245-251. 

Chen M, Hough AM, Lawrence TS. The role of p53 in gemcitabine-mediated cytotoxicity and radiosensitization. Cancer Chemother Pharmacol 2000 45(5) 369-374. 

Fields MT, Eisbruch A, Normolle D, et al. Radiosensitization produced in vivo by once- vs. twice-weekly 2 2 -difluoro-2 -deoxycytidine (gemcitabine). Int J Radiat Oncol Biol Phys 2000 47(3) 785-791. 

Gemcitabine, a new pyrimidine antimetabolite, is of substantial interest as a radiosensitizer in the treatment of pancreatic cancer. An ongoing multi-institutional Phase II study of preoperative EBRT and concomitant gemcitabine therapy for resectable adenocarcinoma will provide useful information (57-60). 

Gemcitabine, which is another radiation sensitizer, was also shown to deplete the pool of deoxynucleosides and is integrated into DNA. The drug is known to exert a pronounced radiosensitizing effect in squamous cancer cells, as well as adenocarcinoma cells from pancreatic... 

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... 

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