Cell cycle redistribution

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). 

Cell cycle redistribution may not be the sole factor if cells are irradiated before drug exposure, but it has been shown that 5-FU can sensitize even when cells are irradiated before drug exposure. Byfield et al. found that 5-FU radiosensitizes HeLa cells only when the drug exposure followed radiation (the cells were treated with 5-FU, either before or after radiation, for up to 8 d). A similar finding was observed on HT29 human colon cancer cells, except that in these experiments cells were exposed to 5-FU for a maximum of only 30 min before radiation (33). These observations demonstrate that radiosensitization can be produced in the absence of cell cycle redistribution. 

Lawrence TS, Davis M, Tang HY, et al. Fluorodeoxyuridine-mediated radiosensitization of human colon cancer cells is not caused by cell cycle redistribution. ProcAACR 1992 33 502, (abstr 3002). 

In human breast and prostate cancer cell fines, retinoids have been shown to induce apoptosis via induction of p21/ WAF/cipl (Thompson et al., 1996 Li et al., 1996) and affect G1 cell cycle arrest through mitogen-activated protein kinase phosphorylation (Nakagawa et al., 2003). Zhang and Rosdahl (2005) demonstrated that expression of Idl protein decreased and that of pi6 protein increased in melanoma cell fines exposed to all-rntwr-RA, and suggested that these alterations may be involved in the observed apoptosis and cell cycle redistribution. 

McGinn CJ, Miller EM, Lindstrom MJ, et al (1994) The role of cell cycle redistribution in radiosensitization implications regarding the mechanism of fluorodeoxyuridine radiosensitization. Int J Radiat Oncol Biol Phys 30 851-859 McGinn CJ, Shewach DS, Lawrence TS (1996) Radiosensitiz-ing nucleosides. J Natl Cancer Inst 88 1193-1203 Milas L, Hunter NR, Mason KA, et al (1994) Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel. Cancer Res 54 3506-3510 Milas L, Hunter NR, Mason KA, et al (1995) Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res 55 3564-3568 Miller EM, Kinsella TJ (1992) Radiosensitization by fluorodeoxyuridine effects of thymidylate synthase inhibition and cell synchronization. Cancer Res 52 1687-1694 Miller SJ, Lavker RM, Sun TT (2005) Interpreting epithelial cancer biology in the context of stem cells tumor properties and therapeutic implications. Biochem Biophys Acta 1756 25-52... 

Redistribution There are results of classical experiments that show that cells respond differently to radiation depending on which part of the cell cycle they are in when radiation is delivered. For human cancer cells the G2M boundary appears to be the position in the cell cycle associated with the greatest sensitivity. It is likely that a drug that is able to block cell cycle progression in a radiosensitive phase will be associated with significant radiosensitization. The taxanes are an example of such a compound (40). 

The mechanisms of interaction between fluorouracil and radiation are not clearly understood. Different hypotheses have been postulated to explain the synergistic or potentiated effect of 5-FU with radiation including redistribution of cells to a more radiosensitive cell cycle phase, deranged pyrimidine pools with reduced capacity for repair of DNA damage, and activation of apoptosis. The effect of 5-FU on radiation damage also appears to vary in different cell lines, thus complicating the extrapolation of laboratory results into clinical practice. 

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

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. 

Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA (2001a) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer s disease. J Neurochem 76 435 41 Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA (2000) Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59 880-888... 

Lippincott-Schwartz J, Yuan LC, Bonitacino JS, et ol. (1989) Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A Evidence for membrane cycling from the Golgi to the ER. In Cell 56 801 -813. 

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