Several growth factors have been found to be radioprotective, especially when given before irradiation. Among these are the cytokines IL1, granulocyte colony stimulating factor (G-CSF), and some members of the FGF family. Irradiation can also cause the release of cytokines. For example, irradiation of mononuclear phagocytes can cause release of platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-a) and insulin-like growth factor-1 (IGF-I) (53), which may, in addition to altering cell survival, play a significant role in the pathogenesis of irradiation-induced pulmonary fibrosis (53). Thus, the role of growth factors at the cellular and organism level is complex, and the net effect of growth factor release by host and tumor cells on the radiosen-sitivity of either host or tumor will depend on the site of release, and the cells involved in the response to these factors. The work described here focuses on the effect of bFGF in the radiation resistance of transformed cells.
bFGF expression has been associated with advanced stage or poor prognosis in a number of solid tumors, including pancreatic and renal malignancies (54-56), and is frequently expressed by glioblastoma cells (57-60). bFGF has been shown in several studies to be a radioprotector agent both for hematopoietic tissues and endothelial cells. In vitro, exogenous bFGF has been implicated in protection of bovine endothelial cells (BAEC) from the lethal effects of ionizing radiation via an autocrine loop (61). This radioprotective effect is not owing to preferential repair of DNA breaks but rather to an inhibition ofinterphase apoptosis (16) involving protein kinase C (62). Langley et al. (63) reported that bFGF has a radioprotective effect in microvessels cells, and that either bFGF withdrawal or ionizing radiation induce apoptosis in confluent monolayers of capillary endothelial cells, and that radiation apoptosis was decreased but not abolished in the presence of bFGF.
Studies in vivo have also shown that bFGF is radioprotective when administered before total body irradiation. This effect was attributed to myeloprotection, and did not appear to affect the radiation response of tumors (64-66). Thus, protection appeared to be specific for normal tissue in these studies. A radioprotective effect was also reported by Fuks etal. (16), who showed that bFGF prevented lethal radiation-induced pneumonitis in C3H/HeJ mice. The authors suggested that this was owing to bFGF protection of pulmonary endothelial cells from radiation-induced apoptosis. Another study by Tee and Travis (67), however, failed to detect protection by bFGF from death owing to classical radiation pneumonitis in two different strains of mice. They also observed that the incidence of apoptotic bodies did not exceed 1%, were scattered throughout the lung, and were not located selectively in endothelial cells (67). Thus, the exact role, ifany, ofbFGF in radiation-induced pneumonitis is debatable. Another member of the FGF family, FGF4, when transfected in adrenal cortical carcinoma cells, caused enhanced cell survival to ionizing radiation, an effect that was correlated with a pronounced increase in the duration ofG2 arrest (68). Khan etal. (18) have also shown that keratinocytes growth factor (KGF), a member of the FGF7 family administered intravenously before total body irradiation increased the survival of irradiated murine intestinal crypt cells in the duodenum, jejunum, and ileum. These studies have shown that the cellular response to radiation can include the production of cytokines, and that certain of these can, in some cases provide a measure of protection to irradiated cells. This conclusion led to examination of the possibility that inhibiting signaling from these cytokine pathways could diminish the protective effect of cytokine production.
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