Radiation-induced cytotoxicity

As detailed in the context of the hypoxic sensitizer discussion above, the idea that an easy-to-reduce species could function as a radiation sensitizer is not new [113-117]. Indeed, there is considerable precedent for it both in the radiation sensitization literature per se [113-115,118,125-129,132-135,138,139,142] and in classic mechanistic explanations of radiation-induced cytotoxicity [143-145]. However, as has also been made clear in the context of this earlier discourse, this idea has yet to translate into an FDA-approved XRT sensitizing product. However, as noted above, PCI-0120 (3) possesses special features that led to the consideration that it... 

Fluoropyrimidines cause changes in nucleotide pools that alone increase the cytotoxicity of radiation (i.e., by depleting substrates used in the repair of radiation-induced DNA damage). 

Therapeutic irradiation is known to have multiple interactions with the vasculature of the irradiated tissue (12). Radiation has direct cytotoxic effects on the vascular endothelium, likely due to induction of oxidative injury. Radiation-induced injury stimulates inflammation and influx of inflammatory cells in addition to creating aprocoagulant state in the vascular space by the transcriptional induction of tissue factor with the subsequent activation of coagulation factors as well as von Willebrand factor and platelets. Experimental evidence suggests that the mechanism by which radiation initiates these responses is in part through the induction of cell-adhesion molecules including ICAM-1, E-selectin, and P-selectin and in part through local cytokine production and release (13). 

The above are but a few examples of carcinogenesis in which the initiating effects of radiation have been enhanced by subsequent exposure to appropriate promoting stimuli. The cytotoxic effects of irradiation themselves have also been postulated to promote the development of radiation induced neoplasia in other situations e.g., in the pathogen-... 

Mantena SK, Meeran SM, Elmets CA, Katiyar SK. 2005. Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. J Nutr 135 2871-2877. 

Figure 6 SAHA enhances the radiation-induced kiiiing of hypoxic A549 and HT29 ceiis. The cells were treated under aerobic conditions for 24 h with 2.5 pM SAHA, subjected to anoxic conditions for 1 h and then exposed to a range of radiation doses. The radiation survival curve was corrected for SAHA cytotoxicity. The mean SERo.oi are 1.33 (n=2) and 1.59 (n — 2) for A549 and l-fT29, respectively.

Fig. 5.5. A summary of our current knowledge how integrin signaling critically modifies certain cellular response pathways upon radiation- or drug-induced cytotoxic stress. Cascades in green mediate prosurvival signals from transmembrane located integrins and RTKs via Ras/MEK/MAPK, Akt, or FAK/Src/Cas in a cell type- and/or context-dependent manner. The cascade in red transduces anti-survival signals via ILK, caspase-8 and cas-pase-3 to promote apoptosis...

Datta, R, Manome, Y, Taneja, N, Boise, LH, Weichselbaum, R, Thompson, CB, Slapak, CA and Kufe, D (1995) Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced intern ucleosomal DNA fragmentation. Gell Growth Differ, 6, 363-370. 

The cytotoxic effects of radiotherapy are only partially the result of radiation-induced DNA damage in tumor cells. By release of NO and other reactive species not only from myeloid-derived cells but also from stromal cells, tumor cells, and endothelial cells, secondary cytotoxicity will evolve. 

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