Assessment of Apoptosis Following Radiotherapy

Cell death can occur in a disorganized, nonphysiological fashion (necrosis) or in a carefully orchestrated sequence (apoptosis) that leaves little, if any, residue. Most cancer therapies initiate several physiological stimuli that trigger a programmed cellular set of events resulting in apoptotic cell death (117). Apoptotic cell death eventually leads to the shrinkage of a lesion. These anatomical changes can be staged by many noninvasive imaging techniques, such as ultrasound, CT, MRI, or even scintigraphic imaging. However, these anatomical manifestations of lesions occur only slowly, and imaging of this process does not permit one to monitor the functional cellular changes that trigger cell apoptosis in the early state of a therapeutic intervention. Imaging apoptosis can lead researchers to determine noninvasively the effectiveness of a given therapeutic treatment at a very early stage before anatomical shrinkage of a treated lesion is apparent.

DNA fragmentation is one of the hallmarks of apoptosis (118). Improved immunohistochemical techniques have permitted the identification of apoptosis in situ by specific labeling of nuclear DNA fragments (TUNEL) (119). An earlier indicator of apoptosis, however, arises from membrane phospholipid rearrangements that elevate phosphatidylserine on the cell surface (118). Phosphatidylserine is exposed well before cell necrosis and before the characteristic morphological changes of plasma membrane blebbing, vesicle formation, or cytoskeletal disruption. The phosphatidylserines in turn provide a high-affinity (Kd = 7 nM) binding site for annexin-V, a 36-kDa human protein (120). Tc-99m-annexin-V has been prepared and utilized successfully to visualize cancer cells undergoing apoptosis (121).

This method has specifically been applied to identify apoptosing cells following antisense treatment (122). Furthermore, Tc-99m-annexin-V has been shown to image apoptosis in vivo (123). Hence, we propose noninvasive monitoring of apoptosis induced in vivo by Re-188-PNA-peptides by Tc-99m-annexin-V scintigraphy. The onset of apoptosis induces membrane phospholipid rearrangements that elevate phosphatidylserine on the cell surface well before cell necrosis and before the characteristic morphological changes of plasma membrane blebbing, vesicle formation, or cytoskeletal disruption (118).

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