Esophagitis is a significant complication of concurrent chemotherapy and radiotherapy for thoracic malignancies, with an incidence up to 80% of patients in some treatment protocols (19
). Analgesics are used to manage pain (19
). Drugs including sucralfate and amifostine have shown limited effectiveness in radiation esophagitis (20
). We now present evidence that intraesophageal delivery of the p53/Mdm2/Mdm4 inhibitor BEB55, and the GS-nitroxide JP4-039, in F15 formulation, ameliorate radiation esophagitis in single-fraction and fractionated irradiated mice.
Two populations of cells could be targeted for preventing irradiation-induced esophagitis: quiescent stem cells and rapidly dividing populations (8
). We demonstrated that the GS-nitroxide JP4-039 is taken up by both the stem cell enriched SP and differentiated NSP cells. Successful detection in SP cells after drug delivery to esophageal cells may have been due to the slow esophageal transit of the F15 formulation and the extended release of JP4-039 containing liposomes (2
). SP cells had 41-fold greater uptake of JP4-039 per cell compared to the NSP population, contrary to the expected equal uptake by SP and NSP cells (21
). One possible explanation for the relative increase in SP cells may have been that the metabolically quiescent progenitor cells did not clear nitroxide as quickly as the more rapidly proliferating NSP cells.
We evaluated whether radioprotection of the esophagus by BEB55 was associated with alteration of cell cycle progression (18
). The data with BEB55 indicate that intraesophageal administration allowed irradiated esophageal cells to remain in G0
, which are more radioresistant phases of the cell cycle (18
). As an inhibitor of p53/Mdm2/Mdm4 complex formation, BEB55 should increase available p53, slowing cell cycle progression and increasing the checkpoint time for DNA repair (12
). This mechanism of protection may have been more effective in rapidly proliferating cells than in quiescent cells.
In vivo, both BEB55 and JP4-039 were effective radioprotectors against single- and multiple-fraction upper-body radiation. Since clinical radiation therapy protocols require multiple radiation doses administered over many weeks, the effectiveness of JP4-039 and its detection in several mouse organs after intraesophageal administration indicates that this drug may have utility in the clinic. Neither BEB55 nor JP4-039 was radioprotective for tumors, further supporting a potential clinical application for selectively protecting normal tissue during radiation therapy.
While BEB55 and JP4-039 confer radioprotection by different mechanisms, previous work did not detect an additive effect when combining the two drugs in vitro
compared to each alone (9
). This may be due to competitive uptake of the drugs and perhaps could be overcome by spacing the times of administration (21
). Further investigation may reveal that BEB55 increases the uptake of JP4-039, or a synergistic radioprotective effect may be found when the two compounds are spaced appropriately.
These results are significant in highlighting a potential advantage of the small molecule protectors JP4-039 and BEB55 as esophageal radioprotectors over MnSOD-PL gene therapy (22
). The small molecule protectors are relatively inexpensive to produce and do not require 24 h administration to show efficacy. Instead, they can be given immediately prior to radiation therapy (2
), and are quickly cleared from tissues. The potential utility of BEB55 and JP4-039 as radiation protectors in the clinic justifies further investigation.