| Abstract |
PURPOSE: For the development of new anti-cancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated neighboring cells because they may affect the therapeutic efficacy and contribute to side effects.
EXPERIMENTAL DESIGN: Here, we investigated the contribution of non-targeted cytotoxic and genotoxic effects in vitro and in vivo in (xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT).
RESULTS: Between 67 and 94% (alpha RIT) and 8 and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7-36% (alpha RIT) and 27-29% (Auger RIT) of cells were killed by non-targeted effects. We then demonstrated that the non-targeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and c-JUN N-terminal kinases (JNK). Reactive oxygen species also played a significant role in these non-targeted effects, as demonstrated by NF-kB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo These results were supported by an inhibitory effect of pravastatin on Auger RIT.
CONCLUSIONS: Cell membrane-mediated non-targeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy. |
Institut de Recherche en Cancérologie de
