Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity

YAGIZ; FOULAD; ALZADEH; TESARFREUND; MUHAMMAD; PUNTEL; KROEGER; LIU; LEE; CURTIN; KING; LERNER; SATO; MINEHARU; XIONG; LOWENSTEIN; CASTRO

CLINICAL CANCER RESEARCH

American Association for Cancer Research

Año: 2009 p. 4401 - 4414

1078-0432

Purpose: In preparation for a phase I clinical trialusing a combined cytotoxic/immunotherapeuticstrategy with adenoviruses (Ad) expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) totreat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimaltumor-killing agent in relation to efficacy and safety when compared with other proapoptoticapproaches.Experimental Design:The efficacy and neurotoxicity of Ad-TK+GCV was compared with Adsencoding the proapoptotic cytokines [tumor necrosis factor-a, tumor necrosis factor ^ relatedapoptosis-inducing factor (TRAIL), and Fas ligand (FasL)], alone or in combination withAd-Flt3L. In rats bearing small GBMs (day 4), onlyAd-TK+GCVorAd-FasL improved survival.Results: In rats bearing large GBMs (day 9), the combination of Ad-Flt3L with Ad-FasL did notimprove survival over FasL alone, whereas Ad-Flt3L combined with Ad-TK+GCV led to 70%long-terms urvival. Expression of FasL andTRAIL caused severe neuropathology, which was notencountered when we used Ad-TK+/-Ad-Flt3L. In vitro, all treatments elicited release of highmobility group box 1protein (HMGB1) from dying tumor cells. In vivo, the highest levels of circulatingHMGB1were observed after treatment with Ad-TK+GCV+Ad-Flt3L; HMGB1was necessaryfor the therapeutic efficacy of AdTK+GCV+Ad-Flt3L because its blockade with glycyrrhizincompletely blocked tumor regression.We also showed the killing efficacy of Ad-TK+GCV inhuman GBMcell lines and GBMprimary cultures, which also elicited release of HMGB1.Conclusions: Our results indicate that Ad-TK+GCV+Ad-Flt3L exhibit the highest efficacy andsafety profile among the several proapoptotic approaches tested. The results reported furthersupport the implementation of this combined approach in a phase I clinical trial for GBM.