Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity

被引：83

作者：

Candolfi, Marianela ^{[1
,2
]}

Yagiz, Kader ^{[1
,2
]}

Foulad, David ^{[1
,2
]}

Alzadeh, Gabrielle E. ^{[1
,2
]}

Tesarfreund, Matthew ^{[1
,2
]}

Muhammad, A. K. M. Ghulam ^{[1
,2
]}

Puntel, Mariana ^{[1
,2
]}

Kroeger, Kurt M. ^{[1
,2
]}

Liu, Chunyan ^{[1
,2
]}

Lee, Sharon ^{[1
,2
]}

Curtin, James F. ^{[1
,2
]}

King, Gwendalyn D. ^{[1
,2
]}

Lerner, Jonathan ^{[1
,2
]}

Sato, Katsuaki ^{[3
]}

Mineharu, Yohei ^{[1
,2
]}

Xiong, Weidong ^{[1
,2
]}

Lowenstein, Pedro R. ^{[1
,2
]}

Castro, Maria G. ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Gene Therapeut Res Inst, David Geffen Sch Med,Dept Med, Los Angeles, CA 90048 USA

[2] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Gene Therapeut Res Inst, David Geffen Sch Med,Dept Mol & Med Pharmacol, Los Angeles, CA 90048 USA

[3] RIKEN Yokohama Inst, Lab Dendrit Cell Immunobiol, Res Ctr Allergy & Immunol, Kanagawa, Japan

来源：

CLINICAL CANCER RESEARCH | 2009年 / 15卷 / 13期

关键词：

APOPTOSIS-INDUCING LIGAND; NECROSIS-FACTOR-ALPHA; MEDIATED GENE-THERAPY; HUMAN BRAIN; RECEPTOR EXPRESSION; THYMIDINE KINASE; MALIGNANT GLIOMA; DENDRITIC CELLS; FAS LIGAND; TK GENE;

D O I：

10.1158/1078-0432.CCR-09-0155

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Purpose: In preparation for a phase I clinical trial using a combined cytotoxic/immunotherapeutic strategy with adenoviruses (Ad) expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor-killing agent in relation to efficacy and safety when compared with other proapoptotic approaches. Experimental Design: The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the proapoptotic cytokines [tumor necrosis factor-alpha, tumor necrosis factor-related apoptosis-inducing factor (TRAIL), and Fas ligand (FasL)], alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival. Results: In rats bearing large GBMs (day 9), the combination of Ad-Flt3L with Ad-FasL did not improve survival over FasL alone, whereas Ad-Flt3L combined with Ad-TK+GCV led to 70% long-term survival. Expression of FasL and TRAIL caused severe neuropathology, which was not encountered when we used Ad-TK+/-Ad-Flt3L. In vitro, all treatments elicited release of high mobility group box 1 protein (HMGB1) from dying tumor cells. In vivo, the highest levels of circulating HMGB1 were observed after treatment with Ad-TK+GCV+Ad-Flt3L; HMGB1 was necessary for the therapeutic efficacy of AdTK+GCV+Ad-Flt3L because its blockade with glycyrrhizin completely blocked tumor regression. We also showed the killing efficacy of Ad-TK+GCV in human GBM cell lines and GBM primary cultures, which also elicited release of HMGB1. Conclusions: Our results indicate that Ad-TK+GCV+Ad-Flt3L exhibit the highest efficacy and safety profile among the several proapoptotic approaches tested. The results reported further support the implementation of this combined approach in a phase I clinical trial for GBM.

引用

页码：4401 / 4414

页数：14

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