TY - JOUR
T1 - TRAIL and doxorubicin combination induces proapoptotic and antiangiogenic effects in soft tissue sarcoma in vivo
AU - Wang, Suizhao
AU - Ren, Wenhong
AU - Liu, Jeffery
AU - Lahat, Guy
AU - Torres, Keila
AU - Lopez, Gonzalo
AU - Lazar, Alexander J.
AU - Hayes-Jordan, Andrea
AU - Liu, Kebin
AU - Bankson, Jim
AU - Hazle, John D.
AU - Lev, Dina
PY - 2010/5/1
Y1 - 2010/5/1
N2 - Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xeno-grafts in vivo. Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes. Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro. Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted.
AB - Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xeno-grafts in vivo. Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes. Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro. Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted.
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U2 - 10.1158/1078-0432.CCR-09-2443
DO - 10.1158/1078-0432.CCR-09-2443
M3 - Article
C2 - 20406839
AN - SCOPUS:77951714797
SN - 1078-0432
VL - 16
SP - 2591
EP - 2604
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -
