Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of transformed cells while sparing normal cells. To enhance the therapeutic index of soluble (s)TRAIL, we used CD34+ cells transduced with a replication-deficient adenovirus encoding the human TRAIL gene (CD34-TRAIL+) for the systemic delivery of membrane-bound (m)TRAIL to lymphoid tumors. CD34-TRAIL+ cells were evaluated for their activity in vitro and in vivo in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with sTRAIL-sensitive and -resistant tumors. In vitro, coculturing CD34-TRAIL+ cells with sTRAIL-sensitive or -resistant lymphoma cell lines induced significant levels of caspase-dependent tumor cell death. In vivo, CD34-TRAIL+ cells significantly increased the survival of NOD/SCID mice bearing sTRAIL-sensitive or -resistant lymphoid tumors at an early or advanced stage of disease. No obvious toxicity was observed on administration of CD34-TRAIL+ cells. Histological analysis revealed high-level expression of the agonistic receptor TRAIL-R2 by tumor endothelial cells, and efficient tumor homing of transduced cells. Injection of CD34-TRAIL+ cells resulted in extensive damage of tumor vasculature followed by hemorrhagic necrosis exhibiting a perivascular distribution. These results show that CD34-TRAIL+ cells might be an efficient vehicle for mTRAIL delivery to tumors, where they exert a potent antitumor effect possibly mediated by both direct tumor cell killing and indirect vascular-disrupting mechanisms.
Antitumor activity of human CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (mTRAIL) / C. Carlo-Stella, C. Lavazza, M. Di Nicola, L. Cleris, P. Longoni, M. Milanesi, M. Magni, D. Morelli, A. Gloghini, A. Carbone, A.M. Gianni. - In: HUMAN GENE THERAPY. - ISSN 1043-0342. - 17:12(2006), pp. 1225-1240.
|Titolo:||Antitumor activity of human CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (mTRAIL)|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||2006|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1089/hum.2006.17.1225|
|Appare nelle tipologie:||01 - Articolo su periodico|