Antineoplastic activity of lentiviral vectors expressing interferon-alpha in a preclinical model of primary effusion lymphoma.
The peculiar site of development of primary effusion lymphoma (PEL) highlights a specific role of body cavities in the pathogenesis of this neoplasia. We used a xenograft murine model of PEL to characterize the contribution of the host microenvironment to PEL growth. The activity of a murine (ie, host-specific) interferon-alpha(1) (IFN-alpha(1))-expressing lentiviral vector (mIFN-alpha(1)-LV) was compared with that of a human (h) IFN-alpha(2)b-LV. LVs efficiently delivered the transgene to PEL cells and conferred long-term transgene expression in vitro and in vivo. Treatment of PEL-injected severe combined immunodeficiency mice with hIFN-alpha(2)b-LV significantly prolonged mice survival and reduced ascites development. Interestingly, mIFN-alpha(1)-LV showed an antineoplastic activity comparable with that observed with hIFN-alpha(2)b-LV. As mIFN-alpha(1) retained species-restricted activity in vitro, it probably acted in vivo on the intracavitary murine milieu. mIFN-alpha(1)-treated murine mesothelial cells were found to express tumor necrosis factor-related apoptosis-inducing ligand and to significantly trigger apoptosis of cocultured PEL cells in a tumor necrosis factor-related apoptosis-inducing ligand-dependent manner. These data suggest that the interaction between lymphomatous and mesothelial cells lining the body cavities may play a key role in PEL growth control and also indicate that the specific targeting of microenvironment may impair PEL development.
Calabrò
Maria Luisa
ML
Immunology and Diagnostic Molecular Oncology, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy. lcalabro@unipd.it
Gasperini
Paola
P
Di Gangi
Iole Maria
IM
Indraccolo
Stefano
S
Barbierato
Massimo
M
Amadori
Alberto
A
Chieco-Bianchi
Luigi
L
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins
D000970:Antineoplastic Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins