Modulation of innate immunological factors by STEALTH liposome-encapsulated tumor necrosis factor-alpha in a colon tumor xenograft model.
BACKGROUND
Previous studies have shown that tumor necrosis factor-alpha (TNF-alpha) encapsulated in sterically-stabilized PEGylated STEALTH liposomes (SL) can better and more safely augment the efficacy of other treatment modalities than free TNF-alpha. The aim of this study was to examine the effects of SL-TNF-alpha in the LS174T human colon tumor xenograft model and to correlate its administration with alterations in innate immune system parameters.


METHODS
Nude mice (n = 128) were injected subcutaneously with LSI 74T cells and treated intravenously with SL-TNF-alpha SL-placebo, or free recombinant human TNF-alpha; the animals were euthanized at 6, 18, 36 and 96 hours after injection.


RESULTS
Significant increases in leukocyte, granulocyte, monocyte and NK cell numbers were observed early (6 hours) in the blood from both SL-TNF-alpha and free TNF-alpha treated mice compared to the control group. In contrast, during the 18- to 36-hours interval, SL-TNF-alpha induced significantly higher (p<0.05) leukoctyte, T cell, and NK cell numbers, basal leukocyte proliferation, and CD25+ activation marker expression; the modulation occurred primarily in the spleen.


CONCLUSIONS
These data indicate that both SL-TNF-alpha and free TNF-alpha can induce dramatic up-regulation in leukocyte populations early after injection. However, the up-regulation produced by SL-TNF-alpha was more prolonged and pronounced than that of TNF-alpha and had better correlation with cell activation. These findings suggest that sustained leukocyte recruitment and/or activation may be an important factor in the greater than additive or synergistic antitumor effects observed when SL-TNF-alpha is used in combination with other cancer therapies.
Kim
Dong W
DW
Department of Radiation Medicine, Loma Linda University and Medical Center, CA 92354, USA. dkim03mz@som.llu.edu
Andres
Melba L
ML
Kajioka
Eric H
EH
Dutta-Roy
Radha
R
Miller
Glen M
GM
Seynhaeve
Ann L B
AL
ten Hagen
Timo L M
TL
Gridley
Daila S
DS
D000818:Animals; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007958:Leukocyte Count; D008081:Liposomes; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism
D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha