Interleukin-12 administration is more effective for preventing metastasis than for inhibiting primary established tumors in a murine model of spontaneous hepatic metastasis.
OBJECTIVE
The effect of interleukin-12 (IL-12) on tumor growth at the primary site and its therapeutic efficacy against metastasis were examined using a model of spontaneous hepatic metastasis.


METHODS
IL-12 was peritumorally injected into RL male1 tumor-bearing BALB/c male mice at the different tumor stage.


RESULTS
Striking inhibition of hepatic metastasis in both athymic and euthymic mice was induced by the administration of IL-12 irrespective of the stage of tumor progression. In contrast, IL-12 failed to produce any antitumor effect in athymic mice which lack conventional T cells. These results suggest that the antitumor effect of IL-12 is mediated mainly by T cells, and that the antimetastatic effect is mediated mainly by natural killer (NK) and/or NKT cells. Next we examined the direct effect of IL-12 on these cells. IL-12-induced T-cell proliferation was remarkably augmented in the early stage, then decreased dramatically in the advanced stage, while IL-12-induced cytotoxic activity, mediated by NK and NKT cells, was not attenuated even in the advanced stage. This dissociation in IL-12 responsiveness appeared to be the reason for the remarkable antimetastatic effect but insufficient antitumor effect of IL-12 in the advanced stage.


CONCLUSIONS
The findings of this study support the clinical use of IL-12 for immunotherapy against either occult or evident liver metastasis.
Kobayashi
Terutada
T
Department of Surgery, Postgraduate School of Medicine, Tohoku University, Sendai, Japan.
Shiiba
Ken-ichi
K
Satoh
Masayuki
M
Hashimoto
Wataru
W
Mizoi
Takayuki
T
Matsuno
Seiki
S
Takeda
Kazuyoshi
K
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control; D013154:Spleen; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018664:Interleukin-12