Distinct antitumor mechanisms of recombinant interleukin-2 on recombinant interleukin-2-activated killer-sensitive and -resistant murine tumors.
The antitumor mechanism of recombinant human interleukin-2 (rIL-2) was studied using two murine tumor systems. Meth 8 tumor cells were easily lysed in vitro by rIL-2-activated killer (AK) cells, which mainly consisted of Thy1.2+, Lyt2.2+, L3T4- T cells, and asialo GM1+ natural killer (NK) cells; on the other hand, X5563 tumor cells were only slightly lysed in vitro by AK cells under the same conditions. One of these two tumors was inoculated i.d. into C3H/HeN mice and then rIL-2 (5 X 10(4) J.U./mouse/day) was repeatedly injected s.c. For AK-sensitive Meth 8-bearing mice, rIL-2 therapy starting 1 day after tumor inoculation was more effective for the growth than the therapy starting 7 days later and the therapeutic effect was abrogated by in vivo treatment with anti-asialo-GM1 serum. In contrast, for mice bearing AK-resistant X5563 tumor cells, delayed administration starting on day 7 or later was more beneficial than earlier administration on day 1 or 4. This treatment schedule resulted in complete tumor regression in a dose-dependent manner including significant inhibition of metastases in the spleen and/or lymph nodes. These therapeutic effects of rIL-2 on X5563 were not seen in T-depleted mice with anti-mouse thymocyte serum but were found in NK-depleted mice upon treatment with anti-asialo-GM1 serum. The results of these studies showed that the growth of AK-sensitive Meth 8 tumor was inhibited by AK cells, while the growth and metastases of AK-resistant X5563 tumor was inhibited by tumor-specific T cells, which were generated after tumor development and activated by rIL-2 therapy, rather than AK cells.
Maekawa
R
R
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Kitagawa
T
T
Koizumi
K
K
Sato
K
K
Homma
M
M
D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D000970:Antineoplastic Agents; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005677:G(M1) Ganglioside; D006028:Glycosphingolipids / Q000276:immunology; D007116:Immunization, Passive; D007376:Interleukin-2 / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D006028:Glycosphingolipids; D007376:Interleukin-2; D011994:Recombinant Proteins; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside