Enhanced antitumor efficacy in mice by combination treatment with interleukin-1 alpha and interferon-alpha.
The antitumor efficacy of recombinant murine interleukin-1 alpha (rMuIL-1 alpha) was evaluated either alone or in combination with recombinant human hybrid interferon alpha A/D (IFN-alpha A/D) against the murine B16 F10 malignant melanoma. Treatment of subcutaneous tumor-bearing mice intraperitoneally with rMuIL-1 alpha resulted in a dose-dependent inhibition of tumor growth with the greatest activity obtained with the maximum tolerated dose of rMuIL-1 alpha (10 micrograms per treatment). Augmented tumor inhibition comparable to that seen in mice treated with a high dose of rMuIL-1 alpha was observed in subcutaneous tumor-bearing mice injected with the combination of IFN-alpha A/D and a low dose of rMuIL-1 alpha. Similar inhibition of subcutaneous tumor growth was obtained in T-cell-deficient nude or natural killer cell-deficient beige mice. In contrast, treatment of mice bearing B16F10 experimental pulmonary metastases with rMuIL-1 alpha resulted in no decrease in the number of metastases, and rMuIL-1 alpha did not potentiate the antimetastatic activity of IFN-alpha A/D. A synergistic induction of IL-6 was induced in mice treated with the combination of rMuIL-1 alpha plus IFN-alpha A/D but the level of IL-6 induced was not correlated with inhibition of tumor growth because this elevation of IL-6 was not observed in tumor-bearing nude mice. No direct antiproliferative activity was demonstrable in vitro against B16 F10 cells with rMuIL-1 alpha, IL-6, or rMuIL-1 alpha plus IL-6, and addition of these cytokines did not enhance the antiproliferative activity of IFN-alpha A/D.(ABSTRACT TRUNCATED AT 250 WORDS)
Brunda
M J
MJ
Department of Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Wright
R B
RB
Luistro
L
L
Harbison
M L
ML
Anderson
T D
TD
McIntyre
K W
KW
D000818:Animals; D005260:Female; D016898:Interferon-alpha / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D007375:Interleukin-1; D015850:Interleukin-6; D011994:Recombinant Proteins