In vivo studies with interleukin-12 alone and in combination with monocyte colony-stimulating factor and/or fractionated radiation treatment.
Interleukin-12 (IL-12) was found to be an active anti-tumor agent in 3 established murine solid tumors: B16 melanoma, Lewis lung carcinoma and renal cell carcinoma (RenCa). IL-12 was well tolerated over a 100-fold dose range. Only the high-dose treatment of IL-12 resulted in a clear reduction in the number of lung metastases from B16 melanoma and Lewis lung carcinoma. Treatment of animals bearing Lewis lung carcinoma with IL-12 in combination with fractionated radiation therapy was markedly dose-modifying, indicating that IL-12 was acting synergistically with radiation. Treatment of animals bearing the same tumor with monocyte colony-stimulating factor (M-CSF) along with fractionated radiation therapy resulted in a parallel increase in tumor growth delay with increasing dose of M-CSF, indicating that M-CSF was affecting a subpopulation of tumor cells in addition to those killed by radiation therapy. The combination of IL-12 with M-CSF was most effective with radiation therapy, especially in the clinically relevant dosages of 2 and 3 Gy per fraction. By isobologram analysis, IL-12 and M-CSF, along with fractionated radiation therapy, resulted in a greater-than-additive (synergistic) tumor response.
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
B A
BA
Teicher
G
G
Ara
K
K
Menon
R G
RG
Schaub
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D018664:Interleukin-12 / Q000008:administration & dosage*; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D008297:Male; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D018664:Interleukin-12; D016173:Macrophage Colony-Stimulating Factor