Protective effects of recombinant human interleukin-1 alpha in doxorubicin-treated normal and tumor-bearing mice.
Experiments were performed to determine whether treatment with recombinant human IL-1 alpha (rhuIL-1 alpha) would protect C3H mice from the toxic effects of the widely used chemotherapeutic agent, doxorubicin (DXR). Pretreatment of mice with rhuIL-1 alpha was found to protect 85-90% of mice tested from the acute toxic effects of a lethal dose of doxorubicin (25 mg/kg). Late deaths (> 20 days post-DXR) were observed in a substantial proportion (40-45%) of rhuIL-1 alpha-pretreated mice. However, the data clearly demonstrate a beneficial effect of rhuIL-1 alpha pretreatment on the overall survival of mice challenged with DXR, since both the median survival (32 days) and proportion (53%) of surviving mice were significantly increased (P < 0.0001) compared to the control group (8 days and 14%, respectively). The beneficial effects mediated by rhuIL-1 alpha treatment were both dose- and schedule-dependent and were associated with decreases in the level and duration of DXR-induced neutropenia, and amelioration of the suppressive effects of DXR on myeloid progenitor cells (granulocyte/monocyte colony forming units) as evidenced by milder depressions in marrow cellularity and enhanced recovery of granulocyte/monocyte colony forming unit activity. Finally, pretreatment of mice bearing a solid tumor with rhuIL-1 alpha permitted effective dose escalation with DXR that resulted in decreased tumor growth rates and increased survival (90%) as compared to non-rhuIL-1 alpha-treated groups (20% survival). Thus, effective chemotherapeutic dose escalation is made feasible by rhuIL-1 alpha pretreatment of mice, but may ultimately be limited by nonhematological toxicities associated with DXR.
Lynch
D H
DH
Department of Immunology, Immunex Research and Development Corporation, Seattle, Washington 98101.
Rubin
A S
AS
Miller
R E
RE
Williams
D E
DE
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D008231:Lymphopenia / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008809:Mice, Inbred C3H; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy; D011292:Premedication; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D011994:Recombinant Proteins; D004317:Doxorubicin