| Abstract: |
Background: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T-cell responses and may have therapeutic utility in the treatment of cancer, asthma, and a variety of infectious diseases. Methods: In a phase I trial, recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at a fixed dose of 0.1 to 1.0 μg/kg to 24 patients with renal cell carcinoma. A similar study was later performed in mice to evaluate the mechanism of down-regulation of pharmacokinetic-pharmacodynamic response observed in patients with cancer. Results: Adverse events, serum IL-12 levels, and serum levels of interferon-γ (IFN-γ) and interleukin-10 (IL- 10) produced in response to IL-12 were all maximum in the week after the first dose of rHuIL-12 and decreased after long-term administration. Similar to these results, repetitive subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice led to down-regulation of serum levels of IL- 12 and IFN-γ measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL- 12 receptor. The down-regulation of serum IFN-γ levels correlated with decreased IFN-γ messenger ribonucleic acid expression and may result from feedback inhibition of IL-12 signaling or from a more specific inhibition of IFN-γ synthesis. Conclusion: Administration of rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of IFN-γ, a secondary cytokine believed to be critical to response of IL-12. A better understanding of the complex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 should facilitate the development of more effective dosing regimens for its use in the clinic. |
| Keywords: |
adult; clinical article; controlled study; aged; middle aged; clinical trial; fatigue; area under the curve; nonhuman; animal cell; mouse; animals; mice; animal tissue; controlled clinical trial; drug administration schedule; interleukin 10; animal experiment; down-regulation; enzyme linked immunosorbent assay; mice, inbred c57bl; kidney carcinoma; kidney neoplasms; fever; gene expression regulation, neoplastic; gamma interferon; carcinoma, renal cell; messenger rna; rna, messenger; multicenter study; recombinant proteins; drug clearance; down regulation; beta 2 microglobulin; drug blood level; phase 1 clinical trial; adjuvants, immunologic; drug binding; receptor upregulation; radioimmunoassay; interleukin-12; interferon type ii; recombinant interleukin 12; interleukin 12 receptor; humans; human; male; female; priority journal; article; beta 2-microglobulin
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