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Interleukin-1 receptor antagonist inhibits subcutaneous B16 melanoma growth in vivo
R C McKenzie1, A Oran, C A Dinarello
1Department of Dermatology, University of Edinburgh, Scotland, UK.
Background:
Previously we demonstrated that injection of Interleukin-alpha (IL-1) stimulated B16 melanoma tumour growth in vivo, associated with increased intercellular adhesion molecule-1 (ICAM-1) expression on the tumour cells (Photodermatol Photoimmunol Photomed 1994; 10: 74-79, ).
Methods:
In the present study, we examined the effect of blocking IL-1 receptors - by addition of recombinant Interleukin-1 receptor antagonist (IL-1RA) - on melanoma tumour growth in vivo and in vitro.
Results:
Subcutaneous co-injection of IL-1RA with B16 tumour cells into C57BL/6 mice, followed by injection of IL-1RA every second day reduced tumour growth significantly from day 18 to day 33 post-injection. Treatment with IL-1RA appeared to have a bi-phasic effect, low doses being more effective than dosed > 1 microgram/mouse. After 33 days, mice treated with 1.0 or 0.1 micrograms/2nd day had significantly smaller tumours than controls (p < 0.05), however, mice treated with 10 micrograms had tumours no different in size from those of untreated controls. However, survival of IL-RA-treated mice was not significantly different between treatment groups. Addition of IL-1RA to B16 cultures in vitro caused a small dose-dependent decrease in cell growth. Maximum inhibition (64% of control numbers) was observed after 48h in media containing > or = 10 ng/ml Il-1RA (p < 0.05). Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), we examined the expression of ICAM-1 message in B16 cells treated in culture with 10 ng/ml IL-1RA or 10 ng/ml IL-1 alpha for 6h or 24h. In IL-1-treated cultures ICAM-1 mRNA expression was increased to 161% of control levels. After 24h, ICAM-1 message was 198% control levels (p = 0.0008). Treatment with IL-1RA reduced the constitutive ICAM-1 expression to 75% of basal after 6h and to 68% of basal after 24h 9 (p = 0.011).
Conclusion:
Abrogation of IL-1 activity, in combination with other systemic therapies may prove useful in the treatment of melanoma.