Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice.

Abstract

Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted >1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Dunn). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers.

• Authors: David M Weinreich, Dina M Elaraj, Markus Puhlmann, Stephen M Hewitt, Nancy M Carroll, Elizabeth D Feldman, Ewa M Turner, Paul J Spiess, H Richard Alexander
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 18 Pg. 5957-61 (Sep 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14522922 (Publication Type: Journal Article)

Chemical References

• IL1RN protein, human
• Il1rn protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1
• Sialoglycoproteins

Topics

• Animals
• Enzyme-Linked Immunosorbent Assay
• Genetic Therapy (methods)
• Humans
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1 (metabolism)
• Melanoma (genetics, metabolism, therapy)
• Mice
• Mice, Nude
• Sialoglycoproteins (biosynthesis, genetics, physiology)
• Transduction, Genetic
• Transfection
• Xenograft Model Antitumor Assays