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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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/106 cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/106 cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted > 1000 pg/ml/106 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.

Original languageEnglish (US)
Pages (from-to)5957-5961
Number of pages5
JournalCancer Research
Volume63
Issue number18
StatePublished - Sep 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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