This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hoving, S. Articles by ten Hagen, T. L.M. Search for Related Content PubMed PubMed Citation Articles by Hoving, S. Articles by ten Hagen, T. L.M.

Synergistic Antitumor Response of Interleukin 2 with Melphalan in Isolated Limb Perfusion in Soft Tissue Sarcoma–Bearing Rats

¹ Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands and ² Department of Experimental Oncology, University of Leuven, Leuven, Belgium

Requests for reprints: Timo L.M. ten Hagen, Laboratory of Experimental Surgical Oncology, Department of Surgical Oncology, Erasmus MC, Room Ee 0102a, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands. Phone: 31-10-408-7682; Fax: 31-10-408-9471; E-mail: t.l.m.tenhagen{at}erasmusmc.nl.

The cytokine interleukin 2 (IL-2) is a mediator of immune cell activation with some antitumor activity, mainly in renal cell cancer and melanoma. We have previously shown that tumor necrosis factor (TNF)- has strong synergistic antitumor activity in combination with chemotherapeutics in the isolated limb perfusion (ILP) setting based on a TNF-mediated enhanced tumor-selective uptake of the chemotherapeutic drug followed by a selective destruction of the tumor vasculature. IL-2 can cause vascular leakage and edema and for this reason we examined the antitumor activity of a combined treatment with IL-2 and melphalan in our well-established ILP in soft tissue sarcoma–bearing rats (BN175). ILP with either IL-2 or melphalan alone has no antitumor effect, but the combination of IL-2 and melphalan resulted in a strong synergistic tumor response, without any local or systemic toxicity. IL-2 enhanced significantly melphalan uptake in tumor tissue. No signs of significant vascular damage were detected to account for this observation, although the tumor sections of the IL-2– and IL-2 plus melphalan–treated animals revealed scattered extravasation of erythrocytes compared with the untreated animals. Clear differences were seen in the localization of ED-1 cells, with an even distribution in the sham, IL-2 and melphalan treatments, whereas in the IL-2 plus melphalan–treated tumors clustered ED-1 cells were found. Additionally, increased levels of TNF mRNA were found in tumors treated with IL-2 and IL-2 plus melphalan. These observations indicate a potentially important role for macrophages in the IL-2–based perfusion. The results in our study indicate that the novel combination of IL-2 and melphalan in ILP has synergistic antitumor activity and may be an alternative for ILP with TNF and melphalan.

This article has been cited by other articles:

				A. L.B. Seynhaeve, S. Hoving, D. Schipper, C. E. Vermeulen, G. aan de Wiel-Ambagtsheer, S. T. van Tiel, A. M.M. Eggermont, and T. L.M. ten Hagen Tumor Necrosis Factor {alpha} Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response Cancer Res., October 1, 2007; 67(19): 9455 - 9462. [Abstract] [Full Text] [PDF]

				R. van Horssen, T. L. M. ten Hagen, and A. M. M. Eggermont TNF-{alpha} in Cancer Treatment: Molecular Insights, Antitumor Effects, and Clinical Utility. Oncologist, April 1, 2006; 11(4): 397 - 408. [Abstract] [Full Text] [PDF]