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

Abstract

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)-A 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 wellestablished 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. (Cancer Res 2005; 65(10): 4300-8)

Tumor Necrosis Factor α Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response

“…These findings led to our search for alternative agents with known vascular permeability increasing activity, such as histamine and interleukin-2. We have shown that these agents also enhance drug accumulation in the tumor resulting in synergistic antitumor activity in an isolated setting (13,44). Apparently, this dual approach consisting of a combination of tumor cell-and tumor vasculature-directed therapy is an important concept for a good tumor response.…”

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

“…Promising findings have been reported for histamine [164,165], interleukin 2 [166] and the nitric oxide synthase inhibitor L-NAME [167]. Improved response rates have also been reported following the upregulation of endothelial monocyte-activating polypeptide II (EMAP-II) in extremity soft tissue sarcomas [168].…”

Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer

“…In particular, in rat models of isolated limb perfusion -a technique used to deliver high doses of drugs into the bloodstream of a limb -coadministration of chemotherapeutic drugs with biomolecules able to affect the integrity of the endothelial lining of vessels, such as TNFa, histamine, or IL-2, can increase drug penetration in tumors [55][56][57]. Remarkably, the addition of TNF-a to regional isolated limb perfusion with melphalan or doxorubicin also produces response rates higher than those obtained with chemotherapy alone in patients with softtissue sarcomas or melanomas [58].…”