Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism

Abstract

This study was undertaken to investigate the antitumor effect of liposomal hexadecylphosphocholine (L-HPC), a synthetic phospholipid encapsulated into multilamellar vesicles (MLV). The effect of these liposomes was tested in an orthotopic nude mouse model using the human mammary carcinomas MDA-MB 435 and 231. The main interest of the investigation was to study whether activated macrophages are substantially involved in the tumor growth inhibition mechanism. The growth of both MDA-MB 435 and 231 tumors in the mammary fat pad was significantly inhibited by a 14-day intraperitoneal therapy with L-HPC. The remaining tumors were shown to be heavily infiltrated with macrophages. In vitro studies of mPEM demonstrated a significant induction of macrophage-mediated tumor cytotoxicity (MMCTX) against the 2 cell lines by L-HPC. The L-HPC-mediated activation mechanism was characterized to be IL-6 and TNFalpha dependent but rather independent of IL-1alpha and nitric oxide (NO). NMA, a specific inhibitor of NO production, did not inhibit L-HPC-induced MMCTX. Furthermore, L-HPC was shown to upregulate the matrixmetalloproteinases MMP-9 and MMP-2 secretion into the supernatant. Considering cytokine release and production of collagenases, the L-HPC-induced macrophage activation cascade is assumed to be comparable with that of classical activators such as lipopolysaccharide (LPS) and interferon (IFN) gamma. As far as NO production is considered, the L-HPC activation mechanism differs from that caused by LPS and IFN gamma.