ENHANCED THERAPEUTIC EFFECTS OF LIPOSOME-ASSOCIATED O-OCTADECYL-2-O-METHYL-SN-GLYCERO-3-PHOSPHOCHOLINE

The ether-lipid O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET -18-OCH3) has anticancer activity, but systemic toxicity has restricte d its therapeutic use. In this report ''free'' ET-18-OCH3 and a stable , well-characterized, liposome-based formulation of ET-18-OCH3 (ELL-12 ) were compared for ill vivo toxicity in normal mice and for therapeut ic efficacy in three mouse tumor model systems, The entrapment of ET-1 8-OCH, in liposomes decreased the acute toxicity of ET-18-OCH3 after i ,v. administration. The maximum tolerated dose for a single i.v. dose of free ET-18-OCH, was found to be similar to 25 mg/kg, whereas the ma ximum tolerated dose for ELL-12 was approximately 200 mg/kg. ELL-12 wa s much less hemolytic irt vivo than ET-18-OCH3. The therapeutic effica cy of free ET-18-OCH, and ELL-12 was investigated against i.p. P388 le ukemia, Lewis lung cancer lung metastases, and B16/F10 melanoma (lung tumor nodules) in mice. Although ET-18-OCH3 had some anticancer activi ty, it was found that ELL-12 was more effective than ET-18-OCH3 in all three tumor models at lower and nontoxic dose schedules, These result s suggest that association of ET-18-OCH3 in stable, well-characterized liposomes transforms it into an effective antitumor agent.