Enhanced therapeutic effects of liposome-associated 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine
Ahmad, I.; Filep, J.J.; Franklin, J.C.; Janoff, A.S.; Masters, G.R.; Pattassery, J.; Peters, A.; Schupsky, J.J.; Zha, Y.; Mayhew, E.
Cancer Research 57(10): 1915-1921
1997
ISSN/ISBN: 0008-5472 PMID: 9157985 Document Number: 476934
The ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH-3) has anticancer activity, but systemic toxicity has restricted its therapeutic use. In this report "free" ET-18-OCH-3 and a stable, well-characterized, liposome-based formulation of ET-18-OCH-3 (ELL-12) were compared for in vivo toxicity in normal mice and for therapeutic efficacy in three mouse tumor model systems. The entrapment of ET-18-OCH-3 in liposomes decreased the acute toxicity of ET-18-OCH-3 after i.v. administration. The maximum tolerated dose for a single i.v. dose of free ET-18-OCH-3 was found to be apprx 25 mg/kg, whereas the maximum tolerated dose for ELL-12 was approximately 200 mg/kg. ELL-12 was much less hemolytic in vivo than ET-18-OCH-3. The therapeutic efficacy of free ET-18-OCH-3 and ELL-12 was investigated against i.p. P388 leukemia, Lewis lung cancer lung metastases, and B16/F10 melanoma (lung tumor nodules) in mice. Although ET-18-OCH-3 had some anticancer activity, it was found that ELL-12 was more effective than ET-18-OCH-3 in all three tumor models at lower and nontoxic dose schedules. These results suggest that association of ET-18-OCH-3 in stable, well-characterized liposomes transforms it into an effective antitumor agent.