Enhanced therapeutic effects of liposome-associated 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine.
The ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3) has anticancer activity, but systemic toxicity has restricted 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 in vivo toxicity in normal mice and for therapeutic efficacy in three mouse tumor model systems. The entrapment of ET-18-OCH3 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-OCH3 was found to be approximately 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-OCH3. The therapeutic efficacy of free ET-18-OCH3 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-OCH3 had some anticancer activity, 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 results suggest that association of ET-18-OCH3 in stable, well-characterized liposomes transforms it into an effective antitumor agent.
Ahmad
I
I
The Liposome Company, Inc., Princeton, New Jersey 08540, USA.
Filep
J J
JJ
Franklin
J C
JC
Janoff
A S
AS
Masters
G R
GR
Pattassery
J
J
Peters
A
A
Schupsky
J J
JJ
Zha
Y
Y
Mayhew
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D001202:Ascitic Fluid / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006461:Hemolysis; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010742:Phospholipid Ethers / Q000008:administration & dosage* / Q000633:toxicity
D000970:Antineoplastic Agents; D008081:Liposomes; D010742:Phospholipid Ethers; C026659:edelfosine