Activity, pharmacokinetics and tissue distribution of TLC ELL-12 (liposomal antitumor ether lipid) in rats with transplantable, s.c. methylnitrosourea-induced tumors.

Abstract

TLC ELL-12 is a liposomal formulation of the novel antineoplastic compound 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (L-ET-18-OCH(3)). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH(3) when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH(3) and TLC ELL-12 against methylnitrosourea (MNU)-induced tumors grown in vitro was evaluated. Female Buffalo rats were injected s.c. with transplantable MNU-induced tumor cells. Four days later, animals were treated i.v. with L-ET-18-OCH(3) administered as TLC ELL-12 once daily for 5 consecutive days. Another group of MNU-tumor bearing rats was given a single 12.5 mg/kg dose of TLC ELL-12 containing [14C]L-ET-18-OCH(3) by i.v. injection into a tail vein. The 50% growth inhibitory concentration for TLC ELL-12 against MNU tumor cells in vitro was 63 microM (about 30 microg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH(3) concentrations declined in a multiphasic fashion with C(max) and terminal half-life values of approximately 91.1 microg L-ET-18-OCH(3)/ml and 13.1 h, respectively. Tumor L-ET-18-OCH(3) levels increased through the first 16-24 h post-dosing to about 23 microg/g and remained elevated at the terminal time point with little evidence of metabolism. Concentration-time profiles for selected tissues indicate rapid distribution of L-ET-18-OCH(3) from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH(3) as TLC ELL-12 shows both in vitro and in vivo activity against the MNU tumor line. When i.v. administered, L-ET-18-OCH(3) from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.

• Authors: Rupinder Bhamra, Lois E Bolcsak, Imran Ahmad, James Schupsky, Patricia Roberts, Rachel Stevens, Christopher Cavanaugh, Christine E Swenson
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 14 Issue 6 Pg. 481-6 (Jul 2003) ISSN: 0959-4973 [Print] England
• PMID: 12853892 (Publication Type: Journal Article)

Chemical References

• Alkylating Agents
• Antineoplastic Agents
• Liposomes
• Phospholipid Ethers
• edelfosine
• Methylnitrosourea

Topics

• Alkylating Agents (toxicity)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Area Under Curve
• Female
• Half-Life
• Injections, Intravenous
• Liposomes
• Metabolic Clearance Rate
• Methylnitrosourea (toxicity)
• Neoplasms, Experimental (chemically induced, drug therapy, metabolism)
• Phospholipid Ethers (administration & dosage, pharmacokinetics, therapeutic use)
• Rats
• Tissue Distribution