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Reduced Toxicity and Enhanced Antitumor Effects in Mice of the Ionophoric Drug Valinomycin When Incorporated in Liposomes¹

Department of Pharmacology, University of Texas Medical School, Houston, Texas 77225

Valinomycin (NSC 122023) is a cyclic depsipeptide antibiotic with potassium selective ionophoric activity. This drug has been reported to display antitumor effects but its utilization has been limited by its extreme toxicity. Here we report that the incorporation of valinomycin into multilamellar liposomes composed of dimyristoyl phosphatidyl choline:cholesterol:phosphatidyl serine (10:4:1 M ratio) results in a profound reduction in toxicity with maintainence of antitumor efficacy. Thus the median lethal dose (LD₅₀) for i.p. administered valinomycin (VM) in C57BL/6 x DBA/2 mice is 1.7 mg/kg whereas the LD₅₀ for liposome incorporated valinomycin (MVL-VM) is in excess of 50 mg/kg. In like manner, the LD₅₀ for i.v. administered VM is 0.18 mg/kg where the LD₅₀ for MLV-VM preparations passed through a 0.6-µm filter is greater than 10 mg/kg. The antitumor efficacies of i.p. administered VM or MLV-VM against i.p. P388 mouse leukemia were similar in multiple dose formats using doses below the maximal tolerated dose for VM. However, since MLV-VM was substantially less toxic than VM, the liposomal drug also produced significant (170% median survival time of treated mice/median survival time of untreated control) antitumor effects when administered as a single dose at levels above the maximal tolerated dose for free VM; single doses of free VM at the maximal tolerated dose were ineffective in this context. In experiments with i.v. inoculated P388 leukemia, MLV-VM but not free VM, displayed antitumor activity (144% median survival time of treated mice/median survival time of untreated control) when administered i.v. at equitoxic doses. Thus the use of a lipid vesicle drug carrier system permits a reduction in the toxicity of valinomycin with maintainence or enhancement of antitumor activity against i.p. or i.v. P388 leukemia.

¹ Supported by NIH grant CA36840 and by an award from the Elsa Pardee Foundation (R. L. J.).

Received 4/30/86. Revised 7/22/86. Accepted 7/28/86.