The treatment of intravenously implanted Lewis lung carcinoma with two sustained release forms of 1-β- d-arabinofuranosylcytosine

Abstract

Liposomes have been used in recent years as carriers for drugs and molecules of biological importance. In cancer chemotherapy, however, the advantages of liposome encapsulation of antitumor drugs remain uncertain, with the possible exception of the usefulness of encapsulated 1-β- d-arabinofuranosylcytosine (ara-C), an antitumor drug of a very short half-life. Liposome-encapsulated ara-C has been shown by others to enhance significantly the survival time of mice bearing leukemia, and the enhancement may be attributable to the role of liposomes as a slow release system for ara-C. We now further explore the advantages of two sustained release systems for ara-C, namely the liposome-encapsulated ara-C and 1-β- d-arabinofuranosylcytosine-5′-diphosphate- l-1,2-dipalmitin (ara-CDP- l-dipalmitin, a prodrug of ara-C). Intravenously implanted Lewis lung carcinoma is used as a solid tumor model. The therapeutic effectiveness of the two slow release forms of ara-C given by either i.v. or i.p. injections is examined. Viable tumor cells (1.0 × 10 5 cells/mouse) were inoculated i.v. and treatment was initiated 24 hr later using three schedules of multiple treatments for liposomal ara-C and single or multiple injections of ara-CDP- l-dipalmitin. Liposomal ara-C given by the i.p. route consistently increased the number of cures (> 120 days survival). For example, when nine small doses (10 mg/kg) were given on consecutive days by i.p. injections, 50% of mice given liposomal ara-C were cured, compared with 10% cures in the group given ara-C liposomes by i.v. and no cures in mice receiving free ara-C given according to the same schedules. On the other hand, ara-CDP- l-dipalmitin given at a single dose is more effective than an equal dose divided in five injections. However, no cures have been obtained by treatments with ara-CDP- l-dipalmitin. These results have further demonstrated the advantage of lipsomes as carriers for antitumor drugs of short half-life.