Many chemotherapeutic drugs are cell cycle phase specific agents that kill only those cells that happen to be in the vulnerable phase of the cell cycle. Thus, the effectiveness of such drugs are markedly increased when the duration of drug exposure is prolonged. Our overall goal is to study a practical application of this pharmacological principle by using liposomes as biodegradable, slow-releasing drug depot, and ara-C as a model for cell cycle phase specific agent. This program will investigate the use of a novel type of liposomes, made and named by the principal investigator as """"""""multivesicular liposomes"""""""", to increase the duration of ara-C exposure for ovarian carcinoma confined to intraperitoneal space. The multivesicular liposomes are unique by the virture of the numerous, non-concentric internal chambers within a liposome, and the ability to have the average size of the internal chambers and the average outer diameters of the liposomes independently adjusted during the liposome synthesis, which should allow drug relaease kinetics tailor made to any desired specifications. We will a) study the release kinetics of ara-C from multivesicular liposomes as a function of the average internal chamber number and outer diameter, b) compare the activity of ara-C in multivesicular liposomes versus free drug in tissue culture and in clonogenic assay, c) study the pharmacokinetics of ara-C in liposomes in a nude mouse model of human ovarian carcinoma, and d) determine the activity of ara-C in liposomes against human ovarian carcinoma growing in nude mice. If our studies suggest that ara-C entrapped in multivesicular liposome has a therapeutic advantage, a phase I pharmacokinetic trial in patients with advanced ovarian carcinoma will be eventually carried out.
| Roy, R; Kim, S (1991) Multivesicular liposomes containing bleomycin for subcutaneous administration. Cancer Chemother Pharmacol 28:105-8 |
| Kim, S; Howell, S B (1987) Multivesicular liposomes containing cytarabine entrapped in the presence of hydrochloric acid for intracavitary chemotherapy. Cancer Treat Rep 71:705-11 |
| Kim, S; Kim, D J; Geyer, M A et al. (1987) Multivesicular liposomes containing 1-beta-D-arabinofuranosylcytosine for slow-release intrathecal therapy. Cancer Res 47:3935-7 |
| Kim, S; Howell, S B (1987) Multivesicular liposomes containing cytarabine for slow-release Sc administration. Cancer Treat Rep 71:447-50 |
| Kim, S; Kim, D J; Howell, S B (1987) Modulation of the peritoneal clearance of liposomal cytosine arabinoside by blank liposomes. Cancer Chemother Pharmacol 19:307-10 |
