LIPOSOME-ENCAPSULATED VINCRISTINE - PRECLINICAL TOXICOLOGIC AND PHARMACOLOGICAL COMPARISON WITH FREE VINCRISTINE AND EMPTY LIPOSOMES IN MICE, RATS AND DOGS

A preclinical toxicology study of liposome encapsulated vincristine, f ree vincristine and empty liposomes was carried out in mice and dogs b y single and multiple (daily for 5 days) intravenous injection. Single and multiple dose intravenous injection studies in mice showed the en capsulated form of vincristine to be less toxic than free vincristine. Empty liposomes injected intravenously into dogs were without signifi cant toxicity. In dogs, the toxicities seen with liposomal vincristine were qualitatively similar to those of free vincristine with only min or quantitative differences. The principal toxicities of free and lipo somal vincristine in dogs were anorexia, weight loss, pyrexia, myelosu ppression and gastrointestinal toxicity. After single high doses of ei ther formulation gastrointestinal toxicity was the dose-limiting toxic ity, white either hematologic or gastrointestinal toxicity was dose li miting after multiple dose administration of either drug. Histopatholo gic lesions of importance were bone marrow atrophy, necrosis and atrop hy of the lymphoproliferative tissues, necrosis of gastrointestinal tr act mucosa, liver and pancreas, and hemorrhage. Distribution studies i n rats showed significantly higher vincristine levels In serum, spleen , liver, trachea, jejunum, cerebrum, lung, ischiatic nerve and heart, and significantly lower levels in colon, stomach, salivary gland, thym us esophagus and pancreas after injection of the liposome-associated a gent. No toxicities were seen that should preclude safe clinical trial of liposomal vincristine in man.