Liposome encapsulated vincristine: preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposomes in mice, rats and dogs.
A preclinical toxicology study of liposome encapsulated vincristine, free vincristine and empty liposomes was carried out in mice and dogs by single and multiple (daily for 5 days) intravenous injection. Single and multiple dose intravenous injection studies in mice showed the encapsulated form of vincristine to be less toxic than free vincristine. Empty liposomes injected intravenously into dogs were without significant toxicity. In dogs, the toxicities seen with liposomal vincristine were qualitatively similar to those of free vincristine with only minor quantitative differences. The principal toxicities of free and liposomal vincristine in dogs were anorexia, weight loss, pyrexia, myelosuppression and gastrointestinal toxicity. After single high doses of either formulation gastrointestinal toxicity was the dose-limiting toxicity, while either hematologic or gastrointestinal toxicity was dose limiting after multiple dose administration of either drug. Histopathologic lesions of importance were bone marrow atrophy, necrosis and atrophy of the lymphoproliferative tissues, necrosis of gastrointestinal tract mucosa, liver and pancreas, and hemorrhage. Distribution studies in 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, thymus esophagus and pancreas after injection of the liposome-associated agent. No toxicities were seen that should preclude safe clinical trial of liposomal vincristine in man.
James T Grace Jr Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.
P M
PM
Kanter
G M
GM
Klaich
G A
GA
Bullard
J M
JM
King
M B
MB
Bally
L D
LD
Mayer
D000818:Animals; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002784:Cholesterol; D004285:Dogs; D004337:Drug Carriers; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006470:Hemorrhage / Q000139:chemically induced; D007275:Injections, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D008081:Liposomes; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010713:Phosphatidylcholines; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D014018:Tissue Distribution; D014750:Vincristine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity
D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D014750:Vincristine; D002784:Cholesterol; C010942:1,2-distearoyllecithin