Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99) given intraperitoneally to dogs.
A preclinical toxicology study of intraperitoneally administered liposome encapsulated doxorubicin and free doxorubicin was carried out in beagle dogs. Dogs received single intraperitoneal infusions of 1.5 mg free or 1.5, 2.25 or 3.37 mg liposomal doxorubicin/kg. One group of four dogs received 1.5 mg liposomal doxorubicin/kg every three weeks for 4 cycles. The dose limiting toxicity of free or liposomal doxorubicin given by the intraperitoneal route was a dose-related chemical peritonitis. This toxicity was more severe in dogs that received by the intraperitoneal route the previously determined maximally tolerated intravenous dose of liposomal doxorubicin (2.25 mg/kg). The abdominal toxicity was characterized by capsular fibrosis and ascites formation. Abdominal toxicity was life threatening after single doses of 3.37 mg liposomal doxorubicin kg, or after multiple (4) doses of 1.5 mg liposomal doxorubicin/kg. Thoracic toxicity (increased fluid, mediastinal edema, thickening of the parietal pleura) was seen after multiple (every 3 weeks for 4 cycles) intraperitoneal doses of 1.5 mg or single doses of 3.37 mg liposomal doxorubicin/kg. Myelosuppression was seen in all groups, but was less severe after intraperitoneal dosage than after intravenous dosage of liposomal doxorubicin.
Kanter
P M
PM
James T. Grace Jr. Cancer Drug Center, Roswell Park Cancer Institute, New York State Department of Health, Buffalo 14263, USA.
Klaich
G
G
Bullard
G A
GA
King
J M
JM
Pavelic
Z P
ZP
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D005260:Female; D007274:Injections, Intraperitoneal; D007958:Leukocyte Count / Q000187:drug effects; D008081:Liposomes; D008297:Male; D010529:Peritoneal Cavity / Q000473:pathology
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin