Reduced Cardiotoxicity and Nephrotoxicity with Preservation of Antitumor Activity of Doxorubicin Entrapped in Stable Liposomes in the LOU/M Wsl Rat

Abstract LOU M/Wsl rats inoculated s.c. with 10 4 immunoglobulin immunocytoma cells have a palpable tumor at Day 17. Doxorubicin (DXR) has been entrapped in negatively charged liposomes (lip - DXR) composed of egg phosphatidylcholine, cholesterol, and phosphatidylserine and in positively charged liposomes (lip + DXR) composed of phosphatidylcholine, cholesterol, and stearylamine. DXR, lip - DXR, and lip + DXR were administered i.v. (0, 0.25, 0.5, 1.0, and 2.0 mg/kg) at Day 17 for 5 consecutive days and then weekly. Control animals showed progressive tumor growth leading to death 27 days after inoculation. Antitumor activity for all three preparations was dose dependent. DXR and lip - DXR showed the same antitumor activity; lip + DXR had less antitumor activity. The overall survival of tumor-bearing animals treated with 2.0-mg/kg lip - DXR was significantly prolonged ( p - DXR resulted in Grade I cardiomyopathy. In animals treated with 1.0-mg/kg and 2.0-mg/kg free DXR urinary albumin concentrations of 10 g/liter were observed. Treatment with 1.0-mg/kg lip - DXR and 1.0-mg/kg lip + DXR resulted in urinary albumin concentration of - DXR and lip + DXR. Treatment with a 1.0-mg/kg dose of free DXR resulted in severe glomerular and tubular lesions which were not found after treatment with 1.0-mg/kg lip - DXR and 1.0 mg/kg lip + DXR. Administration of lip - DXR resulted in lower DXR levels in cardiac and renal tissue compared to administration of free DXR. After administration of lip + DXR, very low tissue and tumor DXR levels were found. In conclusion, treatment with lip - DXR or lip + DXR resulted in a prolonged survival, less albuminuria, and higher serum albumin levels. Also, fewer lesions in heart and kidney were found, correlating with lower DXR levels in these organs. Only lip - DXR had the same antitumor effect as free DXR.