Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes

The relative cardiotoxicity of pegylated (STEALTH) liposomal doxorubicin (P L-DOX; Doxil) was compared to nonliposomal doxorubicin (Adriamycin) in rabb its and dogs treated i.v, for up to 22 weeks. No histological evidence of c ardiotoxicity was seen in dogs treated with placebo liposomes or PL-DOX eve ry 3 weeks for a total of 10 doses (cumulative doxorubicin dose = 10 mg/kg) either 1 or 5 weeks post-treatment. All dogs treated with the same cumulat ive dose of free doxorubicin showed marked cardiotoxicity (vacuolization an d myofibrillar loss in the myocardium) at both time points, in rabbits, pro gressive cardiomyopathy was seen in both treatment groups, but was more fre quent and severe with free doxorubicin (67% of doxorubicin-treated rabbits, cumulative dose = 12 to 14 mg/kg versus 16% of PL-DOX-treated animals, cum ulative dose = 14 to 21 mg/kg). Five doxorubicin-treated rabbits died of co ngestive heart failure or with histologic evidence of cardiotoxicity (media n severity score = 6). No PL-DOX-treated rabbits died of congestive heart f ailure, although two animals that died early showed microscopic evidence of mild cardiotoxicity (median severity score = 2.5). Cardiotoxicity increase d during the posttreatment period in both treatment groups. Rabbits receive d up to 50% more PL-DOX with no increase in cardiotoxicity. Thus, results i n two species demonstrate that the cardiotoxicity of doxorubicin is signifi cantly decreased when administered as PL-DOX. Significantly more PL-DOX can be given without incurring an increased risk of cardiomyopathy. Recent cli nical studies have confirmed that PL-DOX is also less cardiotoxic than the same dose of unencapsulated doxorubicin in humans.