LIPOSOMAL DOXORUBICIN-INDUCED TOXICITY - DEPLETION AND IMPAIRMENT OF PHAGOCYTIC-ACTIVITY OF LIVER MACROPHAGES

Doxorubicin entrapped within conventional liposomes (200 nm in diamete r; lip-Dox) has major toxic effects on liver macrophages of the rat fo r a considerable period of time following i.v. administration, with re spect to both specific phagocytic capacity and cell numbers. At differ ent time-points after injection of lip-Dox or free doxorubicin, radiol abeled, negatively charged, ''empty'' test liposomes were injected. Ph agocytic capacity was determined by isolating the liver macrophages an d measuring the amount of macrophage-associated radioactivity. Four su bfractions of liver macrophages of different cell-size and with intrin sically different phagocytic capacity were isolated. Twenty-four hours after injection of lip-Dox, the phagocytic capacity of the larger-siz ed liver macrophages was strongly decreased. The relatively low intrin sic phagocytic capacity of the smaller-sized macrophages was only slig htly impaired. Phagocytic capacity after injection of lip-Dox was near ly restored to control values after 14 days. Blood clearance of Klebsi ella pneumoniae bacteria after pre-treatment with lip-Dox was strongly decreased. Pre-treatment with the free drug and/or placebo liposomes had no effect on phagocytic and bacterial blood-clearance capacity. A major depletion of the liver macrophage population was observed, as re vealed by both macrophage isolation and histology. Only 2 weeks after injection of lip-Dox, the number of cells had returned to that seen in control animals. In view of the important host-defense functions of t he liver macrophages, especially in the control of tumor growth and in fection, the findings reported here should be taken into consideration when lip-Dox is to be administered in anti-tumor therapy.