Investigation into the role of tumor-associated macrophages in the antitumor activity of Doxil.
OBJECTIVE
Our recent studies show specific localization of long-circulating liposomes (LCL) within the endosomal/lysosomal compartment of tumor-associated macrophages (TAM). Based on this finding, the present study aims to investigate whether clinically applied LCL formulations such as Doxil (LCL-encapsulated doxorubicin), have alternative mechanisms of action additionally to direct drug-mediated cytotoxicity towards tumor cells.


METHODS
The antitumor activity of Doxil was evaluated in B16.F10 melanoma-bearing mice, in the presence and in the absence of TAM. To suppress TAM functions, liposomal clodronate (Lip-CLOD) was injected 24 h before the actual treatment. The effect of Doxil on the levels of angiogenic factors was determined using an angiogenic protein array. As positive control, the same experiments were conducted with LCL-encapsulated prednisolone phosphate (LCL-PLP), a tumor-targeted formulation with known strong anti-angiogenic/anti-inflammatory effects on TAM.


RESULTS
Our results show that the antitumor efficacy of Doxil was only partially attributed to the inhibition of TAM-mediated angiogenesis whereas LCL-PLP inhibited tumor growth through strong suppressive effects on pro-angiogenic functions of TAM. As described previously, the main mechanism of Doxil might be a cytotoxic effect on tumor cells.


CONCLUSIONS
Our findings suggest that the antitumor activity of Doxil does not depend mainly on the presence of functional TAM in tumors.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Room Z509, P.O. Box 80.082, 2508 TB, Utrecht, The Netherlands. covaciumanu@yahoo.com
Manuela
M
Banciu
Raymond M
RM
Schiffelers
Gert
G
Storm
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers; D007275:Injections, Intravenous; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D004002:Clodronic Acid; D004317:Doxorubicin