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Banciu, M., Schiffelers, R. M., Storm, G. . Investigation into the role of tumor-associated macrophages in the antitumor activity of Doxil. Pharm Res. , 25(8), p. 19481955, 2008.

Abstract: Purpose. 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 (LCLencapsulated
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.

Keywords: angiogenic proteins; doxil; tumor-associated macrophages; tumor cells

Posted by Manuela Banciu


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