Low-dose tumor necrosis factor-α augments antitumor activity of stealth liposomal doxorubicin (DOXIL®) in soft tissue sarcoma-bearing rats

It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (DOXIL®). Addition of TNF-α to a DOXIL® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented DOXIL® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. (C) 2000 Wiley-Liss, Inc.