Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth liposomal doxorubicin (Doxil (R)) in soft tissue sarcoma-bearing rats

It has previously been demonstrated in the setting of an isolated limb perf usion that application of high-dose TNF-alpha in combination with chemother apy (melphalan, doxorubicin) results in strong synergistic antitumor effect s in both the clinical and preclinical settings. In this study, we demonstr ate that systemic administration of low-dose TNF-alpha augments the antitum or activity of a liposomal formulation of doxorubicin (DOXIL(R)), Addition of TNF-alpha to a DOXIL(R) regimen, which by itself induced some tumor grow th delay, resulted in massive necrosis and regression of tumors, Furthermor e, we could demonstrate a significant increase of liposomal drug in the tum or tissue when TNF-alpha had been co-administered. Administration of INF-al pha augmented DOXIL(R) accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-alpha. Drug level s in the tumor interstitium appeared crucial as intracellular levels of fre e or liposome-associated doxorubicin were not increased by TNF-alpha, There fore, we hypothesize that low-dose TNF-alpha augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumo r effects, Regarding the effects of systemic administration of low doses of TNF-alpha, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J, Cancer 87:829-837, 2000, (C) 2000 Wiley-Liss, Inc.