title: Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth liposomal doxorubicin (DOXIL) in soft tissue sarcoma-bearing rats.
abstract: It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-alpha 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-alpha augments the antitumor activity of a liposomal formulation of doxorubicin (DOXIL(R)). Addition of TNF-alpha to a DOXIL(R) 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-alpha had been co-administered. Administration of TNF-alpha augmented DOXIL(R) accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-alpha. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-alpha. Therefore, we hypothesize that low-dose TNF-alpha 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-alpha, these findings may be important for enhanced tumor targeting of various liposomal drug formulations.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. tenhagen@heel.fgg.eur.nl
authors.forename: T L
authors.initials: TL
authors.lastname: Ten Hagen
authors.forename: A H
authors.initials: AH
authors.lastname: Van Der Veen
authors.forename: P T
authors.initials: PT
authors.lastname: Nooijen
authors.forename: S T
authors.initials: ST
authors.lastname: Van Tiel
authors.forename: A L
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D008081:Liposomes; D008297:Male; D051381:Rats; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin