title: Pegylated liposomal tumor necrosis factor-alpha results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil) in soft tissue sarcoma-bearing rats.
abstract: Previously we reported that encapsulation of tumor necrosis factor-alpha (TNF) in pegylated (STEALTH) liposomes (TNF-PEGL) dramatically improved circulation times of the protein and augmented accumulation in tumor tissue. We and others have demonstrated enhanced antitumor activity of doxorubicin or melphalan by free TNF when used in high doses in an isolated limb perfusion setting. In the present study the antitumor activity of TNF-PEGL was studied in combination with liposomal chemotherapy. BN rats with subcutaneous BN175 sarcomas (8-12 mm diameter) received no treatment or pegylated liposomal doxorubicin (Doxil) alone or in combination with various doses of TNF-PEGL (15-200 microg/kg). The evaluated endpoints were tumor response and toxicity of the treatment regimens. Here we demonstrate that TNF-PEGL at a dose of 15 microg/kg markedly augments the antitumor activity of liposomal doxorubicin, without resulting in the increased toxic side effects observed with free TNF at doses resulting in a similar enhancement of the antitumor effects. Even at a TNF dose of 200 microg/kg TNF, repeated administration of TNF-PEGL did not result in severe weight loss or cause diarrhea. Repeated dosing of free TNF at this dose resulted in severe, life-threatening weight loss and occurrence of diarrhea in all animals. These results indicate that pegylated liposomal encapsulation may be effective in systemic application of TNF for combined treatment with liposomal chemotherapy of advanced solid tumors.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. tenhagen@heel.fgg.eur.nl
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Ruiter
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight; D002455:Cell Division; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008297:Male; D051381:Rats; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin