title: Effect of low-dose tumor necrosis factor-alpha in combination with STEALTH liposomal cisplatin (SPI-077) on soft-tissue- and osteosarcoma-bearing rats.
abstract: Cisplatin is a widely used agent for treatment of solid tumors, but its clinical utility is limited by toxicity. Preclinical studies have shown less acute toxicity when STEALTH liposomal cisplatin (SPI-077) is used, with antitumor effects equivalent to those of intravenously administered free cisplatin. We previously reported that systemic treatment with low-dose tumor necrosis factor-alpha (TNF) augments the activity of STEALTH liposomal doxorubicin (Doxil). In this study, we examined the effect of repeated systemic applications of low-dose TNF on the antitumor activity of SPI-077 in rats with soft-tissue sarcoma or osteosarcoma. Addition of TNF to SPI-077 treatment showed an improved tumor growth delay of the soft-tissue sarcoma. The combined SPI-077/TNF treatment resulted in a more prolonged antitumor activity, whereas free cisplatin showed a better tumor response, however with a rapid outgrowth a few days after the end of therapy. In the osteosarcoma, free cisplatin did not have an antitumor effect, but addition of TNF caused a clear tumor growth delay. SPI-077 alone resulted in a tumor growth delay, but combination with TNF had no additive effect. SPI-077 yielded less systemic toxicity than cisplatin. Depending on the type of tumor, the addition of TNF to SPI-077 results in a better tumor growth delay with a prolonged antitumor effect and, in combination with the reduced toxicity of SPI-077, this combination may be preferable to cisplatin.
authors.affiliation: Department of Surgical Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy*; D051381:Rats; D011914:Rats, Inbred BN; D011994:Recombinant Proteins / Q000494:pharmacology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D008081:Liposomes; D011994:Recombinant Proteins; C422270:SPI-77, liposomal; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin