title: In vitro and in vivo effect of doxorubicin combined with liposome-encapsulated muramyl tripeptide on canine monocyte activation.
abstract: Chemotherapeutic agents have been shown to enhance the antitumor activity of biological response modifiers and cytokines in rodents and humans. The purpose of this study was 2-fold: (a) to determine whether doxorubicin (DOX) would enhance or interfere with the effect of muramyl dipeptide and lipopolysaccharide on canine monocyte activation as measured by an in vitro WEHI-164 cell cytotoxicity assay; and (b) to evaluate the in vivo effect of DOX alone and combined with liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) on monocyte activation and serum tumor necrosis factor activity. The in vitro results showed that increasing concentrations of DOX for either 1 or 24 h incubation did not directly enhance or inhibit spontaneous or activated monocyte supernatant-mediated cytotoxicity. The in vivo study showed that monocyte supernatant-mediated cytotoxicity was increased on day 3 and significantly elevated on day 7 (P = 0.016) post-DOX (30 mg/m2, single injection) administration. When DOX was given in combination with L-MTP-PE (2 mg/m2, twice weekly for 3 weeks), monocyte-mediated cytotoxicity was enhanced on days 3 through 10 with a significant increase on day 10 (P < 0.001). In vivo monocyte supernatant-mediated cytotoxicity was significantly elevated in dogs receiving L-MTP-PE alone at 2 h after day 0, 7, and 14 treatment, and this response was further enhanced by DOX. Serum tumor necrosis factor activity at 2 h post-L-MTP-PE was enhanced and sustained for a longer period of time in dogs that also received DOX. We conclude that DOX administered with L-MTP-PE will enhance canine monocyte activation induced by DOX or L-MTP-PE alone, and suggest that DOX may be combined with L-MTP-PE early in the treatment of cancer patients.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison 53706.
authors.forename: F
authors.initials: F
authors.lastname: Shi
authors.forename: E G
authors.initials: EG
authors.lastname: MacEwen
authors.forename: I D
authors.initials: ID
authors.lastname: Kurzman
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers; D005354:Fibrosarcoma / Q000378:metabolism; D066298:In Vitro Techniques; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008081:Liposomes; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D008070:Lipopolysaccharides; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C035104:muramylNAc-Ala-isoGln-Lys-tripeptide; D004317:Doxorubicin