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  • Title: In vitro and in vivo effect of doxorubicin combined with liposome-encapsulated muramyl tripeptide on canine monocyte activation.
    Author: Shi F, MacEwen EG, Kurzman ID.
    Journal: Cancer Res; 1993 Sep 01; 53(17):3986-91. PubMed ID: 8358727.
    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.
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