IN-VITRO AND IN-VIVO EFFECT OF DOXORUBICIN COMBINED WITH LIPOSOME-ENCAPSULATED MURAMYL TRIPEPTIDE ON CANINE MONOCYTE ACTIVATION

Chemotherapeutic agents have been shown to enhance the antitumor activ ity of biological response modifiers and cytokines in rodents and huma ns. The purpose of this study was 2-fold: (a) to determine whether dox orubicin (DOX) would enhance or interfere with the effect of muramyl d ipeptide and lipopolysaccharide on canine monocyte activation as measu red by an in vitro WEHI-164 cell cytotoxicity assay; and (b) to evalua te the in vivo effect of DOX alone and combined with liposome-encapsul ated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) on monocyt e activation and serum tumor necrosis factor activity. The in vitro re sults showed that increasing concentrations of DOX for either 1 or 24 h incubation did not directly enhance or inhibit spontaneous or activa ted monocyte supernatant-mediated cytotoxicity. The in vivo study show ed that monocyte supernatant-mediated cytotoxicity was increased on da y 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 c ytotoxicity was enhanced on days 3 through 10 with a significant incre ase on day 10 (P < 0.001). In vivo monocyte supernatant-mediated cytot oxicity 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 e nhanced 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 tha t also received DOX. We conclude that DOX administered with L-MTP-PE w ill enhance canine monocyte activation induced by DOX or L-MTP-PE alon e, and suggest that DOX may be combined with L-MTP-PE early in the tre atment of cancer patients.