ABSTRACT
We have shown that glucosaminyl muramyl dipeptide (GMDP) has been augmented the antitumor action of chemotherapy drug cisplatin and tumor necrosis factor-alpha (TNFalpha) on the Ehrlich ascites carcinoma and melanoma B-16 mouse tumor models. The doses of cisplatin, TNFalpha and GMDP and also the conditions of the drugs combination injection provided 100% survival of mice with Ehrlich ascites carcinoma were found. Furthermore, it was shown first that GMDP has been decreased toxicity of the cisplatin/TNFalpha combination and normalized the changes in the experimental mice hematological parameters which were produced by the CP/TNFalpha combination.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Acetylmuramyl-Alanyl-Isoglutamine/administration & dosage , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Acetylmuramyl-Alanyl-Isoglutamine/toxicity , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/toxicity , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Carcinoma, Ehrlich Tumor/drug therapy , Cisplatin/administration & dosage , Cisplatin/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Survival , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/toxicityABSTRACT
We have demonstrated that biologically active muramyl peptides, in particular, glucosaminylmuramyl dipeptide (GMDP), augmented in vitro cytotoxic activity of tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma L929 cells. The introduction of GMDP resulted in cytotoxic effect characteristic for substantially higher dose of cytokine. Even more potent was the combination of GMDP, TNF-alpha and Actinomycin D (ActD). According to clonogenic and MTT assays 100% L929 cells could be killed in culture with low doses of TNF-alpha and ActD if GMDP was present. When cisplatin was substituted for ActD similar results were obtained. GMDP also enhanced cytotoxicity of TNF-alpha and cisplatin against human breast carcinoma MCF7 and histiocytic lymphoma U937 cells. Normal cells, namely human peripheral blood leucocytes and murine peritoneal macrophages, were resistant to selected doses of TNF-alpha/cisplatin/GMDP.
