d-609 and Carcinoma

Recombinant human tumor necrosis factor (rh TNF) when administered intravenously together with the phospholipase C inhibitor tricyclodecan-9-yl-xanthogenate (D609) and lauric acid (C12), leads to the partial regression of various human tumor transplants in athymic mice. Extensive necrosis occurred after a single intravenous infusion, with no detectable side effects. TNF-mediated cytotoxicity was found to be correlated with the depletion of energy in HeLa cells. The activity of rh TNF was enhanced by the absence of glucose, while it was reduced by addition of extraneous ATP. In the presence of rh TNF, D609, and C12, cellular energy metabolism was almost completely switched to glycolysis. Under these conditions the cytocidal activity of rh TNF on HeLa cells was amplified at least 60-fold.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma; Cell Line; Drug Screening Assays, Antitumor; Female; Humans; Lauric Acids; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Norbornanes; Recombinant Proteins; Specific Pathogen-Free Organisms; Thiocarbamates; Thiones; Transplantation, Heterologous; Tumor Necrosis Factor-alpha

The antiviral and antitumoral compound tricyclodecan-9-yl-xanthogenate (D609), which is an inhibitor of protein kinase C activation, has been used for tumor prevention in vivo. When applied chronically together with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the classic initiation-promotion mouse-skin model, D609 prevented tumor induction in a dose-dependent manner. At the concentration that inhibited tumor formation by 97%, no toxic effects were detected and the TPA-induced hyperplasia remained unaffected. As D609 failed to prevent the activity of a chronically applied carcinogen, it is concluded that the observed tumor prevention achieved with D609 is tumor-promotion-specific and is not due to killing of tumor cells.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Cutaneous; Animals; Antineoplastic Agents; Antiviral Agents; Bridged-Ring Compounds; Carcinoma; Dose-Response Relationship, Drug; Female; Mice; Norbornanes; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Thiocarbamates; Thiones