A cellular disintegrin and metalloproteinase (ADAM) is a new family of genes with structural homology to the snake venom metalloproteinases and disintegrins. We screened genes which were selectively expressed in the cachexigenic colon 26 adenocarcinoma subline in vivo. It was found that one novel cDNA clone, identified as a cachexigenic tumor selective gene, encodes a cysteinerich protein which shows a sequence similarity to that of both the snake venom metalloproteinases and thrombospondins. We named this cDNA clone A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1). ADAMTS1 consists of six domains, 1) a proand 2) a metalloproteinase, 3) a disintegrin-like, 4) a thrombospondin (TSP) homologous domain containing TSP type I motif, 5) a spacer region, and 6) COOH-terminal TSP submotifs. Unlike other ADAMs, ADAMTS-1 does not possess a transmembrane domain and is a putative secretory protein. Therefore, ADAMTS-1 is a new type of ADAM family protein with TSP type I motifs. We demonstrated that the TSP homologous domain containing the TSP type I motif of ADAMTS-1 is functional for binding to heparin. ADAMTS-1 mRNA could be induced by stimulating colon 26 cells with an inflammatory cytokine, interleukin-1, in vitro. Moreover, intravenous administration of lipopolysaccharide in mice selectively induced ADAMTS-1 mRNA in kidney and heart. These data suggest that ADAM-TS-1 may be a gene whose expression is associated with various inflammatory processes as well as development of cancer cachexia.
The rejection of the cells depends on cytolysis and generates potent and long lasting antitumor immunity. These data suggest that tumor cells transfected with the MIP-1 alpha gene might be useful as an effective therapy for the treatment of certain tumors.
To evaluate the dose dependency in apparent peritoneal permeability (Pd) of benzoic acid as a model compound for a monocarboxylic acid transport system, a kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. We compared the Pd value of benzoic acid to that of phenobarbital which is a more lipophilic drug than benzoic acid. The concentration-time courses of phenobarbital in both peritoneal cavity and serum after the intraperitoneal administration with various doses were parallel according to dose, whereas those of benzoic acid varied in a dose-dependent manner. Using the values of unbound fraction (Fu), the value of Pd for unbound drugs was estimated. The Pd values of benzoic acid at 20 micrograms mL-1 was three times the value determined at 1000 micrograms mL-1. We suggest that certain facilitated transport systems constitute the mechanism of enhanced peritoneal membrane permeability of benzoic acid.
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