Adv Exp Med Biol
-
Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectively profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. ⋯ In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID50 approximately 10 micrograms/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.
-
The effect of a bovine milk protein, lactoferrin (bLf), and a pepsin-generated peptide of bLf, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, was examined in experimental and spontaneous metastasis models using syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-bLf) and Lfcin-B 1 day after tumor inoculation significantly inhibited liver and spleen metastasis of L5178Y-ML25 cells and lung metastasis of B16-BL6 cells, whereas human apo-lactoferrin (apo-hLf) and bovine holo-lactoferrin (holo-Lf) at the dose of 1 mg/mouse did not. ⋯ In spontaneous metastasis model, multiple administration of both apo-bLf and Lfcin-B significantly inhibited lung metastasis of B16-BL6 cells, however it was only apo-bLf that exhibited the inhibitory effect of tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. The results suggest that apo-bLf and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of bLf on tumor metastasis may be related to the property of iron (Fe3+)-saturation.