Abstract 5473: Antiproliferative and antimetastasic activity of a novel vasopressin V2 receptor peptide agonist in a breast cancer model

Abstract

Abstract Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analog of vasopressin with antimetastatic properties. The molecule is a well known and safe hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor, which is expressed in endothelium and also in some tumor cells. Previous data revealed that perioperative administration of desmopressin can minimize the spread and survival of residual cancer cells. This cyclic nonapeptide was substituted in positions 4 and 5 searching for compounds with improved biological activity and half life. Such positions belong to the disulphide loop (between positions 1-6), which have a major interaction with its receptor. In this work, we evaluated the in vitro biological activity of a novel analog designated VQ (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) in MCF7 human mammary carcinoma cells, as well as its in vivo antitumor action in combination with chemotherapy using the syngeneic F3II mammary carcinoma model in Balb/c mice. Because V2 receptor signaling has been associated with cytostatic effects, we have examined peptide ability to modify in vitro cell proliferation of MCF7 cells expressing V2 receptor. Incubation with VQ analog (100-1500 nM) during 72 h significantly reduced cell proliferation (p<0.001) showing a better performance than desmopressin at higher doses of 500-1500 nM (p<0.05). Inhibition of cell proliferation was associated with an increase of intracellular cAMP levels and this was correlated with PKA activation in MCF7 cells. A similar antiproliferative profile was obtained with loop tetrapeptides (aminoacid positions 2-5) at low doses (<500 nM), although cytostatic activity of tetrapeptides was lost at high concentrations. Three weekly i.v. doses of VQ (0.3 µg/kg/dose) reduced by 40% the subcutaneous tumor volume in mice implanted with F3II mammary carcinoma cells, while VQ treatment plus weekly i.p. cycles of carmustine (20 mg/kg/cycle) was even more effective (p<0.001). Furthermore, VQ treatment, either in combination or not with carmustine cycles, prevented lung metastatic progression in tumor-bearing mice. VQ also inhibited F3II lung colonization in the experimental metastasis assay. Our results indicate that the novel cyclic peptide analog VQ can exert a remarkable antitumor and antimetastatic effect in a preclinical model of breast carcinoma. Loop conformation of the peptide seems to be essential for interaction with V2 receptor and for the biological activity of the compound. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5473.