Preclinical efficacy of [V 4 Q 5 ]dDAVP, a second generation vasopressin analog, on metastatic spread and tumor-associated angiogenesis in colorectal cancer

Abstract

Purpose Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V 4 Q 5 ]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of arginine vasopressin type 2 membrane receptor (AVPR2) present in endothelial and tumor cells, [V 4 Q 5 ]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V 4 Q 5 ]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Materials and Methods Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V 4 Q 5 ]dDAVP, both in vitro and in vivo. Results In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained intravenous treatment with [V 4 Q 5 ]dDAVP (0.3 jg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V 4 Q 5 ]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 |jM) and addition to 5-fluorouracil resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. Conclusion The present preclinical study establishes for the first time the efficacy of [V 4 Q 5 ]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.