EFFECT OF 4 DISINTEGRINS ON THE ADHESIVE AND METASTATIC PROPERTIES OFB16F10 MELANOMA-CELLS IN A MURINE MODEL

Four disintegrins, eristostatin, albolabrin, barbourin and echistatin, injected IV into C57BL/6 mice in combination with B16F10 murine melan oma cells, inhibited formation of experimental lung metastases with ID 50s of 0.05, 1.0, 0.9, and 3.7 mu moles per mouse, respectively. When injected 1 h after tumor cells, albolabrin, echistatin and barbourin h ad the same antimetastatic activity, while eristostatin was not active . Eristostatin (IC50 7-8 nM) was more potent than echistatin (IC50 74- 75 nM), barbourin (IC50 46-60 nM), and albolabrin (IC50 130-165 nM) as an inhibitor of murine platelet aggregation induced by ADP or tumor c ells. Fibronectin was the best substrate for melanoma cell adhesion (9 5%), followed by laminin (47%) and vitronectin (24%). Albolabrin was t he strongest and eristostatin the weakest inhibitor of cell adhesion t o all substrata. Adhesion of melanoma cells to albolabrin, echistatin, and barbourin was partially inhibited by monoclonal antibody against mouse alpha(V) subunit. This antibody bound to B16F10 melanoma cells i n suspension and inhibited binding of fluorescein isothiocyanate (FITC )-labeled disintegrins to these cells, being the most effective with F ITC-labeled albolabrin. Our study suggests that a major contribution o f eristostatin to inhibition of lung colonization is via preferential binding to platelet alpha(IIb)beta(3), integrin and blocking tumor cel l interaction with platelets. A major contribution of albolabrin, barb ourin and echistatin appears to be by interference with other integrin receptors on the tumor cell surface. Albolabrin appeared to inhibit R GD-dependent integrins containing alpha(V) subunit, such as alpha(V)be ta(3) and alpha(V) beta(1).