INHIBITION OF RADIATION-ENHANCED EXPRESSION OF INTEGRIN AND METASTATIC POTENTIAL IN B16 MELANOMA-CELLS BY A LIPOXYGENASE INHIBITOR

Low-dose gamma radiation stimulates expression of phenotypic character istics in B16 melanoma cells which regulate metastatic potential. A tr ansient increase in the expression of an integrin receptor (alpha(IIb) beta(3)) was observed after exposure of B16 melanoma cells to 0.25 to 2.0 Gy of gamma radiation. This increased receptor expression resulted in enhanced adhesion of tumor cells to fibronectin in vitro and incre ased experimentally induced metastasis in vivo. In this report, we det ermined a role for the 12-lipoxygenase metabolite, 12-HETE, in radiati on-enhanced metastasis. A significant increase in biosynthesis of 12-H ETE in B16 melanoma cells was detected <5 min after exposure to 0.5 Gy gamma radiation. We then determined that radiation-enhanced expressio n of alpha(IIb)beta(3) integrin and adhesion of B16 melanoma cells to fibronectin in vitro and metastasis in vivo were reduced by treatment of the cells with the lipoxygenase inhibitor NDGA prior to irradiation . These findings suggest that low-dose radiation, at levels comparable to those used in fractionated or hyperfractionated radiotherapy, incr eases the metastatic potential of surviving tumor cells via a rapid an d transient alteration in lipoxygenase metabolism of arachidonic acid and surface expression of an integrin receptor.