Hoyt D G, Rusnak J M, Mannix R J, Modzelewski R A, Johnson C S, Lazo J S
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Cancer Res. 1996 Sep 15;56(18):4146-9.
Tumor endothelium is critical for solid tumor growth and is a potential site for anticancer drug action. Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial cells (TDECs). Etoposide-induced DNA breakage was inhibited by culturing TDECs on gelatin, type IV collagen, laminin, fibronectin, and the integrin ligand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP. It was also inhibited when TDECs were on surfaces coated with antibodies to alpha 5, beta 1, or beta 3 integrin subunits and by clustering integrins with soluble antibodies. After 8 h with etoposide, TDECs detached from the monolayer, and 50-kb DNA fragments were seen. Fibronectin inhibited both processes. Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sensitivity of tumors to drugs.
肿瘤内皮细胞对于实体瘤的生长至关重要，并且是抗癌药物作用的潜在靶点。依托泊苷在2小时内可导致异种移植瘤来源的内皮细胞（TDECs）出现明显的DNA链断裂。在明胶、IV型胶原、层粘连蛋白、纤连蛋白和整合素配体六肽GRGDSP上培养TDECs时，依托泊苷诱导的DNA断裂受到抑制，但在无活性肽GRADSP上培养时则不受抑制。当TDECs置于包被有α5、β1或β3整合素亚基抗体的表面以及通过用可溶性抗体使整合素聚集时，DNA断裂也受到抑制。用依托泊苷处理8小时后，TDECs从单层脱离，并可见50kb的DNA片段。纤连蛋白可抑制这两个过程。因此，整合素是TDECs的存活因子，可抑制依托泊苷的遗传毒性，并可能影响肿瘤对药物的敏感性。
