EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA ON BIODISTRIBUTION OF AN ANTIEPIDERMAL GROWTH-FACTOR RECEPTOR (EGFR) MONOCLONAL-ANTIBODY IN-VIVO

In a previous study we demonstrated that tumor necrosis factor alpha ( TNF alpha)was capable of increasing binding of an anti-epidermal growt h factor receptor monoclonal antibody (Mab), A108, to melanoma cells I n vitro through regulation of the EGFr receptor. To determine whether similar effects occurred in vivo, nude mice bearing subcutaneous and v isceral human tumor xenografts of melanoma cell line DX3 were given TN F alpha (10(3), 10(4) or 10(5) U/day x 6 days) or normal saline (contr ol) followed by intravenous injections of I-125-labeled A108, along wi th control Mab, I-131-NR2AD. Twenty-four hours later mice were sacrifi ced and the percent injected dose of each Mab determined in tumors and normal organs. TNF alpha caused a 1 to 2-fold increase in tumor targe ting of both Mabs over controls (p<0.05). Increased blood and heart up take of both Mabs was also observed. The increase in normal tissues wa s significantly blocked by the administration of N-G-methyl-L-arginine , a selective inhibitor of nitric oxide synthesis. Examination of exci sed tumors for EGFr expression in TNF alpha treated versus saline trea ted mice revealed that specific upregulation of EGFr occurred only in liver tumors. These data suggest that TNF alpha acts to enhance target ing of Mabs through both enhancement of EGFr on tumors as well as by s elective vascular endothelial cell damage...and that these changes var y with respect to tumor location.