Tumor size does not limit radiation‐inducible gene therapy in a human xenograft model

Abstract

AbstractTumor size has been reported to be a limiting factor in both radiotherapy (RT) and gene therapy. Therefore, we assessed the effects of tumor necrosis factor‐alpha (TNF‐α) gene therapy and radiation in relatively large tumors in a human xenograft system. We linked DNA sequences from the promoter region of the radiation‐inducible gene Egr‐1 to the cDNA sequence that encodes human TNF‐α, a radiosensitizing cytokine. The Egr‐TNF construct was transfected into the human hematopoietic cell line HL525. Stable transfectants, exhibiting radiation inducibility of TNF‐α in vitro (clone 2 cells), were directly injected into xenografts of a radioresistant human squamous cell carcinoma cell line, SQ‐20B. In a previous study, 100 mm3 tumors treated with radiation and clone 2 cells demonstrated significant tumor control (P < 0.0001) when compared with tumors treated with clone 2 alone or radiation alone. In the present study, 450 mm3 xenografts treated with clone 2 cells and radiation were significantly smaller (P < 0.01) at the nadir of regression than tumors treated with radiation alone. Because the radiation dose was held constant (40 Gy) in both 100 and 450 mm3 xenografts, only one cure was noted in the larger tumors. These data support an interactive anti‐tumor effect in vivo between radiation and TNF‐α gene therapy which is equal in both small and large human tumor xenograft models. © 1995 Wiley‐Liss, Inc.