GENETIC RADIOTHERAPY OVERCOMES TUMOR RESISTANCE TO CYTOTOXIC AGENTS

We report that radiation enhances gene therapy of a radioresistant tum or by upregulating the induction of a chimeric gene encoding a radiose nsitizing protein, tumor necrosis factor alpha (TNF-alpha). We ligated the radiation-inducible CArG elements of the radiation-inducible Egr- 1 promoter/enhancer region upstream to the transcriptional start site of the human TNF cDNA (pE425-TNF), This construct was transfected usin g cationic liposomes into the variant murine fibrosarcoma cell line, P 4L, The P4L cell line was both radioresistant (D-0 = 188) and resistan t to TNF, After a single intratumoral injection of 10 mu g of pE425-TN F in cationic liposomes and two 20-Gy doses of irradiation, mean tumor volumes were significantly reduced in P4L tumors as compared to those receiving either pE425-TNF in liposomes or radiation alone (P = 0.01) , TNF protein in P4L tumors was induced by radiation as high as 29 tim es control levels and remained detectable for 14 days, Our data indica te that combined gene therapy using liposomes, together with ionizing radiation to locally activate the induction of a radiosensitizing prot ein, is successful at overcoming resistance to both TNF and radiation.