Patients with advanced oral cancer treated with surgery and/or radiotherapy have a poor prognosis and disease recurs predominantly locally and regionally. Surgical management of advanced oral cancer may lead to loss of organ function such as following total or partial glossectomy. The addition of cytotoxic agents results in increased toxicity, requiring regularly scheduled interruptions of radiation therapy. An interruption in the administration of radiation therapy as a single treatment results in lower rates of control. The risk inherent with chemo-radiotherapy regimens, therefore, is the suboptimal delivery of the standard treatment (radiation therapy) to optimize the administration of chemotherapy. We propose the use of localized cytotoxic gene therapy combined with radiotherapy to reduce systemic toxicity and optimize the delivery of cytotoxic agents to the tumor. We have recently demonstrated that cytotoxic therapy can be localized to the tumor while avoiding systemic toxicity. In this approach, the transcription of genes that encode cytotoxic agents is limited to the tumor volume by promoters activated by ionizing radiation. Thus, radiation can be used to induce therapeutic genes within a specific irradiated volume such as locally advance oral carcinoma. DNA sequences that activate transcription after x-irradiation include the CC(A+T)6GG(CArG) elements within the 5' untranslated region of the Egr-1 promoter. These elements are inducible in human head and neck carcinoma cells. TNF-alpha was selected as the therapeutic gene because it enhances tumor control when combined with radiation. We and others have reported that TNF-alpha enhances direct tumor cell killing in vivo and in vitro following exposure to ionizing radiation. A clinical study which combined TNF-alpha and radiation showed promising results in local tumor control; however, systemic toxicity limited the therapeutic efficacy of this treatment regimen. To determine the feasibility of this treatment, we treated human head and neck carcinoma cells with x-irradiation and the viral vector containing the radiation inducible TNF gene in vitro. These cells showed DNA fragmentation and membrane blebbing, characteristic of apoptosis. The combination of proteins produced by radiation-targeted gene therapy and the cytotoxic effect of ionizing radiation may enhance tumor cures without concomitant increases in local or systemic toxicities. Temporally fractionated radiation provides a method for repeated gene induction. This concept of precisely activating gene transcription in a spatiotemporal manner using ionizing radiation may reduce the systemic sequelae of cytotoxic therapy and enhance local control of advanced oral carcinoma. The objective of this pilot project is to assess TNF induction in oral carcinoma (xenografts treated with Ad.Egr-TNF and radiation) and further elucidate the mechanism of interaction between Ad.Egr-TNF and radiation. Our ultimate goal is to develop a new clinical therapy with reduced toxicity and increased antitumor activity.
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