Re-evaluation of cellular radiosensitization by 5-fluorouracil: high-dose, pulsed administration is effective and preferable to conventional low-dose, chronic administration.

PURPOSE: It is widely believed that the anticancer drug 5- fluorouracil (5-FU) must be administered chronically and in low doses to maximize radiosensitization during chemoradiotherapy. The rationale is based upon cell experiments that assumed identical mechanisms of 5-FU action between low-dose chronic (LDC) and high-dose pulsed (HDP) exposures. Here we challenge the paradigm and demonstrate the effectiveness of HDP 5-FU as a radiosensitizer and the wide range of dose/time schedules that can be used to synergize with radiation as compared to the relatively restrictive protocols prescribed for current LDC administrations. MATERIALS AND METHODS: Clonogenic survival of human glioblastoma and colon cancer cell lines, U87MG-VIII and HCT-116, respectively, was used to assess temporal and dose effects of 5-FU on radiosensitivity and in split-dose experiments to characterize changes in sublethal damage repair. RESULTS: We show that HDP 5-FU administration does indeed radiosensitize both the highly radioresistant U87MG-VIII and HCT-116. Additionally, we show that this radiosensitization lasts for at least 24 h if cells are pre-irradiated with 2 Gy immediately after HDP 5-FU exposure as a result of a decrease in sublethal damage repair capacity for subsequent irradiations, suggesting the ideal combination of 5-FU bolus injection with fractionation radiotherapy schemes. CONCLUSIONS: 5-FU bolus administration protocols combined with radiation would not only help improve treatment outcomes and reduce development of 5-FU resistance, but it would greatly benefit patients by shortening clinical stays and lowering overall therapeutic costs.

High-throughput screening identifies two classes of antibiotics as radioprotectors: tetracyclines and fluoroquinolones.

PURPOSE: Discovery of agents that protect or mitigate normal tissue from radiation injury during radiotherapy, accidents, or terrorist attacks is of importance. Specifically, bone marrow insufficiency, with possible infection due to immunosuppression, can occur after total body irradiation (TBI) or regional irradiation and is a major component of the acute radiation syndrome. The purpose of this study was to identify novel radioprotectors and mitigators of the hematopoietic system. EXPERIMENTAL DESIGN: High-throughput screening of small-molecule libraries was done using viability of a murine lymphocyte line as a readout with further validation in human lymphoblastoid cells. The selected compounds were then tested for their ability to counter TBI lethality in mice. RESULTS: All of two major classes of antibiotics, tetracyclines and fluoroquinolones, which share a common planar ring moiety, were radioprotective. Furthermore, tetracycline protected murine hematopoietic stem/progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacine also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure. CONCLUSIONS: Tetracyclines and fluoroquinolones can be robust radioprotectors and mitigators of the hematopoietic system with potential utility in anticancer radiotherapy and radiation emergencies.