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(PP188) Para-aminobenzoic acid (PABA) and high radiation dose rates modulate response to ionizing radiation in experimental lung cancer models.
Buckley, Michael1, Emmolo, Joanna1, Devitt, Mary1, Roth, Jennifer1, Dewyngaert, J Keith1, Peter, Brooks2, Liebes, Leonard1,3, Formenti, C Silvia1,3, Vlachaki, Maria Theodoros*,1, 1 Radiation Oncology, New York, NY, USA2 Cell Biology, New York, NY, USA3 New York University Cancer Institute, New York, NY, USA
ABSTRACT- Purpose/Objective: Lung cancer is the most frequent cause of cancer diagnosis and death in both genders. Modulation of response to conventional therapies may improve outcomes and depends on the genetic profile of tumors. Previous work from our group has shown radiosensitizing effects of PABA, both in vitro and in vivo in various cancer cell lines. Additionally, recent preclinical studies have suggested that tomotherapy enhances cell killing possibly because of its higher dose rate (800cGy/minute). In this study, we assess the impact of dose rate and PABA on radiation response of two lung cancer cell lines with wild-type p53 (wtp53) and null p53. Materials/Methods: Lung cancer cell lines with wtp53 (H460) and null (H358) p53 expression were irradiated at low (100 cGy/minute) and high (2200cGy/minute) dose rates to doses of 12 and 18 Gy, respectively. The cells were exposed to PABA at a concentration of 100 ug/ml 6 hours prior to irradiation. Cell proliferation assays (performed 72 hours after radiation exposure) and the TUNEL techniques were used to assess cell survival and apoptotic responses. Cell cycle analysis and levels of reactive oxygen species were evaluated using propidium iodide and hydroethidine, respectively. Westen blot analysis was used to evaluate p21 expression. Results: With high dose rate, null p53 cells showed growth inhibition increase of 55% at 18 Gy. Growth inhibition increases of 8.3% and 50% were also observed with high dose rate in wtp53 cells at doses of 18 Gy and 12 Gy, respectively. The addition of PABA to radiation in null p53 cells augmented growth inhibition in all treatment groups by 57.8% to 112%. In wtp53 cells, growth inhibition increases of up to 48.2% were observed at 12 Gy with PABA and of 34% at the 18 Gy/high dose rate group. P21 expression was induced by radiation in both cell lines and was proportional to the radiation dose rate. The addition of PABA, however, was associated with a corresponding reduction in the p21 signal only in null p53 cells. Conclusions: Tumor growth inhibition is best achieved with high dose rates at 12 Gy in wtp53 and 18 Gy in null p53 cells. The addition of PABA modulates p53-dependent resistance and this is in inverse correlation with p21 expression. This is the first in-vitro study demonstrating improved cell killing effect with high radiation dose rates and PABA. With the clinical availability of Tomotherapy, it becomes relevant to further study this effect to elucidate the mechanism of action of this combined therapy and assess the role of PABA as potential adjuvant to radiotherapy in lung cancer.
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