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W2130528059 abstract "Ascorbate is a water-soluble antioxidant vitamin that has been shown at milli-molar concentrations to be selectively toxic to a variety of cancer cells, including lung cancer cells while having little effect on normal cells. In vivo experiments with human xenografts as well as human clinical trials with pancreatic cancer demonstrated that high concentrations of ascorbate (∼20 mM) are very well tolerated. Because ascorbate has shown efficacy against other tumor types in pre-clinical studies and high concentrations of ascorbate may be achieved in vivo with minimal clinical toxicity, we hypothesize that pharmacological ascorbate will enhance NSCLC chemo-radio-sensitization. In order to determine if pharmacologic ascorbate enhances NSCLC chemo-radio- sensitization, H292 and H1299 human NSCLC cells were grown in vitro for 24 h and then exposed to 2 mM ascorbate and/or carboplatin 10 μM for 1 h followed by 2 Gy of concurrent irradiation. In the xenograft studies, H292 NSCLC cells were grown in the flanks of nude mice and treated with ascorbate (4 mg/kg IP daily for two weeks), carboplatin (15 mg/kg IP 1 x per week for two weeks) and/or ionizing radiation (6 Gy x 2 fractions 48 h apart). Tumor growth rates were assessed daily with calipers. Mice were sacrificed once tumor diameter exceeded 1.5 cm in greatest dimension. Both H292 and H1299 cell lines demonstrated that ascorbate has an additive effect on chemo-radiation clonogenic cell survival (p < 0.05). In addition, ascorbate toxicity was completely rescued (p < 0.05) with the addition of extracellular addition of 100 U/mL polyethylene glycol conjugated catalase confirming ascorbate mediated tumoricidal effect is mediated by hydrogen peroxide. Mice with H292 NSCLC xenograft tumors treated with ascorbate, carboplatin, and radiation demonstrated significantly slower rates of tumor growth compared to mice receiving carboplatin + radiation alone (p < 0.05). Median survival in mice treated with carboplatin + radiation was 53 days while mice treated with ascorbate + radiation + carboplatin was 80 days (p < 0.05). These data support the hypothesis that pharmacologic ascorbate enhances NSCLC chemo-radio-sensitization via a hydrogen peroxide-dependent mechanism. Further clinical trials are indicated to assess the tolerability and clinical efficacy of pharmacological ascorbate in combination with standard treatments in NSCLC." @default.
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W2130528059 date "2013-10-01" @default.
W2130528059 modified "2023-09-27" @default.
W2130528059 title "Pharmacological Ascorbate Enhances NSCLC Chemo-Radio-Sensitization" @default.
W2130528059 doi "https://doi.org/10.1016/j.ijrobp.2013.06.1735" @default.
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