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466 - Pharmacological Ascorbate in Combination with Standard-Of-Care Radio-Chemotherapy Enhances Tumor Response in an Orthotopic Sarcoma Model
Abstract   Peer reviewed

466 - Pharmacological Ascorbate in Combination with Standard-Of-Care Radio-Chemotherapy Enhances Tumor Response in an Orthotopic Sarcoma Model

Joshua D Schoenfeld, Zita A Sibenaller, Kranti A Mapuskar, Brett Wagner, Benjamin Miller, Varun Monga, Mohammed Milhem, Douglas R Spitz and Bryan G Allen
Free radical biology & medicine, Vol.100, pp.S193-S194
11/2016
DOI: 10.1016/j.freeradbiomed.2016.10.529

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Abstract

Soft tissue sarcomas represent a rare group of cancers (> 150 histological subtypes) that represent < 1% of all cancers in the United States. The current standard-of-care includes combinations of surgery, radiation therapy, and chemotherapy depending on the stage of disease. Our group has previously demonstrated that pharmacological ascorbate (P-AscH–) selectively increases the efficacy of standard-of-care anti-cancer therapies in other disease sites. Therefore, we hypothesized that adjuvant P-AscH– would selectively increase the toxicity of radiation and chemotherapy in preclinical models of sarcoma. To test this, we utilized two human sarcoma cell lines: HT-1080 (fibrosarcoma) and SW872 (liposarcoma). Exposure to P-AscH– demonstrated dose-dependent toxicity in HT-1080 and SW872 cell lines at doses (TD50 < 3 mM) easily achievable in human subjects. Furthermore, P-AscH– significantly enhanced the efficacy of gemcitabine or radiation treatment in both sarcoma cell lines. P-AscH– toxicity was inhibited by the addition of exogenous catalase or by pre-incubation for 3 h with 250 µM desferrioxamine, an iron chelator that inhibits iron redox cycling, demonstrating that P-AscH– toxicity is dependent on H2O2 and redox-active metal ions. Exposure to P-AscH– also significantly increased DNA damage in HT-1080 cells as measured by ɣ-H2Ax staining. In an orthotopic fibrosarcoma (HT-1080) murine model, addition of adjuvant P-AscH– (4 g kg-1) to radiation (12 Gy/ 2 frx) or gemcitabine (weekly, 3 cycles, 60 µg g-1) significantly inhibited tumor growth (p < 0.05) and enhanced overall survival (p < 0.04). No increased normal tissue toxicity was seen in the mice as measured by mouse weight. Consistent with ascorbate selectively acting as a pro-oxidant in cancer tissue while simultaneously acting as an antioxidant in normal tissue, administration of P-AscH– significantly inhibited radiation-induced skin injury (i.e. alopecia) in mice exposed to a single dose of 15 Gy. Together, these results support the hypothesis that adjuvant P-AscH– increases therapy responses in sarcoma while also decreasing toxicity to normal tissue. Supported by The Carver Research Program of Excellence in Redox Biology, T32 CA078586, P30 CA086862, T32GM007337, UIHC Department of Radiation Oncology, and the Holden Comprehensive Cancer Center.

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