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Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(32):11105-9. DOI: 10.1073/pnas.0804226105
Source: PubMed

ABSTRACT

Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

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    • ") and ultimately the tumoricidal H 2 O 2[40,464748. Herein, we compiled a H 2 O 2 -responsive chemotherapeutic drug (camptothecin: CPT) delivery nanocarrier supplemented with PA through formation of polymer prodrug-PA hybrid micelles (HPMs) (Scheme 1). The strategic incorporation of PA is postulated to endow the nanocarriers with selfsufficing H 2 O 2 stimuli, which specifically elevate tumoral H 2 O 2 level via H 2 O 2 production not only improving oxidative stress to the tumors but also triggering CPT release from the delivery nanovehicles. "
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