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Chen, Q., Espey, M.G., Sun, A.Y., Lee, J.H., Krishna, M.C., Shacter, E., Choyke, P.L., Pooput, C., Kirk, K.L., Buettner, G.R. and Levine, M. (2007) Ascorbate in Pharmacologic Concentrations Selectively Generates Ascorbate Radical and Hydrogen Peroxide in Extracellular Fluid in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 8749-8754.
http://dx.doi.org/10.1073/pnas.0702854104

has been cited by the following article:

• TITLE: Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

  AUTHORS: Ajay Kumar, Venkatesh Chelvam, Mahalingam Sakkarapalayam, Guo Li, Pedro Sanchez-Cruz, Natasha S. Piñero, Philip S. Low, Antonio E. Alegria

  KEYWORDS: Cancer, Folate Receptor, Reactive Oxygen Species

  JOURNAL NAME: Open Journal of Medicinal Chemistry, Vol.6 No.1, March 11, 2016

  ABSTRACT: Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a con-stitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered.