The Magnetic Resonance Imaging Contrast Agent Mangafodipir Exerts Antitumor Activity Via a Previously Described Superoxide Dismutase Mimetic Activity

Letters to the Editor

The Magnetic Resonance Imaging Jan Olof G. Karlsson Heidi Brurok Contrast Agent Mangafodipir Rob Towart Per Jynge Exerts Antitumor Activity via a Department of Pharmacology, Previously Described Superoxide University of Linko¨ping, Sweden Department of Circulation and Medical Dismutase Mimetic Activity Imaging, Faculty of Medicine, Norwegian University of Science and Technology, To the Editor: Trondheim, Norway It was recently described in Cancer Research by Laurent et al. (1) how low molecular weight superoxide dismutase (SOD) References 1. Laurent A, Nicco C, Che´reauC, et al. Controlling tumor growth by modulating mimetics increase H2O2 levels, which in turn killed colon endogenous production of reactive oxygen species. Cancer Res 2005;65:948–56. (CT26) and liver (Hepa 1-6) tumor cells. In contrast, the SOD 2. Brurok H, Ardenkjær-Larsen JH, Hansson G, et al. Manganese dipyridoxyl mimetics stimulated proliferation of normal cells. Profound diphosphate: MRI contrast agent with antioxidative and cardioprotective properties? additional effects on the antitumor activity of oxaliplatin were In vitro and ex vivo assessments. Biochem Biophys Res Commun 1999;254:768–72. 3. Karlsson JOG, Brurok H, Eriksen M, et al. Cardioprotective effects of the magnetic shown after treatment with mangafodipir (manganese dipyridoxyl resonance imaging agent manganese dipyridoxyl diphosphate and its metabolite diphosphate, MnDPDP). manganese dipyridoxyl ethyldiamine upon reperfusion of the ischemic porcine myocardium. Acta Radiol 2001;42:540–7. In 1994, our group suggested that MnDPDP possessed SOD 4. Bedda S, Laurent A, Conti F, et al. Manafodipir prevents liver injury induced by activity and later confirmed this by spin trap electron spin acetaminophen in the mouse. J Hepatol 2003;39:765–72. resonance in 1999 (2). It was subsequently shown that MnDPDP 5. Kensler TW, Bush DM, Kozumbo WJ. Inhibition of tumour promotion by a biomimetic SOD. Science 1983;221:75–81. possessed cardioprotective effects due to SOD mimetic activity (3). In 2003, Batteux et al. reported in Journal of Hepatology, protective effects of MnDPDP in vivo against acetaminophen-induced murine In Response: acute liver failure (4). Without mentioning our original work, they stated: ‘‘Considering the structure of Mangafodipir trisodium I acknowledge that we did not quote the publications referenced (MnDPDP), a contrast agent currently used in MR imaging of the in the letter by Karlsson et al. The first reason is that their liver neoplasm, we hypothesized that this molecule could also exert demonstration of the superoxide dismutase (SOD)–like activity of an antioxidant activity and be possible used as treatment of APAP- mangafodipir was incomplete because they did not quantify the induced ALF.’’ Although one of us made it clear in a Letter to the enzyme-like activity and made no comparisons with other Editor of the journal that this was a discovery made many years standard SOD mimics. The second reason was that their work ago, Batteux still refers to their 2003 article as being an original dealt with ischemic heart disease, which is far from our own field discovery. Furthermore, Kensler et al. first described the anti- of research. carcinogenic activity of SOD mimetics already in 1983 (5). The aim of our work was to analyze the modulation of tumor Cellular effects described by us and Batteux require that the growth by reactive oxygen species (ROS). For that purpose, 13 SOD mimetic enters the intracellular space. Due to its hydro- pharmacologic modulators of ROS have been studied. Three of philicity, it is unlikely that MnDPDP penetrates the plasma them were SOD mimics: CuDIPS, MnTBAP, and MnDPDP membrane. After being injected, MnDPDP is dephosphorylated (mangafodipir) that was only tested in the two last experiments into lipophilic MnPLED, which probably crosses the membrane (Figs. 5 and 6). As stressed by Karlsson et al., the mechanism of (3). By omitting the original references, relevant mechanistic intracellular penetration of mangafodipir does not modify the information is omitted from the discussion. enzymatic properties of the molecule. Therefore, we feel that there Another relevant item for discussion is Batteux’s earlier finding would have been no relevance in discussing the mechanism of that MnDPDP possesses catalase activity (4), which is in opposite intracellular penetration of mangafodipir. to our results showing no catalase activity (2). Whether or not Many SOD mimics have several enzymatic properties, but SOD MnDPDP possesses catalase activity is of course crucial to the activity remains their principal characteristic. In our report, we suggested mechanism behind the tumor killing effect of SOD have used MnDPDP because of its SOD activity, which is 300-fold mimetic drugs (i.e., increase in H2O2). This interesting matter is not higher than its catalase activity. To modulate the catalase pathway, discussed in the Cancer Research article. It would be highly we have used catalase NAC and ATZ. The low level of catalase valuable to have Batteux’s comments on their previously described activity of mangafodipir compared with its SOD activity certainly catalase activity of MnDPDP. explains the high effectiveness of mangafodipir against cancer cells Although there is little doubt that the work done by Batteux and is consistent with our observation that a high level of catalase et al. on liver protective (4) and antitumor (1) effects of MnDPDP activity stimulates cancer cell proliferation. This has been represents high-quality science, it is regrettable that they have discussed in-depth in our article. omitted our original references showing SOD mimetic activity of both MnDPDP and its metabolite MnPLED. Frederic Batteux, Ph.D. Laboratoire d’Immunologie, I2006 American Association for Cancer Research. Hardy RDC, Hopital Cochin, doi:10.1158/0008-5472.CAN-05-2053 Cedex 14, Paris, France

Cancer Res 2006; 66: (1). January 1, 2006 598 www.aacrjournals.org

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2006 American Association for Cancer Research. The Magnetic Resonance Imaging Contrast Agent Mangafodipir Exerts Antitumor Activity via a Previously Described Superoxide Dismutase Mimetic Activity

Jan Olof G. Karlsson, Heidi Brurok, Rob Towart, et al.

Cancer Res 2006;66:598.

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