The magnetic resonance imaging contrast agent mangafodipir exerts antitumor activity via a previously described superoxide dismutase mimetic activity.

It was recently described in Cancer Research by Laurent et al. (1) how low molecular weight superoxide dismutase (SOD) mimetics increase H2O2 levels, which in turn killed colon (CT26) and liver (Hepa 1-6) tumor cells. In contrast, the SOD mimetics stimulated proliferation of normal cells. Profound additional effects on the antitumor activity of oxaliplatin were shown after treatment with mangafodipir (manganese dipyridoxyl diphosphate, MnDPDP). In 1994, our group suggested that MnDPDP possessed SOD activity and later confirmed this by spin trap electron spin resonance in 1999 (2). It was subsequently shown that MnDPDP 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 acute liver failure (4). Without mentioning our original work, they stated: ‘‘Considering the structure of Mangafodipir trisodium (MnDPDP), a contrast agent currently used in MR imaging of the liver neoplasm, we hypothesized that this molecule could also exert an antioxidant activity and be possible used as treatment of APAPinduced ALF.’’ Although one of us made it clear in a Letter to the Editor of the journal that this was a discovery made many years ago, Batteux still refers to their 2003 article as being an original discovery. Furthermore, Kensler et al. first described the anticarcinogenic activity of SOD mimetics already in 1983 (5). Cellular effects described by us and Batteux require that the SOD mimetic enters the intracellular space. Due to its hydrophilicity, it is unlikely that MnDPDP penetrates the plasma membrane. After being injected, MnDPDP is dephosphorylated into lipophilic MnPLED, which probably crosses the membrane (3). By omitting the original references, relevant mechanistic information is omitted from the discussion. Another relevant item for discussion is Batteux’s earlier finding that MnDPDP possesses catalase activity (4), which is in opposite to our results showing no catalase activity (2). Whether or not MnDPDP possesses catalase activity is of course crucial to the suggested mechanism behind the tumor killing effect of SOD mimetic drugs (i.e., increase in H2O2). This interesting matter is not discussed in the Cancer Research article. It would be highly valuable to have Batteux’s comments on their previously described catalase activity of MnDPDP. Although there is little doubt that the work done by Batteux et al. on liver protective (4) and antitumor (1) effects of MnDPDP represents high-quality science, it is regrettable that they have omitted our original references showing SOD mimetic activity of both MnDPDP and its metabolite MnPLED. Jan Olof G. Karlsson Heidi Brurok Rob Towart Per Jynge Department of Pharmacology, University of Linköping, Sweden Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway