Mangafodipir a Selective Cytoprotectant - with Special Reference to Oxaliplatin and Its Association to Chemotherapy-Induced Peripheral Neuropathy (CIPN).

Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival substantially in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. Oncologists included for years calcium and magnesium infusion as part of clinical practice for preventing CIPN. Results from a phase III prospective study published in 2014, however, overturned this practice. No other treatments have been clinically proven to prevent this toxicity. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) is an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy. MnPLED, the metabolite of MnDPDP, attacks cellular oxidative stress at several critical levels. Firstly, MnPLED catalyzes dismutation of superoxide (O2•-), and secondly, having a tremendous high affinity for iron (and copper), PLED binds and disarms redox active iron/copper, which is involved in several detrimental oxidative steps. A case report from 2009 and a recent feasibility study suggest that MnDPDP may prevent or even cure oxaliplatin-induced CIPN. Preliminary results from a phase II study (PLIANT) suggest efficacy also of calmangafodipir, but these results are according to available data obscured by a surprisingly low number of adverse events and a seemingly lower than expected efficacy of FOLFOX.

Effects of MnDPDP and ICRF-187 on Doxorubicin-Induced Cardiotoxicity and Anticancer Activity.

Oxidative stress participates in doxorubicin (Dx)-induced cardiotoxicity. The metal complex MnDPDP and its metabolite MnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice were injected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, the left atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility was measured for 60 minutes. In parallel experiments, 10 µM MnDPDP or MnPLED was added directly into the organ bath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780) was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP, and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuated the negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLED attenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the anti-tumor activity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed an in vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized to MnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotection takes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest that the previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.

First clinical experience with the magnetic resonance imaging contrast agent and superoxide dismutase mimetic mangafodipir as an adjunct in cancer chemotherapy-a translational study.

Preclinical research suggests that the clinically approved magnetic resonance imaging contrast agent mangafodipir may protect against adverse events (AEs) caused by chemotherapy, without interfering negatively with the anticancer efficacy. The present translational study tested if pretreatment with mangafodipir lowers AEs during curative (adjuvant) FOLFOX6 chemotherapy in stage III colon cancer (Dukes' C). The study was originally scheduled to include 20 patients, but because of the unforeseen withdrawal of mangafodipir from the market, the study had to be closed after 14 patients had been included. The withdrawal of mangafodipir was purely based on commercial considerations from the producer and not on any safety concerns. The patients were treated throughout the first 3 of 12 scheduled cycles. Patients were randomized to a 5-minute infusion of either mangafodipir or placebo (7 in each group). AEs were evaluated according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events and the Sanofi-NCI criteria. The primary end points were neutropenia and neurosensory toxicity. There were four AEs of grade 3 (severe) and one AE of grade 4 (life threatening) in four patients in the placebo group, whereas there were none in the mangafodipir group (P < .05). Of the grade 3 and 4 events, two were neutropenia and one was neurosensory toxicity. Furthermore, white blood cell count was statistically, significantly higher in the mangafodipir group than in the placebo group (P < .01) after treatment with FOLFOX. This small feasibility study seems to confirm what has been demonstrated preclinically, namely, that pretreatment with mangafodipir lowers AEs during adjuvant 5-fluorouracil plus oxaliplatin-based chemotherapy in colon cancer patients.

Superior therapeutic index of calmangafodipir in comparison to mangafodipir as a chemotherapy adjunct.

Mangafodipir is a magnetic resonance imaging contrast agent with manganese superoxide dismutase (MnSOD) mimetic activity. The MnSOD mimetic activity protects healthy cells against oxidative stress-induced detrimental effects, e.g., myelosuppressive effects of chemotherapy drugs. The contrast property depends on in vivo dissociation of Mn(2+) from mangafodipir-about 80% dissociates after injection. The SOD mimetic activity, however, depends on the intact Mn complex. Complexed Mn(2+) is readily excreted in the urine, whereas dissociated Mn(2+) is excreted slowly via the biliary route. Mn is an essential but also a potentially neurotoxic metal. For more frequent therapeutic use, neurotoxicity due to Mn accumulation in the brain may represent a serious problem. Replacement of 4/5 of Mn(2+) in mangafodipir with Ca(2+) (resulting in calmangafodipir) stabilizes it from releasing Mn(2+) after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn(2+) release from mangafodipir is governed by the presence of a limited amount of plasma zinc (Zn(2+)). Zn(2+) has roughly 10(3) and 10(9) times higher affinity than Mn(2+) and Ca(2+), respectively, for fodipir. Replacement of 80% of Mn(2+) with Ca(2+) is enough for binding a considerable amount of the readily available plasma Zn(2+), resulting in considerably less Mn(2+) release and retention in the brain and other organs. At equivalent Mn(2+) doses, calmangafodipir was significantly more efficacious than mangafodipir to protect BALB/c mice against myelosuppressive effects of the chemotherapy drug oxaliplatin. Calmangafodipir did not interfere negatively with the antitumor activity of oxaliplatin in CT26 tumor-bearing syngenic BALB/c mice, contrary calmangafodipir increased the antitumor activity.

The Contractility of Isolated Rat Atrial Tissue during Hypoxia is Better Preserved in a High- or Zero-Glucose Environment than in a Normal Glucose Environment.

AIM: Hyperglycemia is known to be associated with an increase in mortality in myocardial infarction and intensive care patients despite the fact that glucose metabolism plays a central role in myocardial protection. We studied the effect of different glucose levels (22 mM L(-1); 5.5 mM L(-1); and 0 mM L(-1)) on the contractile reserve of isolated rat atrial myocardium during and after hypoxia. METHODS: We observed the contraction of isolated rat atrium strips caused by electrical-field stimulation in a modified Krebs-Henseleit Buffer (KHB) organ bath oxygenated with 95% O2 + 5% CO2 at 37°C. We applied two periods of hypoxia and two periods of reoxygenation. Three glucose concentrations were used in the buffer to study the effect of glucose (high- n=6; normal- n=7; and zero-glucose n=6). The effect of isoproterenol 1 µM L(-1) was tested during the second ischemic period. RESULTS: The main finding was that both a zero-glucose (27.8 ± 5.9 vs. 14.7 ± 3 % of baseline tension) and a high-glucose environment (38.5 ± 14 vs. 14.7 ± 3 % of baseline tension) had a positive effect in terms of better contractility than the normal-glucose buffer during both the first (p=0.00062) and the second ischemic period (31.2 ± 5.9 % zero-glucose vs. 14.7 ± 4.2 normal-glucose vs. 35.3 ± 15.9% high-glucose p=0.0038). CONCLUSION: Both zero-glucose and high-glucose environments resulted in a better contractile reserve in isolated rat atrial myocardium during hypoxia than in a normal one. The exact clinical relevance of this observation is, at present, unclear.