Superior Therapeutic Index of Calmangafodipir in Comparison to Mangafodipir as a Chemotherapy Adjunct
2012 (English)In: TRANSLATIONAL ONCOLOGY, ISSN 1944-7124, Vol. 5, no 6, 492-502 p.Article in journal (Refereed) Published
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 Mn2+ from mangafodipir-about 80% dissociates after injection. The SOD mimetic activity, however, depends on the intact Mn complex. Complexed Mn2+ is readily excreted in the urine, whereas dissociated Mn2+ 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 Mn2+ in mangafodipir with Ca2+ (resulting in calmangafodipir) stabilizes it from releasing Mn2+ after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn2+ release from mangafodipir is governed by the presence of a limited amount of plasma zinc (Zn2+). Zn2+ has roughly 10(3) and 10(9) times higher affinity than Mn2+ and Ca2+, respectively, for fodipir. Replacement of 80% of Mn2+ with Ca2+ is enough for binding a considerable amount of the readily available plasma Zn2+, resulting in considerably less Mn2+ release and retention in the brain and other organs. At equivalent Mn2+ 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. Translational Oncology (2012) 5, 492-502
Place, publisher, year, edition, pages
NEOPLASIA PRESS, 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA , 2012. Vol. 5, no 6, 492-502 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-88464DOI: 10.1593/tlo.12238ISI: 000313359800014OAI: oai:DiVA.org:liu-88464DiVA: diva2:604050
Funding Agencies|Medical Research Council of Southeast Sweden|FORSS-85191|PledPharma AB||2013-02-072013-02-072014-12-03