Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir.
BACKGROUND
Anticancer drugs act by increasing intracellular hydrogen peroxide levels. Mangafodipir, a superoxide dismutase (SOD) mimic with catalase and glutathione reductase activities, protects normal cells from apoptosis induced by H2O2. We investigated its and other oxidative stress modulators' effects on anticancer drug activity in vitro and in vivo.


METHODS
Cell lysis and intracellular reactive oxygen species levels were assessed in vitro in human leukocytes from healthy subjects and in murine CT26 colon cancer cells. Cells were exposed to the chemotherapeutic agents paclitaxel, oxaliplatin, or 5-fluorouracil, either in the presence or absence of mangafodipir and other oxidative stress modulators. Cell viability was evaluated by the methylthiazoletetrazolium assay. The effects of mangafodipir and other oxidative stress modulators on peripheral blood counts and on tumor growth were studied in BALB/c mice that were implanted with CT26 tumors and treated with 20 mg/kg paclitaxel. Survival of BALB/c mice infected with Staphylococcus aureus was also examined by treatment group. Statistical tests were two-sided.


RESULTS
In vitro lysis of leukocytes exposed to paclitaxel, oxaliplatin, or 5-fluorouracil in combination with mangafodipir was decreased by 46% (95% confidence interval [CI] = 44% to 48%), 30.5% (95% CI = 29% to 32%), and 15% (95% CI = 10% to 20%), compared with lysis of cells treated with anticancer agent alone. Mangafodipir also statistically significantly enhanced in vitro anticancer drug cytotoxicity toward CT26 cancer cells. In vivo, mangafodipir protected mice against paclitaxel-induced leukopenia. Moreover, the survival rate of mice infected with S. aureus and treated with paclitaxel was higher when mangafodipir was also administered (survival: 3 of 17 versus 14 of 17, P < .001). In addition, mangafodipir amplified the inhibitory effect of paclitaxel on CT26 tumor growth in mice.


CONCLUSIONS
Mangafodipir decreased hematotoxicity and enhanced cytotoxicity of anticancer agents.
Université Paris-René Descartes, Faculté de Médecine, Assistance Publique-Hopitaux de Paris, Hôpital Cochin, EA 1833, Paris, France. jerome.alexandre@cch.aphp.fr
Jérôme
J
Alexandre
Carole
C
Nicco
Christiane
C
Chéreau
Alexis
A
Laurent
Bernard
B
Weill
François
F
Goldwasser
Frédéric
F
Batteux
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016001:Confidence Intervals; D004357:Drug Synergism; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013203:Staphylococcal Infections / Q000150:complications / Q000378:metabolism; D013211:Staphylococcus aureus; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D013481:Superoxides; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid; D017239:Paclitaxel; D005472:Fluorouracil