Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model.
OBJECTIVE
The role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading.


BACKGROUND
Doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially life-threatening cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through free-radical injury.


METHODS
Male Sprague Dawley rats fed iron-rich chow (n = 8) and regular chow (n = 8) were treated with DOX or saline (4 animals in each arm). Cardiotoxicity was assessed using mortality, weight changes, Tc-99m annexin-V imaging, histopathology, and immunohistochemistry.


RESULTS
Animals fed iron-rich chow showed significantly higher DOX cardiotoxicity as evidenced by greater weight loss (107 +/- 14 g vs. 55 +/- 10 g weight loss, p < 0.05), higher annexin uptake (0.14 +/- 0.01% vs. 0.08 +/- 0.01% injected dose/g of myocardium, p < 0.05), more severe myocyte injury on electron microscopy, and significantly higher cleaved caspase-3 staining compared with regular chow fed rats given DOX. Feeding iron-rich chow alone did not result in any cardiotoxicity.


CONCLUSIONS
Dietary iron loading resulted in a substantially increased DOX cardiotoxicity in rats. Body iron stores as well as its bioavailability in tissue may be important independent predictors of susceptibility to DOX cardiotoxicity in man. Further clinical studies are warranted.
Panjrath
Gurusher S
GS
Division of Cardiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
Patel
Virender
V
Valdiviezo
Carolina I
CI
Narula
Navneet
N
Narula
Jagat
J
Jain
Diwakar
D
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D019266:Iron, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009206:Myocardium / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D019266:Iron, Dietary; D004317:Doxorubicin