Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats.
OBJECTIVE
Doxorubicin (DOX), an effective antineoplastic agent is known for its cardiotoxicity attributed mainly to free radical formation. Preliminary data indicated that oral glutamine (GLN) reduced cardiac oxidative damages in experimental rats treated with DOX. This study investigated the effect of GLN on DOX accumulation in tumors and normal tissues, troponin plasma concentration and functional alternations associated with DOX-induced myocardial damage.


METHODS
Female Fisher344 rats (n = 40) with implanted MatBIII mammary tumors were randomized to receive oral GLN (1 g/kg/day) (n = 20) or to serve as controls (n = 20) and were treated with a single i.p. injection of 12 mg/kg DOX. Ten normal rats (n = 10) without treatment served as naive controls. Cardiac physiologic alterations resulting from DOX treatment in GLN-supplemented and control rats were assessed by micro-ultrasound imaging at 3 and 10 days after DOX injection. Ten rats from each GLN-supplemented and control groups were killed at 3 and 10 days after DOX administration. At killing, hearts, livers, spleens, kidneys, tumors and sera were examined for DOX concentration by measuring DOX natural fluorescence. Hearts were examined for Von Willebrand factor (vWF) expression using immunohistochemistry.


RESULTS
Glutamine supplementation resulted in a significant reduction of DOX concentration in the normal tissues, without a significant effect on tumor DOX concentration. GLN-supplemented rats had lower plasma cTnI levels and lower cardiac levels of vWF. DOX-induced alterations in the echocardiographic parameters were significantly reduced in the GLN-supplemented rats.


CONCLUSIONS
These data indicate that GLN supplement is able to reduce DOX-induced cardiac damage and thus to enhance DOX therapeutic effectiveness.
Todorova
Valentina K
VK
Division of Breast Surgical Oncology, Department of Surgery, University of Arkansas for Medical Sciences (UAMS), 4301W, Markham St., Mail Slot 725, Little Rock, AR, USA. todorovavalentinak@uams.edu
Kaufmann
Yihong
Y
Hennings
Leah J
LJ
Klimberg
V Suzanne
VS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000633:toxicity; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005973:Glutamine / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging; D006334:Heart Function Tests; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced; D014336:Troponin / Q000097:blood; D014463:Ultrasonography; D014841:von Willebrand Factor / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D014336:Troponin; D014841:von Willebrand Factor; D005973:Glutamine; D004317:Doxorubicin