Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats

Valentina K. Todorova, Yihong Kaufmann, Leah J. Hennings, Vicki Klimberg

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Purpose: 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 weretreated 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.

Original languageEnglish (US)
Pages (from-to)315-323
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number2
DOIs
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Heart Neoplasms
Glutamine
Doxorubicin
Rats
Tumors
von Willebrand Factor
Rat control
Tissue
Plasmas
Neoplasms
Injections
Troponin
Liver
Antineoplastic Agents

Keywords

  • Cardiotoxicity
  • Doxorubicin
  • Glutamine
  • Plasma cardiac troponin I
  • Thrombocytopenia
  • Von Willebrand factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats. / Todorova, Valentina K.; Kaufmann, Yihong; Hennings, Leah J.; Klimberg, Vicki.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 2, 07.2010, p. 315-323.

Research output: Contribution to journalArticle

Todorova, Valentina K. ; Kaufmann, Yihong ; Hennings, Leah J. ; Klimberg, Vicki. / Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 2. pp. 315-323.
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abstract = "Purpose: 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 weretreated 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.",
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N2 - Purpose: 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 weretreated 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.

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