Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism

K. Rouse, E. Nwokedi, J. E. Woodliff, J. Epstein, Vicki Klimberg

Research output: Contribution to journalArticle

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Abstract

Objective: Chemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione (GSH) content. The authors hypothesized that supplemental oral glutamine (GLN) would increase the therapeutic index of methotrexate (MTX) by improving host tolerance through changes in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response to methotrexate. Methods: Thirty- six 300-g Fischer 344 rats were implanted with fibrosarcomas. On day 21 after implantation, rats were randomized to receive isonitrogenous isocaloric diets containing 1 g/kg/day glutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeeding, rats were randomized to one of the following four groups receiving an intraperitoneal injection of methotrexate (20 mg/kg) or saline (CON): GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. On day 24, rats were killed and studied for arterial glutamine concentration, tumor volume, tumor, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung). Results: Provision of the glutamine- enriched diets to rats receiving MTX decreased tumor glutathione (2.38 ± 0.17 in GLN + MTX vs. 2.92 ± 0.20 in GLY + MTX, p < 0.05), whereas increasing or maintaining host glutathione stores (in gut, 2.60 ± 0.28 in GLN + MTX vs, 1.93 ± 0.18; in GLY + MTX, p < 0.05). Depressed glutathione levels in tumor cells increases susceptibility to chemotherapy. Significantly decreased glutathione content in tumor cells in the GLN + MTX group correlated with enhanced tumor volume loss (-0.8 ± 1.0 mL in GLN + MTX vs. +9.5 ± 2.0 mL in GLY + MTX, p < 0.05). Conclusion: These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to chemotherapy treatment-related injury.

Original languageEnglish (US)
Pages (from-to)420-426
Number of pages7
JournalAnnals of Surgery
Volume221
Issue number4
StatePublished - 1995
Externally publishedYes

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Glutamine
Methotrexate
Glutathione
Drug Therapy
Glycine
Neoplasms
Tumor Burden
Glutaminase
Diet
Kidney
Fibrosarcoma
Liver
Inbred F344 Rats
Wounds and Injuries
Intraperitoneal Injections
Oxidants
Antineoplastic Agents
Myocardium

ASJC Scopus subject areas

  • Surgery

Cite this

Rouse, K., Nwokedi, E., Woodliff, J. E., Epstein, J., & Klimberg, V. (1995). Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. Annals of Surgery, 221(4), 420-426.

Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. / Rouse, K.; Nwokedi, E.; Woodliff, J. E.; Epstein, J.; Klimberg, Vicki.

In: Annals of Surgery, Vol. 221, No. 4, 1995, p. 420-426.

Research output: Contribution to journalArticle

Rouse, K, Nwokedi, E, Woodliff, JE, Epstein, J & Klimberg, V 1995, 'Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism', Annals of Surgery, vol. 221, no. 4, pp. 420-426.
Rouse, K. ; Nwokedi, E. ; Woodliff, J. E. ; Epstein, J. ; Klimberg, Vicki. / Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. In: Annals of Surgery. 1995 ; Vol. 221, No. 4. pp. 420-426.
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abstract = "Objective: Chemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione (GSH) content. The authors hypothesized that supplemental oral glutamine (GLN) would increase the therapeutic index of methotrexate (MTX) by improving host tolerance through changes in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response to methotrexate. Methods: Thirty- six 300-g Fischer 344 rats were implanted with fibrosarcomas. On day 21 after implantation, rats were randomized to receive isonitrogenous isocaloric diets containing 1 g/kg/day glutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeeding, rats were randomized to one of the following four groups receiving an intraperitoneal injection of methotrexate (20 mg/kg) or saline (CON): GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. On day 24, rats were killed and studied for arterial glutamine concentration, tumor volume, tumor, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung). Results: Provision of the glutamine- enriched diets to rats receiving MTX decreased tumor glutathione (2.38 ± 0.17 in GLN + MTX vs. 2.92 ± 0.20 in GLY + MTX, p < 0.05), whereas increasing or maintaining host glutathione stores (in gut, 2.60 ± 0.28 in GLN + MTX vs, 1.93 ± 0.18; in GLY + MTX, p < 0.05). Depressed glutathione levels in tumor cells increases susceptibility to chemotherapy. Significantly decreased glutathione content in tumor cells in the GLN + MTX group correlated with enhanced tumor volume loss (-0.8 ± 1.0 mL in GLN + MTX vs. +9.5 ± 2.0 mL in GLY + MTX, p < 0.05). Conclusion: These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to chemotherapy treatment-related injury.",
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