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rIFN-gamma-mediated growth suppression of platinum-sensitive and -resistant ovarian tumor cell lines not dependent upon arginase inhibition.

Melichar B, Hu W, Patenia R, Melicharová K, Gallardo ST, Freedman R - J Transl Med (2003)

Bottom Line: However, supplementation of the medium with polyamine pathway products did not interfere with the growth-inhibitory effects of rIFN-gamma EOC cells.CONCLUSIONS: Increased arginase activity, specifically identified with arginase II, is present in most of the tested EOC cell lines. rIFN-gamma inhibits or stimulates arginase activity in certain EOC cell lines, though the decrease in arginase activity does not appear to be associated with the in vitro antiproliferative activity of rIFN-gamma.Since cells within the stroma of EOC tissues could also contribute to arginine metabolism following treatment with rIFN-gamma or rIFN-gamma-inducers, it would be helpful to examine these effects in vivo.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gynecologic Oncology, The University of Texas, M,D, Anderson Cancer Center, Houston, Texas, U,S,A. rfreedma@mdanderson.org

ABSTRACT
BACKGROUND: Arginine metabolism in tumor cell lines can be influenced by various cytokines, including recombinant human interferon-gamma (rIFN-gamma), a cytokine that shows promising clinical activity in epithelial ovarian cancer (EOC). METHODS: We examined EOC cell lines for the expression of arginase in an enzymatic assay and for transcripts of arginase I and II, inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO) by reverse transcription-polymerase chain reaction. The effects of rIFN-gamma on arginase activity and on tumor cell growth inhibition were determined by measuring [3H]thymidine uptake. RESULTS: Elevated arginase activity was detected in 5 of 8 tumor cell lines, and analysis at the transcriptional level showed that arginase II was involved but arginase I was not. rIFN-gamma reduced arginase activity in 3 EOC cell lines but increased activity in the 2008 cell line and its platinum-resistant subline, 2008.C13. iNOS transcripts were not detected in rIFN-gamma-treated or untreated cell lines. In contrast, IDO activity was induced or increased by rIFN-gamma. Suppression of arginase activity by rIFN-gamma in certain cell lines suggested that such inhibition might contribute to its antiproliferative effects. However, supplementation of the medium with polyamine pathway products did not interfere with the growth-inhibitory effects of rIFN-gamma EOC cells. CONCLUSIONS: Increased arginase activity, specifically identified with arginase II, is present in most of the tested EOC cell lines. rIFN-gamma inhibits or stimulates arginase activity in certain EOC cell lines, though the decrease in arginase activity does not appear to be associated with the in vitro antiproliferative activity of rIFN-gamma. Since cells within the stroma of EOC tissues could also contribute to arginine metabolism following treatment with rIFN-gamma or rIFN-gamma-inducers, it would be helpful to examine these effects in vivo.

No MeSH data available.


Related in: MedlinePlus

Arginine pathway. L-arginine is metabolized either by nitric oxide synthase to N-hydroxy-L-arginine and NO, or by arginase to ornithine and urea. IFN-γ induces nitric oxide synthase, but inhibits arginase. N-hydroxy-L-arginine inhibits arginase, and NO inhibits ornithine decarboxylase.
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Figure 1: Arginine pathway. L-arginine is metabolized either by nitric oxide synthase to N-hydroxy-L-arginine and NO, or by arginase to ornithine and urea. IFN-γ induces nitric oxide synthase, but inhibits arginase. N-hydroxy-L-arginine inhibits arginase, and NO inhibits ornithine decarboxylase.

Mentions: Arginine metabolism to nitric oxide (NO) via nitric oxide synthase or to ornithine via arginase is an important biological pathway (see Fig. 1). NO has many important functions, including regulating vascular tone and facilitating cell-mediated cytotoxicity [1], and ornithine is the immediate precursor of polyamines, which are important in cell proliferation [2]. In addition to competition for the substrate, L-arginine, there are other interactions between the two pathways of arginine metabolism, such as the inhibition of arginase by NG-hydroxy-L-arginine, an intermediate in NO biosynthesis [3,4].


rIFN-gamma-mediated growth suppression of platinum-sensitive and -resistant ovarian tumor cell lines not dependent upon arginase inhibition.

Melichar B, Hu W, Patenia R, Melicharová K, Gallardo ST, Freedman R - J Transl Med (2003)

Arginine pathway. L-arginine is metabolized either by nitric oxide synthase to N-hydroxy-L-arginine and NO, or by arginase to ornithine and urea. IFN-γ induces nitric oxide synthase, but inhibits arginase. N-hydroxy-L-arginine inhibits arginase, and NO inhibits ornithine decarboxylase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC222988&req=5

Figure 1: Arginine pathway. L-arginine is metabolized either by nitric oxide synthase to N-hydroxy-L-arginine and NO, or by arginase to ornithine and urea. IFN-γ induces nitric oxide synthase, but inhibits arginase. N-hydroxy-L-arginine inhibits arginase, and NO inhibits ornithine decarboxylase.
Mentions: Arginine metabolism to nitric oxide (NO) via nitric oxide synthase or to ornithine via arginase is an important biological pathway (see Fig. 1). NO has many important functions, including regulating vascular tone and facilitating cell-mediated cytotoxicity [1], and ornithine is the immediate precursor of polyamines, which are important in cell proliferation [2]. In addition to competition for the substrate, L-arginine, there are other interactions between the two pathways of arginine metabolism, such as the inhibition of arginase by NG-hydroxy-L-arginine, an intermediate in NO biosynthesis [3,4].

Bottom Line: However, supplementation of the medium with polyamine pathway products did not interfere with the growth-inhibitory effects of rIFN-gamma EOC cells.CONCLUSIONS: Increased arginase activity, specifically identified with arginase II, is present in most of the tested EOC cell lines. rIFN-gamma inhibits or stimulates arginase activity in certain EOC cell lines, though the decrease in arginase activity does not appear to be associated with the in vitro antiproliferative activity of rIFN-gamma.Since cells within the stroma of EOC tissues could also contribute to arginine metabolism following treatment with rIFN-gamma or rIFN-gamma-inducers, it would be helpful to examine these effects in vivo.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gynecologic Oncology, The University of Texas, M,D, Anderson Cancer Center, Houston, Texas, U,S,A. rfreedma@mdanderson.org

ABSTRACT
BACKGROUND: Arginine metabolism in tumor cell lines can be influenced by various cytokines, including recombinant human interferon-gamma (rIFN-gamma), a cytokine that shows promising clinical activity in epithelial ovarian cancer (EOC). METHODS: We examined EOC cell lines for the expression of arginase in an enzymatic assay and for transcripts of arginase I and II, inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO) by reverse transcription-polymerase chain reaction. The effects of rIFN-gamma on arginase activity and on tumor cell growth inhibition were determined by measuring [3H]thymidine uptake. RESULTS: Elevated arginase activity was detected in 5 of 8 tumor cell lines, and analysis at the transcriptional level showed that arginase II was involved but arginase I was not. rIFN-gamma reduced arginase activity in 3 EOC cell lines but increased activity in the 2008 cell line and its platinum-resistant subline, 2008.C13. iNOS transcripts were not detected in rIFN-gamma-treated or untreated cell lines. In contrast, IDO activity was induced or increased by rIFN-gamma. Suppression of arginase activity by rIFN-gamma in certain cell lines suggested that such inhibition might contribute to its antiproliferative effects. However, supplementation of the medium with polyamine pathway products did not interfere with the growth-inhibitory effects of rIFN-gamma EOC cells. CONCLUSIONS: Increased arginase activity, specifically identified with arginase II, is present in most of the tested EOC cell lines. rIFN-gamma inhibits or stimulates arginase activity in certain EOC cell lines, though the decrease in arginase activity does not appear to be associated with the in vitro antiproliferative activity of rIFN-gamma. Since cells within the stroma of EOC tissues could also contribute to arginine metabolism following treatment with rIFN-gamma or rIFN-gamma-inducers, it would be helpful to examine these effects in vivo.

No MeSH data available.


Related in: MedlinePlus