The Effect of Arginase on the Retardation of Tumour Growth

Bach, S. J.; Swaine, D.

doi:10.1038/bjc.1965.45

Cited by 51 publications

(24 citation statements)

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“…The second is experimental, and the technology needed to achieve low blood arginine is highly complicated , although it is being further developed (Shettigar, 1990). The third approach has been adopted by a number of groups, and involves enzymatic degradation of arginine in situ (Bach and Swaine, 1965;Storr and Burton, 1974;Terayama et al, 1982;Gong et al, 2000;Miyazaki et al, 1990). In all probability, the combined use of these strategies will be required.…”

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Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

2003

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Arginase added to culture medium reduced arginine to negligible levels within B6 h, and enzyme activity persisted relatively undiminished for at least 3 days. Human and bovine arginase proved equally effective. The response of normal cells was to enter G1 (G0) arrest, from which most of the cells could be recovered weeks later. In contrast, malignant cell lines treated with unpegylated or pegylated enzyme resulted in cell death on a massive scale within 3 -5 days, with a very low to negligible percentage of cells (o0.01%) being recoverable on restoration with arginine. Although pegylation resulted in a 40% drop in specific activity, arginase was considerably more stable and remained active for b8 days. Arginine decarboxylase caused malignant cell arrest at the same units per millilitre as arginase. Its breakdown product, agmatine, was relatively nontoxic in the presence of arginine, but exacerbated cell death above millimolar concentration in its absence. Although ornithine failed to rescue cells from deprivation, citrulline recovered cells in all cases, although less well in fast-growing tumour cell populations, whereas readdition of arginine failed to work unless a complete medium change was given (because of the persistence of the enzymes in the medium catabolising its destruction). The advantages and disadvantages of these two arginine-catabolising enzymes are discussed, and compared with arginine deiminase.

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Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

2003

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“…days or weeks in experiments examining its possible effect on turnouts [25,26]. Importantly, there was no effect on systemic blood pressure (results not shown) implying that synthesis of NO by the vascular calcium-dependent nitric oxide synthase was not inhibited.…”

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confidence: 97%

l‐Arginine depletion by arginase reduces nitric oxide production in endotoxic shock: an electron paramagnetic resonance study

et al. 1995

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Nitric oxide (NO) synthesis was measured in the liver, lung, spleen and kidney of Iipopolysaccharide-treated male rats using the nitric oxide spin trap, iron (ll)-dlethyldithiocarbamate (FeDETC2). Nitric oxide formation in vlvo was determined by the Increase in intensity of the characteristic triplet hyperflne EPR spectrum of [NO-FeDETC,]. Intravenous bovine liver arginase, nt a dose which completely depleted circniating arginlne, significantly reduced the formation of nitric oxide in these tissues. The general decrease in NO levels was confirmed by the decrease in plasma nitrite levels. These results directly demonstrate that NO formation in endotoxic shock depends on extracellular arginine; depletion of plasma arginine may be a useful therapeutic strategy.

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“…Plasma citrulline remained normal, and therefore the tumour cells must have converted citrulline to arginine fast enough to sustain relatively normal tumour growth rate (Wu and Morris, 1998;Philip et al, 2003). This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine with arginine deiminase (EC 3.5.3.6) could not be rescued with citrulline, but grew when argininosuccinate, the immediate downstream intermediate, was supplied.…”

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Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Wheatley

Campbell

2003

Br J Cancer

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Arginine deprivation causes death of up to 80% of cancer cell lines in vitro, but in the body, citrulline would be available as a convertible source of this amino acid in vivo. Some tumour cell lines, notably the vast majority of melanomas and hepatocellular carcinomas, tend to be deficient in argininosuccinate synthetase (EC 6.5.4.3.), and therefore cannot recycle citrulline to arginine. Argininosuccinate synthetase is present at levels that convert enough citrulline to arginine to allow limited growth in about half of a modest range of malignant cell types analysed in this study. Attempts to rescue cells that are unable to utilise citrulline with the immediate downstream product, argininosuccinate, had very limited success in a few tumour cell lines. Particularly noteworthy is the demonstration that argininosuccinate was totally incapable of rescuing cells that utilise citrulline efficiently, consistent with tight channelling (coupling) of argininosuccinate synthetase and argininosuccinate lyase in the urea cycle. The findings suggest that an excellent opportunity exists for further exploitation of arginine deprivation in the selective killing of tumour cells. Arginine is a vital amino acid for many metabolic processes other than protein synthesis (e.g. creatine production, polyamine synthesis and nitric oxide (NO) generation). Its removal from culture medium by medium formulation or arginase treatment quickly leads to death in B80% of tumour cell lines (Scott et al, 2000). The addition of citrulline can often circumvent this deficiency, but few cells are capable of its biosynthesis in culture. Arginine deficiency in vivo has been induced by various means, but is less effectively achieved because body homeostasis is too robust, and citrulline generation is difficult to control. Having successfully reduced L1210 cells in culture to negligible viability in 3-5 days with arginase (EC 3.5.3.1), citrulline supplementation in the continued presence of the enzyme partially circumvented the arginine deficiency. The rate of conversion became a rate-limiting factor, most noticeably in such fast-growing leukaemia as L1210 (Philip et al, 2003). In a corresponding in vivo study, arginase treatment of DBA/2 mice injected intraperitoneally with 1210 cells increased neither their survival time nor decreased tumour burden, despite plasma arginine falling to B1-2 mM level. Plasma citrulline remained normal, and therefore the tumour cells must have converted citrulline to arginine fast enough to sustain relatively normal tumour growth rate (Wu and Morris, 1998;Philip et al, 2003). This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine w...

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The Effect of Arginase on the Retardation of Tumour Growth

Cited by 51 publications

References 6 publications

Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures

l‐Arginine depletion by arginase reduces nitric oxide production in endotoxic shock: an electron paramagnetic resonance study

Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

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