Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase

Shen, Li-Jiuan; Beloussow, Karin; Shen, Wei‐Chiang

doi:10.1016/j.canlet.2005.01.007

Cited by 56 publications

(48 citation statements)

References 15 publications

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“…In this regard, Shen et al have shown that the addition of putrescine to ADI did not affect the antitumor activity of ADI, however it abolished the antitumor effect of DFMO, an ornithine decarboxylase inhibitor [10]. Furthermore, in CHO cells which lack ASS expression, treatment with ADI did not affect intracellular polyamine concentration.…”

Section: Other Biological Effects Of Adimentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

196

188

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Certain cancers may be auxotrophic for a particular amino acid and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(−) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in-vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.

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Section: Other Biological Effects Of Adimentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

196

188

View full text Add to dashboard Cite

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“…ADI can inhibit cell proliferation by arresting the cell cycle in G1 and/or S phase and inducing apoptosis [37]. Other investigators have looked at the modulation of arginine metabolic pathways as a potential mechanism of ADI's anti-tumour effect [38]. ADI was found to inhibit de novo protein synthesis in cells with low ASS activity, but not in cells with high ASS activity, whereas polyamine synthesis was not significantly affected.…”

Section: Expert Opinion and Conclusionmentioning

confidence: 99%

“…ADI was found to inhibit de novo protein synthesis in cells with low ASS activity, but not in cells with high ASS activity, whereas polyamine synthesis was not significantly affected. Thus the inhibitory effect of ADI on ADI-sensitive tumour cells may be due to inhibition of de novo protein synthesis [38]. The authors' laboratory studies suggest that apoptosis by ADI-PEG20 appears to involve the TNF-related apoptosis-inducing ligand (TRAIL) pathway [39].…”

Section: Expert Opinion and Conclusionmentioning

confidence: 99%

Pegylated arginine deiminase: a novel anticancer enzyme agent

Feun¹,

Savaraj²

2006

Expert Opinion on Investigational Drugs

106

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Pegylated arginine deiminase (ADI-PEG20) is a novel anticancer enzyme that produces depletion of arginine, which is a nonessential amino acid in humans. Certain tumours, such as malignant melanoma and hepatocellular carcinoma, are auxotrophic for arginine. These tumours that are sensitive to arginine depletion do not express argininosuccinate synthetase, a key enzyme in the synthesis of arginine from citrulline. ADI-PEG20 inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Phase I -II trials in patients with melanoma and hepatocellular carcinomas have shown the drug to have antitumour activity and tolerable side effects. Large Phase II trials and randomised, controlled Phase III trials are needed to determine its overall efficacy in the treatment of these malignancies and others.

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“…It has been postulated that the anti-tumor action of this enzyme is mediated by the direct inhibition of tumor cell growth via the downregulation of polyamine-biosynthesis in tumor cells [9]. Shen et al suggests that the inhibition of de novo protein synthesis is the likely mechanism for the inhibitory effect of ADI on the proliferation of ADI-sensitive tumor cells [10].…”

Section: Introductionmentioning

confidence: 99%

Extrinsic nitric oxide donor partially reverses arginine deiminase induced cell growth inhibition through NFκB and Bcl-XL

et al. 2008

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Arginine deiminase (ADI) is known to be an inducer of apoptosis in vitro and an anti-tumor agent in vivo in some cancers. ADI causes the enzymatic depletion of arginine which may inhibit nitric oxide (NO) synthesis. However, the effect of ADI treatment on NO synthesis has not been clearly elucidated. With the goal of understanding the role of ADI in NO synthesis, we used the Ramos human lymphoma cell line, which is known to be ADI-sensitive. After determining an optimal experimental ADI concentration (0.001 U/ml), we studied the effects of ADI treatment when combined with different concentrations of the extrinsic NO donor, sodium nitroprusside (SNP) (i.e., control, ADI only, ADI with 10 microM/ml SNP, ADI with 50 microM/ml SNP, and ADI with 100 microM/ml SNP). An MTT assay was used to assess cell survival after treatment, nitric oxide assays to determine nitrite levels and Western blot analysis to determine the expression of the NO mediators, NFkappaB and Bcl-X L. Interestingly, we found that the extrinsic NO donor only partially reversed ADI-induced inhibition of cell growth in a dose-dependent pattern and resulted in an induction of NFkappaB and Bcl-X L expression. In conclusion, we suggest that there might be an association between reversal of cell growth inhibition by extrinsic NO donor with Bcl-X L and NFkappaB expression in ADI-treated Ramos cell.

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Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase

Cited by 56 publications

References 15 publications

Arginine Deprivation as a Targeted Therapy for Cancer

Arginine Deprivation as a Targeted Therapy for Cancer

Pegylated arginine deiminase: a novel anticancer enzyme agent

Extrinsic nitric oxide donor partially reverses arginine deiminase induced cell growth inhibition through NFκB and Bcl-XL

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