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A rational approach to the systemic treatment of cancer involving medium-term depletion of arginine

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A rational approach to the systemic treatment of cancer involving medium-term depletion of arginine

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... The apoptotic effect increased with increasing incubation time and ADI concentration, this indicates that the enzyme is potent with low amounts in death program of ANG cell line, but it was safe with REF cell line when the same concentrations were used as described in (table 4) and in figures (4 and 6) with non-significant differences at P ≤ 0.05 in comparison to control. Many researchers [22] found that the killing of cancer cell lines by arginine deprivation is also selective because deprived normal cells will have become quiescent but soon recover on restitution of the missing nutrient, whereas tumor cells in cycle can be hit by low doses of cycle-dependent cytotoxic drugs. The results described in (table 4) showed that the ADI enzyme had very low cytotoxicity for REF cell line which increased with increasing /ml of ADI used, the apoptosis ratio of the amount of enzyme. ...
... 2-Stay in cycle instead of moving out of it into G1 or G0 [25]. Die within 3-4 days in many cases, probably as a result of trying to cycle when insufficiently resourced [22,25]. Because they stay in cycle, they continue to be suitable targets for cell cycle-dependent cytotoxic agents [26], where as normal cells become quiescent and relatively resistant. ...
... Because they stay in cycle, they continue to be suitable targets for cell cycle-dependent cytotoxic agents [26], where as normal cells become quiescent and relatively resistant. 5-As long as arginine is reduced to the micromolar level, many cancer cells will die, while normal cells recover from quiescence when enzyme is removed [22]. ...
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Purified arginine deiminase from Enterococcus faecium M1 isolate is the strongest cancer treatment enzyme due to its activity and stability in different environmental conditions. The cytotoxicity of ADI to glioblastoma multiforme (ANG) cancer cell line and rat embryo fibroblast(REF) normal cell line for (24, 48 and 72h) were estimated, the inhibition rate(IR) increased with raising of ADI concentration and incubation period for ANG cell line but these results were opposite for REF cell line that IR decreased with increment of incubation period. Different concentrations (2-1000ng) of enzyme were used, the significant once were between (30-100ng) that they were safe for most cells of REF normal cell line but they inhibited the large numbers of glioblastoma cells, that the IC50 of ADI was 37ng/ml for this cancer cell line during 72h of incubation time and the IR reached to 75.4% after 48h incubation with 100ng/ml of enzyme. The ability of ADI to produce intrinsic mitochondrial apoptosis effect on ANG and REF cell lines was investigated, the results showed that the main reason of cell cytotoxicity was the induction of apoptosis process by ADI enzyme and they were compatible to the results of cytotoxicity test. We concluded that ANG cancer cell line could not produce arginine amino acid thus it was highly sensitive to arginine deprivation by the robust activity of arginine deiminase enzyme, but it was safe for REF normal cell line could produce arginine during the incubation time with enzyme.
... The apoptotic effect increased with increasing incubation time and ADI concentration, this indicates that the enzyme is potent with low amounts in death program of ANG cell line, but it was safe with REF cell line when the same concentrations were used as described in (table 4) and in figures (4 and 6) with non-significant differences at P ≤ 0.05 in comparison to control. Many researchers [22] found that the killing of cancer cell lines by arginine deprivation is also selective because deprived normal cells will have become quiescent but soon recover on restitution of the missing nutrient, whereas tumor cells in cycle can be hit by low doses of cycle-dependent cytotoxic drugs. The results described in (table 4) showed that the ADI enzyme had very low cytotoxicity for REF cell line which increased with increasing /ml of ADI used, the apoptosis ratio of the amount of enzyme. ...
... 2-Stay in cycle instead of moving out of it into G1 or G0 [25]. Die within 3-4 days in many cases, probably as a result of trying to cycle when insufficiently resourced [22,25]. Because they stay in cycle, they continue to be suitable targets for cell cycle-dependent cytotoxic agents [26], where as normal cells become quiescent and relatively resistant. ...
... Because they stay in cycle, they continue to be suitable targets for cell cycle-dependent cytotoxic agents [26], where as normal cells become quiescent and relatively resistant. 5-As long as arginine is reduced to the micromolar level, many cancer cells will die, while normal cells recover from quiescence when enzyme is removed [22]. ...
Article
Full-text available
Purified arginine deiminase from Enterococcus faecium M1 isolate is the strongest cancer treatment enzyme due to its activity and stability in different environmental conditions. The cytotoxicity of ADI to glioblastoma multiforme (ANG) cancer cell line and rat embryo fibroblast(REF) normal cell line for (24, 48 and 72h) were estimated, the inhibition rate(IR) increased with raising of ADI concentration and incubation period for ANG cell line but these results were opposite for REF cell line that IR decreased with increment of incubation period. Different concentrations (2-1000ng) of enzyme were used, the significant once were between (30-100ng) that they were safe for most cells of REF normal cell line but they inhibited the large numbers of glioblastoma cells, that the IC50 of ADI was 37ng/ml for this cancer cell line during 72h of incubation time and the IR reached to 75.4% after 48h incubation with 100ng/ml of enzyme. The ability of ADI to produce intrinsic mitochondrial apoptosis effect on ANG and REF cell lines was investigated, the results showed that the main reason of cell cytotoxicity was the induction of apoptosis process by ADI enzyme and they were compatible to the results of cytotoxicity test. We concluded that ANG cancer cell line could not produce arginine amino acid thus it was highly sensitive to arginine deprivation by the robust activity of arginine deiminase enzyme, but it was safe for REF normal cell line could produce arginine during the incubation time with enzyme.
... Arginine degrading enzymes have been used to treat cancer for some time [1,2] . We have recently published findings with pegylated arginase both in vitro and in vivo [3,4]; a brief overview can be found in Cheng and Wheatley, 2007 [5] that show how effective pegylation can be in protecting even a native human enzyme from rapid elimination by one means and another from the bloodstream. ...
... In contrast, tumor necrosis factor-α as well as ADI retained approximately half of its biological activity when ~40–50% of its primary amines were conjugated with PEG molecules [21,27]. We set out to determine the effects of pegylation on the activity of arginase – a urea cycle enzyme that can potentially be used in anti-cancer treatment [2,4,28] – in an attempt to improve its therapeutic properties. ...
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Protein used in medicine, e.g. interferon, are immunogenic and quickly broken down by the body. Pegylation is a recognized way of preserving their integrity and reducing immune reactions, and works well with enzymes used to degrade amino acids, a recent focus of attention in controlling cancer growth. Of the two arginine-degrading enzymes being explored clinically, arginine deiminase is a decidedly foreign mycoplasm-derived enzyme, whereas human arginase 1 is a native liver enzyme. Both have been pegylated, the former with adjuncts of 20 kD, the latter with 5 kD PEG. Pegylation is done by several different methods, not all of which are satisfactory or desirable. The preparation of novel polyethylene glycol (PEG) derivatives for modifying proteins is described, but directed specifically at pegylation of recombinant human arginase 1 (rhArg1). rhArg1 expressed in Escherichia coli was purified and coupled in various ways with 5 different PEG molecules to compare their protective properties and the residual enzyme activity, using hepatocellular cell lines both in vitro and in vivo. Methoxypolyethylene glycol-succinimidyl propionate (mPEG-SPA 5,000) coupled with very high affinity under mild conditions. The resulting pegylated enzyme (rhArg1-peg5,000 mw) had up to 6 PEG chains of 5K length which not only protected it from degradation and any residual immunogenicity, but most importantly let it retain >90% of its native catalytic activity. It remained efficacious in depleting arginine in rats after a single ip injection of 1,500 U of the conjugate as the native enzyme, plasma arginine falling to >0.05 microM from approximately 170 microM within 20 min and lasting 6 days. The conjugate had almost the same efficacy as unpegylated rhArg1 on 2 cultured human liver cancer (HCC) cell lines. It was considerably more effective than 4 other pegylated conjugates prepared. Valuable data on the optimization of the pegylation procedure and choice of ligand that best stabilizes the enzyme arginase 1 are presented, a protocol that should equally fit many other enzymes and proteins. It is a long lasting arginine-depleting enzyme in vivo which will greatly improve its use in anti-cancer therapy.
... As chemoradiotherapy is less effective in hypoxic, solid tumours, they are usually surgically resected. This can restore vascularity (and oxygen supply) [5,16], to make for more effective cytotoxicand radiotherapy. These surgical procedures are unfortunately often accompanied by cancer cell leakage [17] and consequential metastases [18]. ...
... Dialysis may be applied via the brachial artery [117][118][119]. Controlling the expected flow of inflammatory chemicals from the resulting necrotic material [16] should also be accounted for. Cytotoxic drugs (such as cisplatin) may additionally be administered with this treatment, but will in this case still have systemic effects due to, among others, the highly glycolytic brain also receiving the drug. ...
Article
Many difficult-to-treat solid cancer tumours and metastases have high-glucose uptake, usually under hypoxic conditions. Hypoxic tumours suppress the immune system and are insensitive to traditional chemoradiotherapies. The only therapy usually available is surgical resection. However, with widespread metastases, surgery often becomes unviable. Surgery in itself can also result in metastasis. The need for investigating adjuvant treatments is obvious. Here we investigate whether the high-glucose uptake of hypoxic tumours could lead to such a treatment. Before any treatment can be hypothesised, it is crucial to understand how this glycolytic cancer phenotype fits in with the normal body's blood glucose cycle. The brain creates the healthy body's largest demand for blood glucose (BG) and ensures a very high level of control on in vivo supply. It is hypothesised that, through somatic evolution, high-glycolytic cancer cells opportunistically tap into this very stable energy environment. It is shown that therapies which target the glycolytic cancers' high BG needs cannot be developed without addressing the brain's energy needs. Based on this knowledge, and to initiate thinking on potential BG therapies, a first attempt is made at hypotheses for potential control of the in vivo brain demand as well as the available in vivo BG. The aim is to adversely affect primary as well as metastatic tumours without damaging brain and innocent bystander cells.
... During recent years, arginase is considered as a prospective pharmaceutical in the enzymotherapy of several types of tumors that are auxotrophic for arginine (e.g., melanoma, hepatocarcinoma, retinoblastoma, prostate cancers) [10][11][12][13][14][15]; its enzymotherapeutic use would be similar to the treatment of leukemia with recombinant bacterial asparaginase [16,17]. ...
Article
Arginase (EC 3.5.3.1; L-arginine amidinohydrolase) is a key enzyme of the urea cycle that catalyses the conversion of arginine to ornithine and urea, which is the final cytosolic reaction of urea formation in the mammalian liver. The recombinant strain of the yeast Saccharomyces cerevisiae that is capable of overproducing arginase I (rhARG1) from human liver under the control of the efficient copper-inducible promoter CUP1, was constructed. The (His)(6)-tagged rhARG1 was purified in one step from the cell-free extract of the recombinant strain by metal-affinity chromatography with Ni-NTA agarose. The maximal specific activity of the 40-fold purified enzyme was 1600 μmol min(-1) mg(-1) protein.
... Arginine dependence of the tumor cells has been considered as the 'Achilles heel' of tumor cells. 195 Inability of tumor cells to proliferate in the absence of arginine can be targeted for their selective destruction by arginine-depriving enzymes. Large numbers of enzyme-based anti-cancer therapies are currently undergoing clinical evaluation. ...
Article
Full-text available
Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.Oncogene advance online publication, 25 April 2016; doi:10.1038/onc.2016.37.
... Abbreviations: CHX, cycloheximide; DMSO, dimethyl sulfoxide; ER, endoplasmic reticulum; Tm, tunicamycin; UPR, unfolded protein response; XBP1s, spliced form of XBP1. Therefore, restriction of the semi-essential amino acid arginine was postulated as a promising approach for the treatment of tumors deficient in arginine anabolism (Wheatley et al., 2005). For some tumor types this therapy already proceeded into clinical trials that utilize recombinant arginine-depleting enzymes (Ascierto et al., 2005;Glazer et al., 2010;Yau et al., 2013). ...
Article
Deprivation for the single amino acid arginine is a rapidly developing metabolic anticancer therapy, which allows growth control in a number of highly malignant tumors. Here we report that one of the responses of human solid cancer cells to arginine starvation is the induction of prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Systematic study of two colorectal carcinoma HCT-116 and HT29, glioblastoma U251 MG and ovarian carcinoma SKOV3 cell lines revealed, however, that the ER stress triggered by the absence of arginine does not result in massive apoptosis despite a profound upregulation of the proapoptotic gene CHOP. Instead, Akt- and MAPK-dependent pathways were activated which may counteract proapoptotic signaling. Treatment with DMSO as a disaggregating agent or with cycloheximide to block protein synthesis reduced ER stress evoked by arginine deprivation. On the other hand, ER stress and apoptosis induction in arginine-starved cells could be critically augmented by the arginine analogue of plant origin canavanine, but not by the classic ER stress inducer tunicamycin. Our data suggest that canavanine treatment applied under the lack of arginine may enhance the efficacy of arginine deprivation-based anticancer therapy.
... Amino acid catabolising enzymes, such as arginase and asparaginase, are known to inhibit growth of some cancer cell lines by depleting the supply of the respective amino acids [553]. Arginine deiminase (ADI) can achieve the same effect if the citrulline to arginine pathway is blocked and this was suggested as a better therapeutic agent against leukaemia than asparaginase (since ADI is highly specific for arginine while asparaginase degrades glutamine just as well as asparagine) [554]. ...
Article
Cancer remains a fundamental burden to public health despite substantial efforts aimed at developing effective chemotherapeutics and significant advances in chemotherapeutic regimens. The major challenge in anti-cancer drug design is to selectively target cancer cells with high specificity. Research into treating malignancies by targeting altered metabolism in cancer cells is supported by computational approaches, which can take a leading role in identifying candidate targets for anti-cancer therapy as well as assist in the discovery and optimisation of anti-cancer agents. Natural products appear to have privileged structures for anti-cancer drug development and the bulk of this particularly valuable chemical space still remains to be explored. In this review we aim to provide a comprehensive overview of current strategies for computer-guided anti-cancer drug development. We start with a discussion of state-of-the art bioinformatics methods applied to the identification of novel anti-cancer targets, including machine learning techniques, the Connectivity Map and biological network analysis. This is followed by an extensive survey of molecular modelling and cheminformatics techniques employed to develop agents targeting proteins involved in the glycolytic, lipid, NAD+, mitochondrial (TCA cycle), amino acid and nucleic acid metabolism of cancer cells. A dedicated section highlights the most promising strategies to develop anti-cancer therapeutics from natural products and the role of metabolism and some of the many targets which are under investigation are reviewed. Recent success stories are reported for all the areas covered in this review. We conclude with a brief summary of the most interesting strategies identified and with an outlook on future directions in anti-cancer drug development.
... In recent years, there is a growing interest in the world in development of new bio-therapeutic approaches to treat cancer [1,2]. It is explained by a fact that antitumor chemotherapeutic drugs which are used in traditional medicine exhibit negative effects on normal cells as a result of considerable general toxicity [3]. ...
Article
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Monitoring of L-arginine in serum blood as well as in wines is very essential in medicine and food industry. A potentiometric L-arginine selective bi-enzyme biosensor based on the recombinant human liver arginase I and commercial urease co-immobilised in calcium alginate gel on the surface of ammonium selective electrode has been described. Two arginase preparations were used: free enzyme (E) and covalently immobilized on the surface of gold nanoparticles (ENPs). Some bioanalytical parameters (sensitivity, selectivity and storage stability) of the developed biosensors were investigated. The biosensors exhibit a good response to the target analyte with the linear range from 0.12 to 40 mM for ENPs-based and from 0.50 to 50 mM, for E-based with detection limit below 10-4 M of L-arginine. The ENPs-based biosensor compared with E-based has demonstrated improved physico-chemical characteristics, namely, a higher sensitivity (5-fold) and storage stability (120%). Moreover, both biosensors are sufficiently stable in exploitation and develop a stationary response during 3-5 min (t95%) to the analyte. The constructed E-based biosensor was tested on the real samples of commercial pharmaceuticals products (“Tivortin”, “Cytrarginine”, “Aminoplazmal 10% E”). The obtained L-arginine content was in a good correlation with that declared by producers.
Article
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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The majority of melanoma cells do not express argininosuccinate synthetase (ASS), and hence cannot synthesize arginine from citrulline. Their growth and proliferation depend on exogenous supply of arginine. Arginine degradation using arginine deiminase (ADI) leads to growth inhibition and eventually cell death while normal cell which express ASS can survive. This notion has been translated into clinical trial. Pegylated ADI (ADI-PEG20) has shown antitumor activity in melanoma. However, the sensitivity to ADI is different among ASS(-) melanoma cells. We have investigated and reviewed the signaling pathways which are affected by arginine deprivation and their consequences which lead to cell death. We have found that arginine deprivation inhibits mTOR signaling but leads to activation of MEK and ERK with no changes in BRAF. These changes most likely lead to autophagy, a possible mechanism to survive by recycling intracellular arginine. However apoptosis does occur which can be both caspase dependent or independent In order to increase the therapeutic efficacy of this form of treatment, one should consider adding other agent(s) which can drive the cells toward apoptosis or inhibit the autophagic process.
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Purified human arginase I preparations homogeneous in SDS-PAAG test were obtained by the affinity chromatography on the synthesized sorbent L-arginine-macroporous glass. Some physico-chemical characteristics of the isolated arginase preparation have been estimated: thermo- and pH-stability, temperature- and pH-optima of the enzyme. The influence of some bivalent metal ions and other additives on enzymatic activity for stabilization of the enzyme and optimization of its storage conditions was studied.
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A highly selective and sensitive method for the quantitative determination of L-arginine (Arg) with a fluorescent detection of the reaction product has been developed. The method is based on the use of human liver arginase I isolated from a recombinant producer strain, yeast Hansenula polymorpha, and 2,3-butanedione monoxime, which is used to detect carbamide—the product of enzymatic reactions. The linear concentration range for determining Arg in the final reaction mixture varies from 0.2 to 250 μM, and the detection limit is 0.16 μM. Tests of the new method using commercial Arg-containing pharmaceutical preparations showed a high correlation (R = 1.0) of the results with the manufacturer’s data and the results of other methods for Arg detection.
Article
This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90 %) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13 %, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95 % CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95 % CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25 %) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.
Article
Arginine deprivation has a marked effect on metabolism. Many cells that cannot make this semi-essential amino acid are particularly vulnerable to a deficiency of it, particularly tumour cells. Many types of malignant cells try to cycle, generally resulting in activation of the apoptotic pathway because they cannot easily progress into or through division. The metabolomics of arginine before, during and after deprivation should be explored in greater detail to exploit the differences between normal and malignant cells for more effective therapy. On its own, arginine deprivation can cause regression of fast-growing tumours, but many more can also succumb to its use with adjunct modalities, making this metabolic intervention a desirable platform for combinatorial protocols. This requires optimisation of the conditions (treatments and their arrangements) to eliminate cancer cells with the least damage to normal cells, thereby sustaining a high quality of life. It is a strategy that requires close dialogue between cancer research specialists and oncologist to achieve the best outcomes. This paper argues for a more concerted effort on development of rational and effective combined therapies, first in vitro and then in animal tumour models where cytotoxic drugs or other agencies can be administered as adjunct interventions at critically low or even subclinical dose levels that minimise side effects. Translation of the findings to the clinic remains a goal for the future.
Chapter
There has been renewed interest in amino acid deprivation to treat various human cancers. Certain tumors do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. These tumors are auxotrophic for arginine and may be inhibited by arginine deprivation. Arginine deprivation can affect growth and apoptotic signaling. In addition, mTOR signaling and RAF/MEK/ERK1/2 signaling are also affected by arginine deprivation. Upon arginine deprivation, tumor cells undergo autophagy as a survival mechanism, but prolonged autophagy can lead to apoptotic cell death. Arginine derivation using pegylated arginine deiminase (ADI-PEG20) has been shown to have activity in malignant melanoma and hepatocellular carcinoma with minimal side effects. Why ASS is silent in certain tumor types is not known. Aberrant DNA methylation which leads to epigenetic silencing has been reported. Reexpression of ASS may lead to resistance to arginine deprivation treatment. Thus, understanding how the ASS gene is regulated is very important for this modality of cancer treatment. © 2012 Springer Science+Business Media, LLC. All rights reserved.
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IntroductionClinical StudiesMechanisms of ActionASS ExpressionFuture DirectionsReferences
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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 that from others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.
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