Pegylated derivatives of recombinant human arginase (rhArg1) for sustained in vivo activity in cancer therapy: preparation, characterization and analysis of their pharmacodynamics in vivo and in vitro and action upon hepatocellular carcinoma cell (HCC)

Tsui, S. M.; Lam, Wai-Man; Lam, Alan Tin-Lun; Chong, Hiu-Chi; So, Pui‐Kin; Kwok, Sui-Yi; Arnold, Simon; Cheng, Paul; Wheatley, Denys N.; Lo, Wai‐Hung; Leung, Yun Chung

doi:10.1186/1475-2867-9-9

Cited by 69 publications

(52 citation statements)

References 22 publications

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“…Thus, normal cells which lack OTC can become toxic while tumor cells which lack both ASS and OTC are more sensitive [36]. Nevertheless, its pegylated and modified form to improve activity and pharmacokinetic profile has been synthesized [37, 38] in preparation for clinical trial. Another factor which influences the response to arginine deprivation is autophagy which enables melanoma cells to survive and hence combination treatment is needed to enhance the apoptotic signal.…”

Section: Discussionmentioning

confidence: 99%

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

Savaraj

et al. 2015

Oncotarget

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Loss of argininosuccinate synthetase (ASS) expression in melanoma makes these tumor cells vulnerable to arginine deprivation. Pegylated arginine deiminase (ADI-PEG20) which degrades arginine to citrulline and ammonia has been used clinically and partial responses and stable disease have been noted with minimal toxicity. In order to improve the therapeutic efficacy of ADI-PEG20, we have combined ADI-PEG20 with a DNA damaging agent, cisplatin. We have shown that the combination of the two drugs together significantly improved the therapeutic efficacy when compared to ADI-PEG20 alone or cisplatin alone in 4 melanoma cell lines, regardless of their BRAF mutation. In-vivo study also exhibited the same effect as in-vitro with no added toxicity to either agent alone. The underlying mechanism is complex, but increased DNA damage upon arginine deprivation due to decreased DNA repair proteins, FANCD2, ATM, and CHK1/2 most likely leads to increased apoptosis. This action is further intensified by increased proapoptotic protein, NOXA, and decreased antiapoptotic proteins, SURVIVIN, BCL2 and XIAP. The autophagic process which protects cells from apoptosis upon ADI-PEG20 treatment also dampens upon cisplatin administration. Thus, the combination of arginine deprivation and cisplatin function in concert to kill tumor cells which do not express ASS without added toxicity to normal cells.

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Section: Discussionmentioning

confidence: 99%

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

Savaraj

et al. 2015

Oncotarget

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“…interferon, are immunogenic and they are 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 cancer therapy [12]. Several other products including pegvisomant and certolizumab pegol have also proven to be effective and they are in high demand [10].…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle PEGylation for Cancer Therapy

Moffatt¹

2015

MOJPB

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Currently, there are more than 35 US FDA-approved NPs utilizing PEG in their biomedical applications. PEGylation, which is the addition of PEG to the NP formulation, provides immunity from the hostile biological environment. The 'stealth' property, further confers on the PEG-NP formulation benefits that are not normally provided by other polymers. This mini-review briefly describes the mechanisms of action, as well as the benefits and challenges of PEG and PEGylation in cancer therapy. General Mechanisms of PEG-Mediated NP ActionUpon administration, NPs are recognized and cleared from circulation by the phagocytes from the reticuloendothelial system (RES). The circulation time of the NPs is largely determined by their surface structure and their hydrophilicity/ hydrophobicity state that governs the amounts of opsonins absorbed. The process of opsonization (opsonin-NP binding) reduces the circulation time of the NPs. Reports indicate that the PEG polymer on the NP surface increases the circulation time by reducing this opsonization process, thereby preventing recognition by monocytes and macrophages, allowing the NPs to remain longer in the blood pool [1]. In addition to NP-RES interactions, poor circulation times can also arise from NP-NP interactions, where NPs with a high surface energy have a greater tendency to aggregate as described by the DerjaguinLandau-Verwey-Overbeek (DLVO) theory [2].PEGylation of small proteins, peptides, and oligonucleotides, has also become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule [3].Many other successful experimental assays depend on the ability to re-engineer the solubility, size, and other properties of drugs, peptides or proteins, in their interactions with PEG in an effort to increase the resident time in circulation. PEGylation, if empirically researched on, would become a very useful method of making these modifications. Benefits and Challenges of NP Applications of PEGThe maor benefits from the use of PEG in NP formulations derives from its "stealth' properties, as well as the increase in circulation times for the NP conjugates. Clearly, the addition of PEG to the NP formulation increases the retention and circulation time by reducing uptake by opsonins in the RES. It was reported previously that particles remained in rat circulation 40-times longer when coated than uncoated with PEG [4]. Additionally, incorporation of dioleoyl N-(monomethoxy polyethylene glycol succinyl) phosphotidylethanolamine (PEG-PE) into posphatidylcholine:cholesterol liposomes (1:1) increased the retention time from thirty minutes to five [5]. By virtue of the fact that PEG is hydrophilic, the serum and other solvent solubility also increases, further enhancing the circulation time. These merits also result in higher targeted and accumulated PEGylated NPs than non-PEGylated counterparts.

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“…Elevated ammonia levels may be toxic in vivo [17]. Pegylated recombinant human arginase [ArgI (Mn)-PEG5000] metabolizes arginine to ornithine and urea and has shown antitumor activity in vitro and in vivo [15,[18][19][20][21]. However, past studies have found that the HuArgI (Mn)-PEG5000 enzyme is unstable in serum and displays low catalytic activity at physiological pH [22].…”

Section: Introductionmentioning

confidence: 99%

“…Pegylated recombinant arginine deiminase (ADI-PEG20) degrades plasma arginine to citrulline and ammonia, but it is immunogenic [14][15][16]. One drawback of ADI-PEG20 is onset of hyperammonemia, which was reported in 5.9% of patients at a dose of 320 IUm -2 [16].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of human recombinant arginase I (Co)-PEG5000 in the presence of supplemental L-citrulline is dependent on decreased argininosuccinate synthetase expression in human cells

et al. 2012

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Human recombinant arginase I cobalt [HuArgI (Co)] coupled with polyethylene glycol 5000 [HuArgI (Co)-PEG5000] has shown potent in-vitro depletion of arginine from tissue culture medium. We now show that HuArgI (Co)-PEG5000 is toxic to almost all cancer cell lines and to some normal primary cells examined. In contrast, HuArgI (Co)-PEG5000 in combination with supplemental L-citrulline is selectively cytotoxic to a fraction of human cancer cell lines in tissue culture, including some melanomas, mesotheliomas, acute myeloid leukemias, hepatocellular carcinomas, pancreas adenocarcinomas, prostate adenocarcinomas, lung adenocarcinomas, osteosarcomas, and small cell lung carcinomas. Unfortunately, a subset of normal human tissues is also sensitive to HuArgI (Co)-PEG5000 with L-citrulline supplementation, including umbilical endothelial cells, bronchial epithelium, neurons, and renal epithelial cells. We further show that cell sensitivity is predicted by the level of cellular argininosuccinate synthetase protein expression measured by immunoblots. By comparing a 3-day and 7-day exposure to HuArgI (Co)-PEG5000 with supplemental L-citrulline, some tumor cells sensitive on short-term assay are resistant in the 7-day assay consistent with the induction of argininosuccinate synthetase expression. On the basis of these results, we hypothesize that HuArgI (Co)-PEG5000 in combination with L-citrulline supplementation may be an attractive therapeutic agent for some argininosuccinate synthetase-deficient tumors. These in-vitro findings stimulate further development of this molecule and may aid in the identification of tissue toxicities and better selection of patients who will potentially respond to this combination therapy.

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Pegylated derivatives of recombinant human arginase (rhArg1) for sustained in vivo activity in cancer therapy: preparation, characterization and analysis of their pharmacodynamics in vivo and in vitro and action upon hepatocellular carcinoma cell (HCC)

Cited by 69 publications

References 22 publications

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin

Nanoparticle PEGylation for Cancer Therapy

Cytotoxicity of human recombinant arginase I (Co)-PEG5000 in the presence of supplemental L-citrulline is dependent on decreased argininosuccinate synthetase expression in human cells

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