A phase I study of recombinant human arginase I (rhArgI) for patients with advanced hepatocellular carcinoma.

Yau, C. C.; Chan, PharmD Juliana; Pang, Rwc; Chan, Wesley; Cheng, Paul; Poon, Rtp

doi:10.1200/jco.2010.28.15_suppl.e13503

Cited by 7 publications

(7 citation statements)

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“…L-citrulline supplementation has not been tested to date with this agent. These results contrast with the in-vivo safety of HuArgI (Mn)-PEG5000 in animals and patients [41,48,50]. This is in addition to the safety and efficacy of ADI-PEG20 in humans [24,25,48].…”

Section: Discussioncontrasting

confidence: 84%

“…Correlation of HuArgI (Co)-PEG5000 cytotoxicity with the argininosuccinate synthetase level A strong correlation between tumor cell ASS levels and IC 50 with HuArgI (Co)-PEG5000 in the presence of supplemental L-citrulline was observed, with Spearman coefficients and P values of -0.854 and < 0.001, -0.496 and 0.019, and -0.729 and < 0.001 for 3-day proliferation inhibition, 3-day protein synthesis inhibition, and 7-day metabolic inhibition, respectively (Table 6 and Fig. 7).…”

Section: Argininosuccinate Synthetase Protein Expression Of Human Cellsmentioning

confidence: 94%

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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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Section: Discussioncontrasting

confidence: 84%

Section: Argininosuccinate Synthetase Protein Expression Of Human Cellsmentioning

confidence: 94%

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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“…131,139,140 Currently, PEGylated derivative of recombinant human arginase I is undergoing clinical trials for the treatment of human HCC. 141,142 Moreover, initiatives are now being taken to overcome the possible problem of accumulation of PEGylated products in the liver by impending approaches such as fusion proteins. 138 …”

Section: Arginasementioning

confidence: 99%

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

et al. 2016

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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.

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“…Results of a Phase I study of recombinant human arginase I (rhArgI[Mn]-PEG5000) in 15 patients with advanced HCC were recently reported 50. Weekly doses of rhArgI(Mn)-PEG5000 ranged from 500–3500 IU/kg, and the maximum tolerated dose was determined to be 1600 IU/kg.…”

Section: Clinical Trials Of Arginine Deprivation Therapy (Table 1)mentioning

confidence: 99%

Arginine deprivation therapy for malignant melanoma

Yoon¹,

Frankel²,

Feun

et al. 2012

CPAA

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Despite recent development of promising immunotherapeutic and targeted drugs, prognosis in patients with advanced melanoma remains poor, and a cure for this disease remains elusive in most patients. The success of melanoma therapy depends on a better understanding of the biology of melanoma and development of drugs that effectively target the relevant genes or proteins essential for tumor cell survival. Melanoma cells frequently lack argininosuccinate synthetase, an essential enzyme for arginine synthesis, and as a result they become dependent on the availability of exogenous arginine. Accordingly, a therapeutic approach involving depletion of available arginine has been shown to be effective in preclinical studies. Early clinical studies have demonstrated sufficient antitumor activity to give rise to cautious optimism. In this article, the rationale for arginine deprivation therapy is discussed. Additionally, various strategies for depleting arginine are discussed and the preclinical and clinical investigations of arginine deprivation therapy in melanoma are reviewed.

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A phase I study of recombinant human arginase I (rhArgI) for patients with advanced hepatocellular carcinoma.

Cited by 7 publications

References 0 publications

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

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

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

Arginine deprivation therapy for malignant melanoma

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