Pegylated Arginine Deiminase Treatment of Patients With Unresectable Hepatocellular Carcinoma: Results From Phase I/II Studies

Izzo, Francesco; Marra, Paolo; Beneduce, Gerardo; Castello, Giuseppe; Vallone, Paolo; Rosa, Vincenzo De; Cremona, Franco; Ensor, Mark; Holtsberg, Frederick W.; Bomalaski, John S.; Clark, Mike A.; Ng, Chaan S.; Curley, Steven A.

doi:10.1200/jco.2004.11.120

Cited by 227 publications

(183 citation statements)

References 32 publications

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“…These numbers are comparable to those reported from the Pascale Cancer Institute and from a phase I/II trial reported from M.D. Anderson [75]. Interestingly, of the 9 patients treated at the University of Miami, two patients had stable disease for at least 12 months.…”

Section: Clinical Studies With Adi-peg20supporting

confidence: 75%

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Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

191

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: Clinical Studies With Adi-peg20supporting

confidence: 75%

“…No toxicity due to the drug was noted. This encouraging response led to a phase I/II trial of ADI-PEG20 in patients with unresectable hepatocellular carcinoma [75]. Patients with hepatocellular carcinoma were accrued from the Pascale Cancer Institute in Naples, Italy.…”

Section: Clinical Studies With Adi-peg20mentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

191

188

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“…A phase I dose escalation study which combined Adi-PEG 20 with cisplatin and pemetrexed provided a signal of efficacy with a 78% response rate (7 out of 9 patients) (163). These findings are consistent with demonstrated efficacy of arginine depletion therapy in other malignancies (164)(165)(166)(167). A phase 2/3 study is currently recruiting patients with MPM with low ASS1 expression to evaluate the efficacy of Adi PEG 20 in combination with pemetrexed and cisplatin (clinicaltrials.gov NCT02709512).…”

Section: Arginine Depletionsupporting

confidence: 53%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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“…The observed 1-h half-life represents many circulation periods and may be sufficient to allow nanotubes that are linked to targeting moieties such as antibodies or peptides to localize in tissues of interest. Moreover, circulation time can probably be significantly extended by PEGylation [poly(ethylene glycol) wrapping] of the nanotube surfaces (16,22). In principle, this may be achieved either by covalent sidewall derivatization or by surrounding the nanotubes with a stable sheath of noncovalently bound PEG-like molecules that will resist displacement by proteins.…”

Section: Resultsmentioning

confidence: 99%

Mammalian pharmacokinetics of carbon nanotubes using intrinsic near-infrared fluorescence

Cherukuri

Gannon

Leeuw

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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447

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Individualized, chemically pristine single-walled carbon nanotubes have been intravenously administered to rabbits and monitored through their characteristic near-infrared fluorescence. Spectra indicated that blood proteins displaced the nanotube coating of synthetic surfactant molecules within seconds. The nanotube concentration in the blood serum decreased exponentially with a half-life of 1.0 ؎ 0.1 h. No adverse effects from low-level nanotube exposure could be detected from behavior or pathological examination. At 24 h after i.v. administration, significant concentrations of nanotubes were found only in the liver. These results demonstrate that debundled single-walled carbon nanotubes are highcontrast near-infrared fluorophores that can be sensitively and selectively tracked in mammalian tissues using optical methods. In addition, the absence of acute toxicity and promising circulation persistence suggest the potential of carbon nanotubes in future pharmaceutical applications.nanoparticle biodistribution ͉ nanoparticle toxicity ͉ luminescence spectroscopy ͉ single-walled carbon nanotubes S ingle-walled carbon nanotubes (SWNTs) are an important class of artificial nanomaterials with remarkable mechanical, thermal, electronic, and optical properties. These properties suggest diverse future biomedical uses in areas such as targeted chemotherapeutics, in vitro cell markers, diagnostic imaging contrast agents, biochemical sensors, and photoablative therapy agents (1-9). Before medical applications can be developed, it is necessary to explore the behavior and fate of SWNTs in mammals. However, little is currently known in this area, in part because of the challenge of detecting and tracking these allcarbon nanoparticles in complex biological environments.SWNTs can be envisioned as sections of graphene sheets rolled up to form seamless cylindrical tubes with a variety of structures (10). Each of these structures has a well defined diameter and chiral angle and shows either semiconducting or metallic behavior. The nanotube preparations used for this study contain several dozen structural types that are Ϸ1 nm in diameter and Ϸ300 nm long. After excitation with visible light, each type of semiconducting SWNT fluoresces at a near-infrared (near-IR) wavelength between Ϸ900 and 1,600 nm that is characteristic of its specific structure (11, 12). We have previously exploited this fluorescence emission to study the active ingestion of SWNTs by macrophage cells in vitro (13).Here we report the use of the intrinsic near-IR fluorescence, which is a property only of individualized SWNTs, to measure their blood elimination kinetics in rabbits and to identify the organs in which they concentrate. These methods and results provide a foundation for developing the targeted delivery of nanotubes to specific tissues for diagnostic and therapeutic uses. In contrast to alternative methods that track carbon nanotubes by linking them covalently or noncovalently to external fluorophores or chelated radioisotopes (1,8,14), the near-IR fluor...

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Pegylated Arginine Deiminase Treatment of Patients With Unresectable Hepatocellular Carcinoma: Results From Phase I/II Studies

Cited by 227 publications

References 32 publications

Arginine Deprivation as a Targeted Therapy for Cancer

Arginine Deprivation as a Targeted Therapy for Cancer

Novel systemic therapy against malignant pleural mesothelioma

Mammalian pharmacokinetics of carbon nanotubes using intrinsic near-infrared fluorescence

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