Arginine Deiminase PEG20 Inhibits Growth of Small Cell Lung Cancers Lacking Expression of Argininosuccinate Synthetase

Overview

Journal Br J Cancer

Specialty Oncology

Date 2011 Dec 3

PMID 22134507

Citations 62

Authors

M P Kelly

A A Jungbluth

B-W Wu

J Bomalaski

L J Old

G Ritter

Affiliations

Soon will be listed here.

Abstract

Background: Some cancers have been shown to lack expression of argininosuccinate synthetase (ASS), an enzyme required for the synthesis of arginine and a possible biomarker of sensitivity to arginine deprivation. Arginine deiminase (ADI) is a microbial enzyme capable of efficiently depleting peripheral blood arginine.

Methods: Argininosuccinate synthetase expression was assessed in human small cell lung cancer (SCLC) by immunohistochemistry (IHC), with expression also assessed in a panel of 10 human SCLC by qRT-PCR and western blot. Proliferation assays and analyses of apoptosis and autophagy assessed the effect of pegylated ADI (ADI-PEG20) in vitro. The in vivo efficacy of ADI-PEG20 was determined in mice bearing SCLC xenografts.

Results: Approximately 45% of SCLC tumours and 50% of cell lines assessed were negative for ASS. Argininosuccinate synthetase-deficient SCLC cells demonstrated sensitivity to ADI-PEG20, which was associated with the induction of autophagy and caspase-independent cell death. Arginine deiminase-PEG20 treatment of ASS-negative SCLC xenografts caused significant, dose-dependent inhibition of tumour growth of both small and established tumours.

Conclusion: These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated.

Citing Articles

Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer.

Yu T, Lok B Cancers (Basel). 2024; 16(20).

PMID: 39456533 PMC: 11506711. DOI: 10.3390/cancers16203438.

Enhanced anti-cancer efficacy of arginine deaminase expressed by tumor-seeking Salmonella Gallinarum.

Duysak T, Kim K, Yun M, Jeong J, Choy H Oncogene. 2024; 43(46):3378-3387.

PMID: 39322639 DOI: 10.1038/s41388-024-03176-0.

Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities.

Zhang J, Zeng X, Guo Q, Sheng Z, Chen Y, Wan S Exp Hematol Oncol. 2024; 13(1):78.

PMID: 39103941 PMC: 11301971. DOI: 10.1186/s40164-024-00548-w.

Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies.

Ng J, Cai L, Girard L, Prall O, Rajan N, Khoo C Clin Cancer Res. 2024; 30(9):1846-1858.

PMID: 38180245 PMC: 11061608. DOI: 10.1158/1078-0432.CCR-23-2360.

A pan-cancer analysis of the role of argininosuccinate synthase 1 in human tumors.

Ding Q, Li R, Wang Q, Yu L, Zi F Front Oncol. 2023; 13:1049147.

PMID: 38053661 PMC: 10694447. DOI: 10.3389/fonc.2023.1049147.

References

Dillon B, Prieto V, Curley S, Ensor C, Holtsberg F, Bomalaski J . Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer. 2004; 100(4):826-33. DOI: 10.1002/cncr.20057. View

Nicholson L, Smith P, Hiller L, Szlosarek P, Kimberley C, Sehouli J . Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. Int J Cancer. 2009; 125(6):1454-63. DOI: 10.1002/ijc.24546. View

Lu S, Hoestje S, Choo E, Epner D . Induction of caspase-dependent and -independent apoptosis in response to methionine restriction. Int J Oncol. 2003; 22(2):415-20. View

Kim R, Bold R, Kung H . ADI, autophagy and apoptosis: metabolic stress as a therapeutic option for prostate cancer. Autophagy. 2009; 5(4):567-8. PMC: 4294541. DOI: 10.4161/auto.5.4.8252. View

Shen L, Lin W, Beloussow K, Shen W . Resistance to the anti-proliferative activity of recombinant arginine deiminase in cell culture correlates with the endogenous enzyme, argininosuccinate synthetase. Cancer Lett. 2003; 191(2):165-70. DOI: 10.1016/s030-43835(02)00693-6. View

Steiger-Barraissoul S, Rami A . Serum deprivation induced autophagy and predominantly an AIF-dependent apoptosis in hippocampal HT22 neurons. Apoptosis. 2009; 14(11):1274-88. DOI: 10.1007/s10495-009-0396-9. View

Dowell J . Small cell lung cancer: are we making progress?. Am J Med Sci. 2009; 339(1):68-76. DOI: 10.1097/MAJ.0b013e3181bccef5. View

Ni Y, Schwaneberg U, Sun Z . Arginine deiminase, a potential anti-tumor drug. Cancer Lett. 2008; 261(1):1-11. DOI: 10.1016/j.canlet.2007.11.038. View

Delage B, Fennell D, Nicholson L, McNeish I, Lemoine N, Crook T . Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010; 126(12):2762-72. DOI: 10.1002/ijc.25202. View

10.

Feun L, You M, Wu C, Kuo M, Wangpaichitr M, Spector S . Arginine deprivation as a targeted therapy for cancer. Curr Pharm Des. 2008; 14(11):1049-57. PMC: 3096551. DOI: 10.2174/138161208784246199. View

11.

Takaku H, Takase M, Abe S, Hayashi H, Miyazaki K . In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. Int J Cancer. 1992; 51(2):244-9. DOI: 10.1002/ijc.2910510213. View

12.

Holtsberg F, Ensor C, Steiner M, Bomalaski J, Clark M . Poly(ethylene glycol) (PEG) conjugated arginine deiminase: effects of PEG formulations on its pharmacological properties. J Control Release. 2002; 80(1-3):259-71. DOI: 10.1016/s0168-3659(02)00042-1. View

13.

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005; 5(9):726-34. DOI: 10.1038/nrc1692. View

14.

Yang T, Lu S, Chao Y, Sheen I, Lin C, Wang T . A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer. 2010; 103(7):954-60. PMC: 2965867. DOI: 10.1038/sj.bjc.6605856. View

15.

Kim J, Kim J, Yu Y, Kim D, Min B, Kim K . Anti-tumor activity of arginine deiminase via arginine deprivation in retinoblastoma. Oncol Rep. 2007; 18(6):1373-7. View

16.

Feun L, Savaraj N . Pegylated arginine deiminase: a novel anticancer enzyme agent. Expert Opin Investig Drugs. 2006; 15(7):815-22. PMC: 3086545. DOI: 10.1517/13543784.15.7.815. View

17.

Sugimura K, Ohno T, Kusuyama T, Azuma I . High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro. Melanoma Res. 1992; 2(3):191-6. DOI: 10.1097/00008390-199209000-00007. View

18.

Shen L, Shen W . Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers. Curr Opin Mol Ther. 2006; 8(3):240-8. View

19.

Shen L, Beloussow K, Shen W . Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase. Cancer Lett. 2005; 231(1):30-5. DOI: 10.1016/j.canlet.2005.01.007. View

20.

Demedts I, Vermaelen K, Van Meerbeeck J . Treatment of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J. 2010; 35(1):202-15. DOI: 10.1183/09031936.00105009. View