De Santo, C. et al. (2018) The arginine metabolome in Acute Lymphoblastic Leukemia can be targeted by the PEG-recombinant Arginase I BCT-100. International Journal of Cancer, 142(7), pp. 1490-1502. (doi: 10.1002/ijc.31170) (PMID:29168171) (PMCID:PMC5849425)
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Abstract
Arginine is a semi-essential amino acid that plays a key role in cell survival and proliferation in normal and malignant cells. BCT-100, a pegylated recombinant human arginase, can deplete arginine and starve malignant cells of the amino acid. Acute Lymphoblastic Leukemia is the most common cancer of childhood, yet for patients with high risk or relapsed disease prognosis remains poor. We show that BCT-100 is cytotoxic to ALL blasts from patients in vitro by necrosis, and is synergistic in combination with dexamethasone. Against ALL xenografts BCT-100 leads to a reduction in ALL engraftment and a prolongation of survival. ALL blasts express the arginine transporter CAT-1, yet the majority of blasts are arginine auxotrophic due to deficiency in either argininosuccinate synthase (ASS) or ornithine transcarbamylase (OTC). Although endogenous upregulation or retroviral transduced increases in ASS or OTC may promote ALL survival under moderately low arginine conditions, expression of these enzymes cannot prevent BCT-100 cytotoxicity at arginine depleting doses. RNA-sequencing of ALL blasts and supporting stromal cells treated with BCT-100 identifies a number of candidate pathways which are altered in the presence of arginine depletion. Therefore BCT-100 provides a new clinically-relevant therapeutic approach to target arginine metabolism in ALL. This article is protected by copyright. All rights reserved.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Cousins, Dr Antony and Halsey, Professor Chris |
| Authors: | De Santo, C., Booth, S., Vardon, A., Cousins, A., Tubb, V., Perry, T., Noyvert, B., Beggs, A., Ng, M., Halsey, C., Kearns, P., Cheng, P., and Mussai, F. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | International Journal of Cancer |
| Publisher: | Wiley |
| ISSN: | 0020-7136 |
| ISSN (Online): | 1097-0215 |
| Published Online: | 23 November 2017 |
| Copyright Holders: | Copyright © 2017 UICC |
| First Published: | First published in International Journal of Cancer 142(7):1490-1502 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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