ATPS-51ESTABLISHING THE ROLE OF ARGININE DEPRIVATION WITH THE RECOMBINANT HUMAN ARGINASE PEG-BCT-100 IN THE TREATMENT OF ADULT GLIOMAS

Abstract

BACKGROUND: Arginine deprivation is a novel approach to limit arginine-dependent tumour growth. The presence of enzymes involved in the de novo synthesis of arginine from citrulline, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and ornithine transcarbamylase (OTC), can influence the sensitivity of tumour to arginine depletion. ASS1, ASL and OTC expressions have been previously described in pediatric gliomas, but such data is lacking in adults. We studied the efficacy of PEG-BCT-100 (also known as rhArg1peg5000), a PEGylated recombinant human arginase 1 on glioma cell lines. METHODS: Cells from 5 representative glioma cell lines (A172, M059J, M059K, T98G and U-87 MG) either incubated in full culture medium (control), arginine free medium or PEG-BCT-100 (1U/ml) treated medium. They were monitored by live cell imaging for 72 hours. Their corresponding IC50 were determined by cell viability assay. An analysis of ASS1, ASL and OTC expression in adult gliomas determined from archival samples. RESULTS: All cell lines were sensitive to PEG-BCT-100 and demonstrated significant cell proliferation inhibition. Their IC50, as determined by cell viability assay were 0.156 U/ml, 0.300 U/ml, 0.312 U/ml, 0.415 U/ml, and 0.522 U/ml for T98G, M059J, A172, U-87 MG and M059K respectively. In particular, cell death with both apoptosis and necrosis were observed in T98G, M059K and A172 cells. When cultured in arginine free medium, growth inhibition were only observed in M059J, M059K and T98G cells, indicating that these cells may be more auxotrophic to arginine. The determination of basal ASS1, ASL an OTC expression in 50 archival samples of adult gliomas is on-going. CONCLUSIONS: Arginine deprivation by PEG-BCT-100 is effective in suppressing glioma cell growth in vitro, suggesting arginine auxotrophism in gliomas. Identification of OTC, ASS and ASL expression levels in adult gliomas may potentially establish a role for these proteins as a predictive biomarker of response to arginine-deprivation therapy.