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Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Downregulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p 5 0.01) and relapsefree survival (p 5 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p 5 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. ' UICCKey words: argininosuccinate synthetase (ASS1); methylation; chemotherapy; ovarian cancer Epigenetic inactivation, frequently occurring via methylationdependent transcriptional silencing, is a common mechanism of inactivation of tumour suppressor genes in cancer.1 Numerous genes have now been described as targets for epigenetic inactivation in human cancer. Despite comprehensive expression profiling of human cancers, which has provided valuable information with relevance to staging and prognosis in different tumour types, relatively little information exists correlating epigenetic inactivation of individual genes or panels of genes with defined clinical endpoints. The studies that have been published clearly show that analysis of specific gene methylation status can have utility in prediction of clinically important parameters such as metastasis, sensitivity/resistance phenomena in chemotherapy-treated cancers and outcome.2,3 The heritability of methylation and the relative biological and chemical stability of 5 0 methyl cytosine suggest that detection of methylated genomic DNA may have several advantages as a robust biomarker for cancer and cancer-associated phenotypes.Ovarian cancer is in many cases a chronic disease, characte...

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