Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia

Abstract

A preliminary study has linked raised blast glutathione levels with chemoresistance in acute myeloid and lymphoblastic leukemia in adults and children. In this study, therefore, the relationship between leukemic blast glutathione levels and prognosis in childhood acute lymphoblastic leukemia (ALL) was investigated. A total of 77 childhood ALL samples were analyzed, 62 at initial presentation and 15 at relapse. A 20-fold interindividual variation in glutathione levels at presentation (median, 6.54 nmol/mg protein; range, 1.37 to 27.9) was demonstrated. The median level in T-lineage ALL was 2.3-fold higher than in B-lineage ALL (Mann-Whitney test, P < .0001). There was a significant correlation between presenting white cell count (WBC) and glutathione level (Spearman rank correlation coefficient, ‫؍‬ 0.45, P ‫؍‬ .001). A high DNA index correlated with low glutathione levels (MannWhitney test, P ‫؍‬ .013). There was no significant relationship between glutathione levels and in vitro drug sensitivity. Patients with glutathione levels above the median had a significantly greater risk of relapse (log-rank test statistic, 5.55; P ‫؍‬ .018), and the overall survival rate was significantly reduced (logrank test statistic, 4.38; P ‫؍‬ .04). Multivariate analysis demonstrated that glutathione concentration was of independent prognostic value when assessed in conjunction with age, gender, WBC, and immunophenotype. The association of elevated blast glutathione levels with an increased risk of relapse suggests that glutathione-depleting agents may be of therapeutic value in patients who present with a high WBC. (Blood. 2001;97:393-398)

Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patients

“…This finding supports the results of previous studies concerning various type of tumours (Goasguen et al, 1996;Buser et al, 1997;Howells et al, 1998;Kearns et al, 2001). For example, Buser et al (1997), in a series of 89 women with untreated breast cancer, found that high levels of Gst and Gpx activities were associated with favourable clinical characteristics and a good prognosis, whereas low levels of Gst activity were associated with more aggressive or more advanced disease, although the results did not reach the limit of statistical significance.…”

“…As GSTP1 is the major GSTs consistently expressed in both normal and tumour breast tissue (Forester, Carcinogenesis 1990;11: 2163-2170, it can be hypothesised that low GSTP1 expression would reduce the global activity of GSTs, and consequently reduce glutathione (GSH) consumption in GSTcatalysed reactions, thereby leading to higher levels of GSH, which would block apoptosis and promote proliferation of tumour cells. This hypothesis was first proposed by Kearns et al (2001), who reported an association between elevated GSH levels in leukaemia cells and an increased risk of relapse in childhood acute lymphoid leukaemia. Morales et al (2005) recently confirmed these results, by showing that intracellular glutathione levels determine cell sensitivity to drug-induced apoptosis.…”

Negative prognostic value of glutathione S-transferase(GSTM1 and GSTT1) deletions in adult acute myeloid leukemia

“…26,27 This concept is supported by data from a recent report in which high intracellular GSH levels in lymphoid blasts were correlated with greater risk of relapse and reduced overall survival in childhood ALL. 21 Interestingly, in the same study there was no relationship between glutathione levels and in vitro drug sensitivity. 21 The prognostic importance of the GST genotype was supported by our multivariate analysis, where the GST genotype was an independent predictor for overall survival.…”

“…21 Interestingly, in the same study there was no relationship between glutathione levels and in vitro drug sensitivity. 21 The prognostic importance of the GST genotype was supported by our multivariate analysis, where the GST genotype was an independent predictor for overall survival. In particular, GST genotyping could discriminate between favorable and unfavorable prognosis in the cytogenetically defined intermediate-risk group, which contains the majority of AML patients.…”

“…Expression of GST enzymes has been linked to in vitro and in vivo chemoresistance of tumor and leukemic cells. 21,22 One might expect that a GST deficiency caused by the null genotype results in better response to chemotherapy. In this line, Stanulla et al 23 showed a reduced risk of relapse in childhood B-cell acute lymphoblastic leukemia (ALL) patients having GSTM1 null or GSTT1 null genotype, whereas in the study of Chen et al, 6 no impact of GST genotypes was seen on patient response to therapy and outcome.…”