Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy

Naoe, Tomoki; Tagawa, Y.; Kiyoi, Hitoshi; Kodera, Yoshihisa; Miyawaki, Shuichi; Asou, Norio; Kuriyama, Kazutaka; Kusumoto, S; Shimazaki, Chihiro; Saito, Kenji; Akiyama, Hideki; Motoji, Toshiko; Nishimura, Miki; Shinagawa, Katsuji; Ueda, Ryuzo; Saito, Hidehiko; Ohno, Ryuzo

doi:10.1038/sj.leu.2402361

Cited by 62 publications

(21 citation statements)

References 21 publications

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“…Our results are consistent with some recent studies but in acute myeloid leukaemia (AML) suggesting that the lack of the GSTT1 gene implies greater toxicity in these patients (25)(26)(27). Similar observations have been made in lung cancer (28).…”

Section: Discussionsupporting

confidence: 93%

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients

Romero¹,

Morales²,

Garcia³

et al. 2006

Oncol Rep

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Abstract.Our aim was to evaluate the role of C-69T in GSTA1, Ile105Val in GSTP1, null allele in GSTT1 and GSTM1 in the prediction of toxicity in patients treated with 5-Fu/CPT-11/Lv regimens in metastatic CRC patients. Fiftyone patients with CRC metastatic disease were analysed. All patients had bidimensionally measurable disease according to WHO criteria. The gender distribution was 37 (74%) males and 13 (26%) females; age ranged from 41 to 71 years; performance status was in all patients ≥80 (Karnofsky index). The analysis of gene polymorphism was performed in lymphocytes by using PCR-RFLP (GSTA1, GSTP1), PCR (GSTT1, GSTM1) and sequencing analysis (UGT1A1 * 28). An appreciable significant association was observed between the GSTT1-null and toxicity: 57% developed gastrointestinal toxicity grade III versus 23% of patients with GSTT1-present genotype (p=0.053). The other polymorphisms analysed did not show any significant relation with toxicity. Our data suggest that GSTT1-null is associated with a greater probability of developing toxicity to 5-Fu/CPT-11/Lv treatments, indicating a potential application of this genetic analysis in predicting adverse effects of this regimen.Introduction 5-Fluouracil (5-FU) has been the mainstay of treatment for patients with advanced colorectal cancer (CRC) for more than five decades. Irinotecan (CPT-11) has been found to demonstrate at least equivalent efficacy to 5-FU in first-line therapy, favorable quality-of-life assessments and prolonged median survival (1,2). In Europe as well as in the USA, the combination of 5-FU plus CPT-11 is currently recommended as first-line therapy for metastatic CRC treatment (3,4). Risk factors with predictive value for toxicity have been identified in several studies. In this sense, age, performance status, bilirubinaemia, the genetic polymorphism of UDP-glucuronyltransferase-1A1 (UGT1A1) and the drug administration schedule have been show to be related with CPT-11 toxicity (5). Inter-individual differences in the pharmacokinetics of its active metabolite, SN-38, cause the variations in the effect of the drug (6). Several studies in relation with different doses and schedules of CPT-11 alone or in combination with other agents are ongoing to investigate its use as first or secondline therapy (7,8), with a view to optimising the therapeutic outcome for these patients.On the other hand, Glutathione S-transferases (GSTs) are considered an important family of detoxifying enzymes for mutagens. They protect cellular macromolecules from damage by catalysing the conjugation of toxic and carcinogenic electrophilic molecules with glutathione. The resulting complex is less toxic and more readily excreted.The implication of GSTs in the detoxification of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) and other carcinogens has been related to GST gene alterations with colorectal cancer risk (9,10). Diverse common single nucleotide polymorphisms (SNPs) have been reported for GSTT1, GSTM1, GSTA1 and GSTP1 genes that either abolish, incr...

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Section: Discussionsupporting

confidence: 93%

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients

Romero¹,

Morales²,

Garcia³

et al. 2006

Oncol Rep

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“…A larger study conducted by the Children's Oncology Group in Ͼ600 children found no association between GSTM1 or GSTT1 polymorphisms and survival in childhood acute lymphoblastic leukemia (51). In children with acute myeloid leukemia, two different groups reported a significant relationship between increased risk for death due to toxicity and GSTT1 null genotype (52,53). In a study of Ͼ200 women with primary breast cancer, GSTT1 and GSTM1 null, and GSTP1 *B or *C variants were related to superior outcome (36,38).…”

Section: Discussionmentioning

confidence: 98%

Glutathione S -Transferase Polymorphisms and Survival in Primary Malignant Glioma

Okcu

Selvan²,

Wang³

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of this research was to investigate the relationship between glutathione S-transferase (GST) polymorphisms and survival, and chemotherapy-related toxicity in 278 glioma patients.Experimental Design: We determined genetic variants for GSTM1, GSTT1, and GSTP1 enzymes by PCR and restriction fragment length polymorphisms. We conducted Kaplan-Meier and Cox-proportional hazard analyses to examine whether the GST polymorphisms are related to overall survival, and logistic regression analysis to explore whether the GST polymorphisms are associated with toxicity.Results: For patients with anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma (n ‫؍‬ 78), patients with GSTP1*A/ *A-M1 null genotype survived longer than did the rest of the group (median survival "not achieved," and 41 months, respectively; P ‫؍‬ 0.06). Among patients treated with nitrosoureas (n ‫؍‬ 108), those with GSTP1*A/*A and GSTM1 null genotype were 5.7 times (95% confidence interval, 0.9 -37.4) more likely to experience an adverse event secondary to chemotherapy, compared with the others.Conclusions: In patients with anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, combination of germ-line GSTP1*A/*A and GSTM1 null genotype confers a survival advantage. Patients with this genotype also have an increased risk of adverse events secondary to chemotherapy that primarily comprised nitrosourea alkylating agents.

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“…The glutathione S-transferases (GSTs) have been implicated as susceptibility genes for a number of cancers. The homozygous deletions of GSTT1 [GSTT1(Ϫ)] group had a worse prognosis than either the homozygous or heterozygous for GSTT1 [GSTT1(ϩ)] group in acute myeloid leukemia (42). On the other hand, the GSTT1(Ϫ) genotype conferred the reduction in risk of relapse compared to the GSTT1(ϩ) in children with acute lymphoblastic leukemia (43,44).…”

Section: Discussion Differentially Expressed Genes In Each Type Of Nsmentioning

confidence: 99%

Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis

Sugimura

Foster

Cummings³

et al. 2004

Clinical Cancer Research

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Purpose: To better understand the molecular mechanisms that underlay the development and progression of nonseminomatous germ cell tumor of testis (NSGCTT) as well as malignant transformation of teratoma and primitive neuroectodermal tumor (PNET).Experimental Design: We studied the gene expression profiles of 17 retroperitoneal NSGCTTs (10 yolk sac tumors, 3 embryonal carcinomas, 4 teratomas) and 2 PNETs obtained from patients with two clinical outcomes. Tissue samples were obtained from the Indiana University. One group of NSGCTT and PNET patients developed metastases within 2 years (early-relapse) of initial successful treatment, and the other group developed metastases after 2 years (late-relapse). Gene expression in these groups of patients was quantified using cDNA microarrays and real-time relative quantitative PCR.Results: We demonstrate that the gene expression profiles of these tumors correlate with histological type. In addition, we identify type-specific genes that may serve as novel diagnostic markers. We also identify a gene set that can distinguish between early-relapse and late-relapse yolk sac tumors. The expression differences of these genes may underlie the differences in clinical outcome and drug response of these tumors.Conclusion: This is the first study that used gene expression profiling to examine the molecular characteristics of the NSGCTTs and drug response in early-and laterelapse tumors. These results suggest that two molecularly distinct forms of NSGCTTs exist and that the integration of expression profile data with clinical parameters could enhance the diagnosis and prognosis of NSGCTTs. More importantly, the identified genes provide insight into the molecular mechanisms of aggressive NSGCTTs and suggest intervention strategies.

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Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy

Cited by 62 publications

References 21 publications

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients

Glutathione S -Transferase Polymorphisms and Survival in Primary Malignant Glioma

Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis

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