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

Abstract

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...

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer

“… 22 A few studies find a correlation between UGT1A1 * 28 and diarrhoea 9 , 17 , 23 , 24 or severe toxicity in general, 24 , 25 whereas others find no correlation with toxicity at all. 26 , 27 …”

Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review

“…Colorectal cancer has been divided into different molecular subtypes based on gene expression profiling. The success of PK dose adjustment is likely to vary by molecular subtype as an association between genotypes and outcomes could be shown [ 56 – 58 ]. With increasing use of genetic profiling, certain cohorts may be defined who would benefit more from PK testing.…”

Predictive diagnostics in colorectal cancer: impact of genetic polymorphisms on individual outcomes and treatment with fluoropyrimidine-based chemotherapy

“…These findings indicated that the null allele in GSTT1 gene might be considered as a new marker when the treatment schedule is administered to metastatic colorectal cancer patients. Besides, the other polymorphisms analysed in that study did not refer to toxicity [ 72 ]. In addition, the neurotoxicity of patients with advanced colorectal cancer treated with a chemotherapy of 5-FU, oxaliplatin and folinic acid was reported to be significantly associated with the 105Ile/Val polymorphism in GSTP1.…”