SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/ 45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P ¼ 0.005). These results maintained the statistical significance in logistic regression analysis (P ¼ 0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1*28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1*28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1*28 polymorphism showed a trend to a poorer OS (P ¼ 0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1*28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.

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Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU).A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p ‫؍‬ 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI ‫؍‬ 1.03-5.6, p ‫؍‬ 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p ‫؍‬ 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p ‫؍‬ 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene. © 2004 Wiley-Liss, Inc. Key words: 5-FU resistance; TS-polymorphism; colorectal cancer; fluoropyrimidine chemotherapyA high proportion of colorectal cancer, which is a leading cause of cancer-related morbidity and mortality in the Western world, is diagnosed at advanced stages when chemotherapy is required for its management. 5-Fluorouracil (5-FU) is a folate-pathway inhibitor that has been available for 50 years, and continues to be a mainstay of treatment of advanced disease. 1 This drug is a fluoropyrimidine that, on activation to the nucleotide form, develops a stable complex with thymidylate synthase (TS), inhibiting the activity of the enzyme. 2 TS catalyzes the reductive methylation of dUMP by 5,10-methylenetetrahydrofolate to form dTNP, which is a critical reaction for cell proliferation. 3 Early in vitro studies have demonstrated more resistance to 5-FU of cell lines with high TS expression 4 or transfected with wild-type TS cDNA. 5 A number of studies have been published indicating that patients with high tumor levels of TS are unlikely to respond to infusion treatment with 5-FU, whereas patients with low levels have response rates that are higher than expected. 6 -13 The agreement between these...

Background:Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.Patients and methods:Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m−2 for the *1/*1, 110 mg m−2 for the *1/*28 and 90 mg m−2 for the *28/*28 genotypes.Results:The dose of irinotecan was escalated to 450 mg m−2 in patients with the *1/*1 genotype, to 390 mg m−2 in those with the *1/*28 genotype and to 150 mg m−2 in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.Conclusions:Our results demonstrated that the recommended dose of 180 mg m−2 for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m−2.