RESUMO
PURPOSE: We investigated whether the determination of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TYMS) polymorphisms could predict the toxicity of 5-fluorouracil (5-FU) in colorectal cancer patients. EXPERIMENTAL DESIGN: The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy. Associations between these polymorphisms and toxicity were evaluated retrospectively. RESULTS: The Ala allele in OPRT Gly213Ala polymorphism and the two tandem repeats (2R) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea. The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [odds ratio, 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat (3R) alleles], whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea (odds ratio, 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype). A significant difference was observed in the time to onset of severe toxicity, defined as grade 4 neutropenia and/or grade 3 to 4 gastrointestinal toxicities according to OPRT and TYMS promoter polymorphisms. CONCLUSION: OPRT Gly213Ala polymorphism seems to be a useful marker for predicting toxicity to bolus 5-FU chemotherapy. Prospective translational treatment trials including larger number of patients are needed to confirm our results.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Orotato Fosforribosiltransferase/genética , Polimorfismo Genético , Adulto , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Regulação Enzimológica da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Orotato Fosforribosiltransferase/metabolismo , Valor Preditivo dos Testes , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Estudos Retrospectivos , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Resultado do TratamentoRESUMO
We evaluated the expression of 5-FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S-1 monotherapy as first line treatment. Five 5-FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real-time reverse transcriptional PCR method. Median values of each gene were selected for cut-off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S-1 chemotherapy.
Assuntos
Fluoruracila/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tegafur/uso terapêutico , Adulto , Idoso , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes of DNA de novo synthesis and the salvage pathway in cancer cells, respectively. Intratumoral TS and DPD gene expressions were evaluated to determine the correlation between the expression of the 2 genes in both normal stromal tissues and tissues with different degrees of malignant differentiation in primary gastric cancer. The study population consisted of 78 consecutive patients with advanced gastric cancer who underwent surgical treatment. Laser-captured microdissection of malignant or normal stromal tissues was performed in formalin-fixed, paraffin-embedded specimens. After extraction of RNA, TS and DPD gene expressions were measured by the real-time reverse transcriptional PCR method. Apart from degree of differentiation, TS and DPD in malignant tissue showed no correlation with clinicopathologic factors. TS in malignant tissue was higher in differentiated type cases than undifferentiated type cases (p < 0.01). However, DPD in malignant tissue of undifferentiated type cases was statistically higher than that of differentiated type cases (p < 0.05). In normal stromal tissue, neither TS nor DPD had any correlation with clinicopathologic factors. TS in malignant tissue was statistically higher than in normal stromal tissue in both differentiated and undifferentiated types (p < 0.0001). DPD in differentiated type malignant tissue was statistically lower than in normal stromal tissue (p < 0.001), but no difference was seen in undifferentiated type cases. TS and DPD gene expressions in primary gastric cancer differ according to degree of differentiation and between malignant and normal stromal tissue.
