PURPOSE: To study the efficacy of capecitabine or S-1 plus oxaliplatin (CAPOX or SOX) for treating thymidine phosphorylase (TP)- or dihydropyrimidine dehydrogenase (DPD)-positive advanced gastric cancer.MATERIALS AND METHODS: Eighty-six patients with stage IIIC to IV gastric cancer were assessed for TP and DPD expression by immunohistochemistry. The association between CAPOX or SOX efficacy and TP/DPD expression was retrospectively analyzed.RESULTS: There were no significant differences in the objective remission rate (ORR, 52.27% vs. 47.62%; P>0.05), disease control rate (72.73% vs. 73.81%, P>0.05), progression-free survival (hazard ratio [HR], 1.119; 95% confidence interval [CI], 0.739–1.741; P=0.586), and overall survival (OS; HR, 0.855; 95% CI, 0.481–1.511; P=0.588) between CAPOX and SOX. A higher number of stage IV patients showed TP positivity, while DPD-positive patients predominantly showed intestinal type of gastric cancer. In TP-positive patients, the ORRs associated with CAPOX and SOX treatments were 57.14% and 38.10%, respectively; OS was better with CAPOX than with SOX (HR, 0.447; 95% CI, 0.179–0.978; P=0.046). Among DPD-positive patients, the SOX treatment-associated ORR (60.87%) was significantly higher than the CAPOX treatment-associated ORR (43.48%). Furthermore, SOX treatment resulted in better OS than did CAPOX treatment (HR, 2.020; 95% CI, 1.019–4.837; P=0.049).CONCLUSIONS: No significant difference in clinical efficacy was found between CAPOX and SOX. TP-positive patients might respond better to CAPOX while DPD-positive patients may respond better to SOX. Our findings might serve as a guide for personalized chemotherapy for gastric cancer.
Capecitabine ; Dihydrouracil Dehydrogenase (NADP) ; Disease-Free Survival ; Drug Therapy ; Humans ; Immunohistochemistry ; Retrospective Studies ; Stomach Neoplasms ; Thymidine Phosphorylase ; Thymidine ; Treatment Outcome

OBJECTIVETo observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients.

METHODSA total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed.

RESULTSThe objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients.

CONCLUSIONSBoth CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.

Antineoplastic Agents ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Capecitabine ; administration & dosage ; adverse effects ; Capsules ; Dihydrouracil Dehydrogenase (NADP) ; metabolism ; Disease Progression ; Humans ; Neoplasm Proteins ; metabolism ; Organoplatinum Compounds ; administration & dosage ; adverse effects ; Oxonic Acid ; administration & dosage ; adverse effects ; Pyridines ; administration & dosage ; adverse effects ; Stomach Neoplasms ; drug therapy ; metabolism ; mortality ; pathology ; Tegafur ; administration & dosage ; adverse effects ; Thymidine Phosphorylase ; metabolism

OBJECTIVETo study the effect of Jianpi Liqi Recipe (JLR) on 5-fluorouracil (5-FU) relevant metabolic enzymes and CYP3A4 (the same enzyme of many chemotherapeutics) of mice with human gastric cancer transplanted tumor.

METHODSTotally 80 mice were randomly divided into the model group, the chemotherapy group, the JLR group, and the combination group (using chemotherapy combined JLR), 20 in each group. The human gastric cancer transplanted tumor mouse model was duplicated by hypodermic inoculating MKN-8 tumor cell suspension from the left armpit. Physiological saline or JLR was given to those in the model group or the JLR group at 0.25 mL each time, twice daily by gastrogavage from the 2nd day after transplantation. Mice in the chemotherapy group were given 0.25 mL physiological saline, twice daily by gastrogavage 2 days after transplantation, for 5 days in succession, and then they were peritoneal injected with 5-FU at the daily dose of 20 mg/kg, once daily for 5 days in succession from the 7th day of transplantation. Those in the combination were given 0.25 mL JLR, twice daily by gastrogavage, for 5 days in succession, and then they were peritoneal injected with 5-FU at the daily dose of 20 mg/kg, once daily for 5 days in succession from the 7th day of transplantation. The mRNA expressions of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and CYP3A4 were detected using RT-PCR.

RESULTSCompared with the model group and the chemotherapy group, mRNA expressions of TP and CYP3A4 obviously increased, mRNA expression of DPD obviously decreased in the JLR group and the combination group (P < 0.01). There was no statistical difference in mRNA expressions of TP, DPD, and CYP3A4 between the JLR group and the combination group (P > 0.05).

CONCLUSIONJLR could promote the activation of 5-FU, suppress the decomposition and inactivation of 5-FU in the tumor tissue of mice, and improve the chemotherapeutic efficacy through up-regulating mRNA expressions of TP and CYP3A4, and suppressing the mRNA expression of DPD.

Animals ; Cytochrome P-450 CYP3A ; genetics ; Dihydrouracil Dehydrogenase (NADP) ; genetics ; Drugs, Chinese Herbal ; pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Inbred Strains ; RNA, Messenger ; genetics ; Stomach Neoplasms ; enzymology ; genetics ; Thymidine Phosphorylase ; genetics ; Xenograft Model Antitumor Assays

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.
African Americans/genetics ; Alleles ; Amino Acids/metabolism ; Asian Continental Ancestry Group/genetics ; Dihydrouracil Dehydrogenase (NADP)/*genetics ; Ethnic Groups/*genetics ; European Continental Ancestry Group/genetics ; Fluorouracil/metabolism ; Gene Frequency ; Genotype ; Humans ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.
African Americans/genetics ; Alleles ; Amino Acids/metabolism ; Asian Continental Ancestry Group/genetics ; Dihydrouracil Dehydrogenase (NADP)/*genetics ; Ethnic Groups/*genetics ; European Continental Ancestry Group/genetics ; Fluorouracil/metabolism ; Gene Frequency ; Genotype ; Humans ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA

BACKGROUNDDihydropyrimidine dehydrogenase (DPD), a key enzyme involved in the catabolism of 5-fluorouracil (5-FU), is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene (DPYD) and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.

METHODSThree hundred and sixty-two patients with gastric cancer in the Chinese population were treated with fluorouracil-based adjuvant chemotherapy. The single nucleotide polymorphic genotypes of DPYD were determined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) using DNA samples isolated from peripheral blood collected before treatment.

RESULTSThe average response rate for chemotherapy was 46.7%. A significantly different distribution of the rs1801159 (c2=8.76, P=0.012) genotypes was observed. Homozygous genotype rs1801159A/A was over-represented in responsive patients. Conversely, carriers of the rs1801159A/G genotype were prevalent in non-responsive patients. In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (c2=3.96, P=0.0465).

CONCLUSIONSThese results suggest that polymorphisms of rs1801159 in DPYD may be used as valuable predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in the Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of DPYD as predictive markers for gastric cancer in response to fluorouracil-based therapies are warranted.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Chemotherapy, Adjuvant ; methods ; Dihydrouracil Dehydrogenase (NADP) ; genetics ; Female ; Fluorouracil ; therapeutic use ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; Stomach Neoplasms ; drug therapy ; genetics ; Treatment Outcome ; Young Adult

This study was purposed to detect single nucleotide polymorphisms (SNP) of 2 pharmacokinetics-related genes in K562 and K562/A02 cell lines. Leukemia cell line K562 and its resistant line K562/A02 were cultured, the genomic DNA was isolated by QIAamp DNA Blood Mini kit, primers were designed, the related DNA fragments were amplified by PCR. The SNP genotyping of mthfr gene rs1801131, rs1801133 and rs2274976 and dpyd gene rs1801159, rs1801160 and rs17376848 was performed by means of matrix assisted laser desorption ionization-time of flight mass spectrometry method (MALDI-TOFMS). The results showed that the genotype of mthfr gene locus 1801131 was AC, rs1801133 was CC, rs2274976 was GG, genotype of dpyd gene locus 1801159 was GG, rs1801160 was GG, rs17376848 was AA in both K562 and K562/A02 cell lines. It is concluded that the above-mentioned loci of mthfr and dpyd genes in K562 and K562/A02 cell lines are not expressed differently.
DNA Mutational Analysis ; DNA Primers ; Dihydrouracil Dehydrogenase (NADP) ; genetics ; Drug Resistance, Multiple ; genetics ; Drug Resistance, Neoplasm ; Genotype ; Humans ; K562 Cells ; Methylenetetrahydrofolate Reductase (NADPH2) ; genetics ; Polymorphism, Single Nucleotide

OBJECTIVETo detect the expression of dihydropyrimidine dehydrogenase (DPD) in pancreatic ductal adenocarcinoma (PDAC), and to investigate the relationships between DPD expression and the prognosis of PDAC.

METHODSImmunohistochemistry and tissue microarray techniques were used to exam the expression of DPD in the cancerous tissue in 156 patients admitted from January 2005 to December 2009, including 89 males and 67 females, with the age ranging from 35 to 81 years. The median age was 55 years.

RESULTSWith the positive rate of DPD 55.1%, the expression of DPD was correlated with the differentiation (P = 0.001), TNM staging of tumor (P = 0.021). No relationship was observed between the vessel invasion (P = 0.265), lymphatic metastasis (P = 0.123), neural invasion (P = 0.598) and DPD expression. In the follow-up 117 patients the overall median survival time was 14.2 months, in 58 cases expressed negative, the median survival time was 20.6 months; 39 cases expressed "+" and "++", the median survival time was 12.3 months; 20 cases expressed "+++", the median survival time was 6.8 months. The expression of DPD in pancreatic cancer was correlated with the prognosis of patients, those with higher expression pattern exhibited shorter survival time (P < 0.05). Univariate survival analysis revealed that DPD expression, TNM staging, lymphatic metastasis and neural invasion were factors related to prognosis (P < 0.05), while differentiation levels and vessel invasion were not. Multivariate survival analysis revealed that DPD expression (P = 0.002), lymphatic metastasis (P = 0.000) were two independent prognostic factors.

CONCLUSIONSThe expression levels of DPD was correlated to differentiation levels of pancreatic cancer and TNM staging; those with higher expression of DPD showed shorter survival time. DPD expression, lymphatic metastasis were independent prognostic factors for pancreatic cancer.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Pancreatic Ductal ; enzymology ; mortality ; Dihydrouracil Dehydrogenase (NADP) ; metabolism ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Pancreatic Neoplasms ; enzymology ; pathology ; Prognosis ; Survival Rate

A mixture of tegafur and uracil (TEGASIL) is a common antineoplastic agent. Tegafur is a fluoropyrimidine structurally similar to 5-fluorouracil (5-FU); uracil slows the degradation of 5-FU by dihydropyrimidine dehydrogenase, which results in higher 5-FU concentrations in tumors. Mucocutaneous side effects induced by this agent are rare and include photosensitivity of lichenoid and eczematous types, acral erythema, hyperpigmentation and palmoplantar keratoderma. However, there have been no reports of fixed drug eruption associated with TEGASIL. We report here on a case of fixed drug eruption due to oral TEGASIL.
Dihydrouracil Dehydrogenase (NADP) ; Drug Eruptions ; Erythema ; Fluorouracil ; Hyperpigmentation ; Keratoderma, Palmoplantar ; Tegafur ; Uracil

Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at risk for experiencing serious adverse effects following 5-fluorouracil (5-FU) based chemotherapy. Neurotoxicity is considered an extremely rare side effect of 5-FU. We report here on an unusual case of 5-FU induced encephalopathy. A 38-year-old woman with advanced gastric carcinoma was treated with adjuvant chemotherapy that consisted of infused 5-FU (1,000 mg/m2) for 5 days and cisplatin (60 mg/m2) on day 1 following total gastrectomy. Nineteen days after starting chemotherapy, the patient displayed a sudden onset of slurred speech, confusion, cognitive disturbances and paranoia. A magnetic resonance image (MRI) of the brain showed no structural abnormalities, and the other laboratory tests provided no explanations for her symptoms, other than a slightly elevated ammonia level. The patient was treated with a lactulose retention enema and thiamine infusion, the 5-FU was halted and her symptoms then recovered after 7 days.
Adult ; Ammonia ; Brain ; Chemotherapy, Adjuvant ; Cisplatin ; Dihydrouracil Dehydrogenase (NADP) ; Enema ; Female ; Fluorouracil ; Gastrectomy ; Humans ; Lactulose ; Magnetic Resonance Spectroscopy ; Paranoid Disorders ; Retention (Psychology) ; Thiamine