Article

Dihydropyrimidine dehydrogenases and cytidine-deaminase gene polymorphisms as outcome predictors in resected gastric cancer patients treated with fluoropyrimidine adjuvant chemotherapy

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Abstract

Single nucleotide polymorphisms of dihydropyrimidine dehydrogenases gene (DPYD) induces dihydropyrimidine dehydrogenase enzyme (DPD) deficiency resulting in increased activity of 5-fluorouracil derivatives. Cytidine-deaminase gene (CDA) polymorphisms have been involved in prognosis in experimental tumours. Analysis of 50 consecutive resected gastric cancer patients who received adjuvant chemotherapy with Tegafur for polymorphisms of genes DPYD1 (A/G; Ile543Val), DPYD2 (C/T; Arg29Cys) and CDA (A/C; Lys27Gin). The status of alleles (wild-type or at least one polymorphism) was correlated with outcome and toxicity. Polymorphisms frequencies wild-type/non-wild-type were 36/14 in DPYD1 (A/G; Ile543Val); 26/24 in DPYD2 (C/T; Arg29Cys); and 17/23 in CDA (A/C; Lys27Gin) or between homozygous/heterozygous were 39/11 in DPYD1; 33/17 in DPYD2 and 26/24 in CDA respectively. After 77 months of median follow-up (SD = 26.3), 18 patients died of tumour relapse. Better survival was observed in DPYD1 patients only, for non-wild-type over wild-type (P = 0.0214); and in patients with one or more heterozygous polymorphisms in any of the three genes tested (P = 0.0017). In 10 pts (20%) total dose was reduced by toxicity, only 3 of them were homozygous. Gene polymorphisms of DPYD and CDA predict survival of gastric cancer patients treated with 5-fluorouracil-based adjuvant chemotherapy.

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... A study conducted by Grau et al. [79] investigated the role of genetic variations in DPYD in place of looking at DPD expression, analyzing the prognostic value of genetic single nucleotide polymorphisms (SNPs) of intratumoral DPYD and CDA (cytidine-deaminase enzyme, which can influence the activity of TS) in patients with GC treated with adjuvant fluoropyrimidine (tegafur). SNP of DPYD1 (A/G; Ile453Val) was associated with better survival while the SNP (C/T; Arg29Cys) of DPYD2 showed a benefit in terms of relapse and survival if associated with the polymorphism of CDA (A/C; Lys27Gln) [79] . ...
... A study conducted by Grau et al. [79] investigated the role of genetic variations in DPYD in place of looking at DPD expression, analyzing the prognostic value of genetic single nucleotide polymorphisms (SNPs) of intratumoral DPYD and CDA (cytidine-deaminase enzyme, which can influence the activity of TS) in patients with GC treated with adjuvant fluoropyrimidine (tegafur). SNP of DPYD1 (A/G; Ile453Val) was associated with better survival while the SNP (C/T; Arg29Cys) of DPYD2 showed a benefit in terms of relapse and survival if associated with the polymorphism of CDA (A/C; Lys27Gln) [79] . ...
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Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.
... The type of chemotherapy was determined as follows: patients in the first-line setting with platinum-sensitive disease but ineligible for cisplatin (and who therefore could not be administered the combination of cisplatin, 5FU, and CTX) received carboplatin and weekly TXL as weekly administration has shown superiority [19]. Patients ineligible for carboplatin or patients treated in the second-line setting, after developing resistance to platinum, received a combination of TXL and CTX. ...
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The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m) and TXL (60-80 mg/m) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23-53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1-4.7 months] and the median OS was 7.6 months [95% CI; 5.3-9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.
... Some molecular or genetic changes have been reported to predict the sensitivity to chemotherapeutics, such as thymidylate synthase or dihydropyrimidine dehydrogenase for fluoropyrimidine [9][10][11], ERCC mRNA levels and the BMP4 epigenetic status for platinum-based chemotherapeutics [12,13], and β-tubulin III for paclitaxel [14]. Additionally, BRCA2 mutations may contribute to the sensitivity to platinum-based chemotherapies in gastric cancer patients [15]. ...
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... Regarding DPYD, the patient had c.496A > G homozygote variant (GG), which caused a deleterious conversion of methionine to valine (M166V), and also had a 85T > C homozygote (CC) variant, which resulted in a conversion of Cys29Arg. Polymorphisms in DPYD have an impact on the activity of the DPD enzyme that would also affect the clinical outcomes of patients treated with 5-FU-based chemotherapy [26]. Most of the studies evaluated the association of these variants with the toxicity of patients with CRC treated with 5-FU-based chemotherapy and have yielded unclear and conflicting results. ...
Article
Early relapse in colorectal cancer (CRC) after curative resection is mainly attributed to the key determinants such as tumor histology, stage, lymphovascular invasion, and the response to chemotherapy. Interindividual variability in the efficacy of adjuvant chemotherapy between patients receiving the same treatment may be ascribed to the patients’ genetic profile. In this report, we highlight a clinical case of a patient with stage II CRC who relapsed within a short period after starting adjuvant chemotherapy and was later found to have multiple genetic polymorphisms in the DPYD , TYMS, MTHFR , and DHFR genes. Based on the clinical data of the patient and the key role of these genes in 5-fluorouracil pathway, we hypothesize that these variants may contribute to the drug response and early relapse in CRC.
... 38,41,53,[164][165][166][167] Likewise, gene polymorphisms, in specifi c genes, have been associated with clinical outcome and response to treatment. [168][169][170] Additionally, specifi c antibodies against molecular targets are being investigated in clinical trials, such as ERBB2, epidermal growth-factor receptor and vascular endothelial growth factor. 171 In a review 172 of phase II studies integrating a targeted drug into chemotherapeutic regimens, objective response rates were 11-65% and time to progression was 2·5-16·0 months in patients with advanced gastric cancer. ...
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... related to outcome of patients operated for locally advanced gastric cancer and treated with adjuvant oral fluoropyrimidine chemotherapy along with a polymorphism of CDA (A/C [Lys27Gln])[59]. ...
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... This compares very favourably to median survival for similar patients treated with standard chemotherapy regimens which is generally less than one year [38,39] . In breast cancer, trastuzumab is associated with increased response rates and improved surgical outcomes when administered neoadjuvantly, and is curative in the adjuvant setting [40,41] . It is therefore a matter of regret that no registration study for trastuzumab was performed in conjunction with peri-operative chemotherapy for resectable gastroesophageal cancer, where up to 25% of patients with junctional cancers (who overexpress HER-2) could benefit [42] . ...
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... CDA SNPs did not influence OS in univariable analysis, but the interaction between CDA -31delC SNP and number of first-line chemotherapy cycles significantly influenced OS. In concordance with our results, others did not report any association of this SNP with tumor response, survival [45], and occurrence of treatment-related hematologic toxicity [46]. ...
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IntroductionClopidogrel and CYP2C19Codeine and CYP2D6Tamoxifen and CYP2D6Fluorouracil Prodrugs and CarboxylesteraseIrinotecan and Carboxylesterase 2OthersDrug Development ImplicationConclusions References
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Background: The fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Pharmacogenetics research could be useful for the identification of predictive markers in chemotherapy treatment. The aim of the study was to investigate the role of five genetic polymorphisms within two genes (DPYD, TYMS) in toxicity and efficacy of fluoropyrimidine-based chemotherapy. Methods: Total genomic DNA was extracted from 83 cancer patients treated with fluoropyrimidine-based chemotherapy. In this study, three polymorphisms were genotyped in dihydropyrimidine dehydrogenase gene c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798) and two polymorphisms, besides the Variable Number of Tandem Repeat (VNTR) polymorphism and 6-bp insertion/deletion polymorphism in thymidylate synthase gene. The analysis of polymorphisms for rs3918290, rs55886062, rs67376798 and 6-bp insertion/deletion in TYMS was done by Polymerase Chain Reaction-restriction Fragment Length Polymorphism (PCRRFLP) TYMS VNTR analysis. 5-FU-related toxicities such as anemia, febrile neutropenia, neurotoxicity, vomiting, nausea, and mucositis were evaluated according to NCI-CTC criteria version 4.0. T-test and chi-square were used and p-values less than 0.05 were considered statistically significant. Results: DPYD gene polymorphisms were not observed in this study. The frequency of the TYMS +6 bp allele was 40.35% and the -6 bp allele was 59.65% in this study. The frequency of VNTR 2R allele was 48.75% and 3R allele was 51.15%. Toxicity grade II diarrhea, mucositis, nausea, vomiting, and neurotoxicity was 2.2, 24.1, 15.7, 6, and 51.8%, respectively. Thymidylate synthase ins/del polymorphisms were associated with increased grade III neurotoxicity (p=0.02). Furthermore, anemia grade III was significantly associated with 2R/2R genotype (0.009). Conclusion: Thymidylate synthase gene polymorphisms may play a key role in fluoropyrimidne -based chemotherapy. Although rare DPYD polymorphisms were not observed in our study, according to large population studies, DPYD gene polymorphisms could be used as a predictive biomarker for patient treatments.
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A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).
Article
We found that vitamin D3 up-regulates the expression of cytidine deaminase (CDD) gene in some human solid tumor cell lines as well as the monocytic leukemia cell lines. Two kinds of full length CDD cDNA were identified from human placenta: one has glutamine and the other one has lysine at codon 27. The expression was tested in various normal tissues and the cancer cell lines. Northern blot analysis demonstrated high levels of CDD mRNA in leukocytes and moderate levels in liver, kidney, placenta, spleen and lung. Expression of CDD in 20 human cancer cell lines was highly variable and not related to its expression in normal tissues. Treatment of the cell lines with 1 α,25-dihydroxyvitamin D3 resulted in up-regulation of CDD expression in some lines but not others. Three of five gastric carcinoma cell lines and five of eight colorectal cancer lines had increased levels of CDD mRNA following 24 h treatment with vitamin D3. Increased mRNA was detected in gastric cancer MKN 45 cells after 3 h of treatment with vitamin D3 and increased enzyme activity was measured after 24 to 48 h. But no combined effect of calcitriol with 9-cis retinoic acid was found. Our results demonstrate that CDD can be up-regulated by vitamin D3 in some solid tumor cell lines.
Article
Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.
Article
We performed a clinical trial to determine whether postoperative adjuvant chemotherapy with two drugs versus one drug could prolong survival. From 1985 to 1996, 85 patients with completely resected locally advanced gastric cancer were enrolled. The subjects were randomized into two treatment groups, as follows: mitomycin (MMC) 10 to 20 mg/m2 intravenously (i.v.) on day 1 every 6 weeks plus ftorafur (FT) 500 mg/m2/d for 36 consecutive days; or MMC alone, 10 to 20 mg/m2 i.v. every 6 weeks. All courses were repeated four times. After a median follow-up duration of 62 months, the overall 5-year survival rates were 67% for the MMC-FT group versus 44% for the MMC group (P = .04). Subgroup analysis to compare survival curves using the method of Mantel-Cox showed survival rates significantly in favor of the MMC-FT group in the subsets of patients with node-negative disease (P = .01) and those whose disease was stage IB or II (P = .008). Significantly better survival results were observed for MMC-FT versus MMC alone. Subset analysis suggest a strong benefit in patients with node-negative and early-stage resected gastric cancer.
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Dihydrouracil dehydrogenase activity, with 5-fluorouracil used as the substrate, was measured in human tissues and leukemic cells. The liver had the highest enzyme activity (mean, 705 nmoles/g tissue/hr) with minimal activity found in the kidneys, spleen, lung, colon, colon tumors, pancreas, breast tissue, breast tumors, bone marrow cells, and peripheral leukemic cells. Wide variations in the enzyme activities were noted in samples collected from different subjects. 5-diazouracil inhibits the enzyme activity with the concentration required for inhibiting 50% (IC50) of the liver enzyme being 3 microM. Other compounds, thymine, thymidine, 6-methoxydiazouracil, and cyclo-5-diazouridine were also tested for their effect on this enzyme. With the exception of cyclo-5-diazouridine, all others produced inhibitory effect. The inhibitory effect of 6-methoxydiazouracil is similar to that of diazouracil. Thymidine and thymine are less active with identical values for IC50 of 80 microM.
Article
We found that vitamin D3 up-regulates the expression of cytidine deaminase (CDD) gene in some human solid tumor cell lines as well as the monocytic leukemia cell lines. Two kinds of full length CDD cDNA were identified from human placenta: one has glutamine and the other one has lysine at codon 27. The expression was tested in various normal tissues and the cancer cell lines. Northern blot analysis demonstrated high levels of CDD mRNA in leukocytes and moderate levels in liver, kidney, placenta, spleen and lung. Expression of CDD in 20 human cancer cell lines was highly variable and not related to its expression in normal tissues. Treatment of the cell lines with 1 alpha,25-dihydroxyvitamin D3 resulted in up-regulation of CDD expression in some lines but not others. Three of five gastric carcinoma cell lines and five of eight colorectal cancer lines had increased levels of CDD mRNA following 24 h treatment with vitamin D3. Increased mRNA was detected in gastric cancer MKN 45 cells after 3 h of treatment with vitamin D3 and increased enzyme activity was measured after 24 to 48 h. But no combined effect of calcitriol with 9-cis retinoic acid was found. Our results demonstrate that CDD can be up-regulated by vitamin D3 in some solid tumor cell lines.
Article
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism. Ethynyluracil (776C) is a very potent, mechanism-based irreversible DPD inhibitor that improves the antitumor efficacy and the therapeutic index of FU in laboratory animals. We tested the cytotoxic effects of the FU-776C combination on a panel of 12 human cancer cell lines (4 breast, 4 head and neck, 3 colon, and 1 duodenum). Basal DPD activity (radioenzymatic assay) and FU sensitivity [FU 50% inhibitory concentration (IC50), 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test] were determined. The FU potentiation by 776C was calculated from the ratio (F) of FU IC50 without 776C divided by FU IC50 with 776C. 776C was not cytotoxic to any of the cell lines tested. On CAL51 cell line expressing a high basal DPD activity, FU enhancement by 776C was a saturable phenomenon related to the 776C concentration; the inhibition of DPD increased between 10(-12) to 10(-6) M of 776C. For the following studies, 776C was tested at 10(-6) M. FU IC50 varied from 15 to 7770 microM among cell lines (median, 390 microM). Basal DPD activity ranged from not detectable (< pmol/min/mg protein) to 320 pmol/min/mg protein among cell lines (median, 53 pmol/min/mg protein). For the 12 cell lines tested, the mean F ranged from 0.7 (no enhancement of FU cytotoxicity by 776C) up to 5.2 and was significantly related to the basal DPD activity: the greater the DPD activity, the greater the FU enhancement factor (Spearman rank correlation, P = 0.019). Enhancement of FU cytotoxicity by 776C occurred only in the six cell lines expressing the greatest basal DPD activity (>50 pmol/min/mg protein, F ranging between 1.7 and 5. 2), whereas 776C did not modify FU cytotoxicity in the remaining cell lines expressing the lowest DPD activity (<50 pmol/min/mg protein, F ranging between 0.7 and 1.4). F was significantly different between these two groups of cell lines (P = 0.005). These results point out that DPD is an interesting target for FU pharmacomodulation.
Article
The cytidine deaminases belong to the family of multisubunit enzymes that catalyze the hydrolytic deamination of their substrate to a corresponding uracil product. They play a major role in pyrimidine nucleoside and nucleotide salvage. The intracellular distribution of cytidine deaminase and related enzymes has previously been considered to be cytosolic. Here we show that human cytidine deaminase (HCDA) is present in the nucleus. A highly specific, affinity purified polyclonal antibody against HCDA was used to analyze the intracellular localization of native HCDA in a variety of mammalian cells by in situ immunochemistry. Native HCDA was found to be present in the nucleus as well as the cytoplasm in several cell types. Indirect immunofluorescence microscopy indicated a predominantly nuclear localization of FLAG-tagged HCDA overexpressed in these cells. We have identified an amino-terminal bipartite nuclear localization signal that is both necessary and sufficient to direct HCDA and a non-nuclear reporter protein to the nucleus. We also show HCDA binding to the nuclear import receptor, importin alpha. Similar putative bipartite nuclear localization sequences are found in other cytidine/deoxycytidylate deaminases. The results presented here suggest that the pyrimidine nucleotide salvage pathway may operate in the nucleus. This localization may have implications in the regulation of nucleoside and nucleotide metabolism and nucleic acid biosynthesis.
Article
We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.
Article
Dihydropyrimidine dehydrogenase (DPD) activity in tumor cells has been suggested to be one of the factors determining the effectiveness of 5-fluorouracil (5-FU). In the present study, we analyzed DPD expression in tumors and investigated retrospectively the relationship between the efficacy of UFT (Tegafur + Uracil) as adjuvant chemotherapy and DPD expression in nonsmall-cell lung cancer (NSCLC). DPD expression of 166 resected p-stage I NSCLC was examined immunohistochemically. Patients who were administered UFT alone as adjuvant therapy comprised the UFT group (n = 54), and those who underwent only surgery comprised the control group (n = 112). DPD expression was categorized as either high or low, according to intensity of staining. DPD expression was high in 98 patients (59.0%) and low in 68 patients (41.0%). Patients with low-DPD tumors who were administered UFT had a significantly better prognosis than those who did not receive adjuvant treatment (P = 0.021). No significant difference was found between the two groups of patients with high-DPD tumors (P = 0.598). DPD expression may predict the efficacy of UFT after surgery for p-stage I NSCLC. A prospective study is needed to confirm the role of DPD expression as a predictor of UFT efficacy.
Article
Dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) gene expressions in metastatic colorectal cancer have been reported to be predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy. In this study, we investigated the association between both DPD and TS expressions in primary colorectal tumor and the antitumor effect in patients with metastatic colorectal cancer when treated with a fluoropyrimidine-based protocol. DPD and TS expressions were measured by reverse transcription-PCR in surgically resected materials of primary colorectal tumors from 37 patients who went on to receive oral treatment of uracil and tegafur and leucovorin for either synchronous or metachronous metastatic diseases. Relative mRNA amounts of DPD or TS were expressed as the ratios of targeted gene to glyceraldehyde-3-phosphate dehydrogenase reverse transcription-PCR products. Median values of DPD mRNA expressions were 0.30 and 0.65 for responding tumors and nonresponding ones, respectively, with a statistical significance (P < 0.0001). No responding tumor had a DPD mRNA expression >/= 0.5. A total of 19 tumors had low DPD mRNA expressions of <0.5, and 63% of them showed response. There was no responding tumor with both high DPD and high TS (TS mRNA expression >/= 1.0). However, the response rate was 75% in tumors with both low DPD and low TS. The median survival time was 16.3 months in patients with both low DPD and low TS versus 8.4 months in patients with high DPD or high TS mRNA expression. In conclusion, the combination of DPD and TS mRNA expressions in the primary tumor might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.
Article
We investigated dihydropyrimidine dehydrogenase (DPD) activity and its expression in breast cancer cases, and evaluated the prognostic significance of DPD expression in invasive breast cancer. A total of 49 paired of breast cancer tissues and the adjacent normal breast tissues were evaluated in this study. DPD expression of 191 patients with invasive breast cancer was also evaluated immunohistochemically. DPD activity in breast cancer ranged from 13.4-360.0 pmol/mg/min (mean, 162.9 pmol/mg/min). DPD activity in breast cancer tissues was significantly (p<0.001) higher than in adjacent normal breast tissue. DPD activity was significantly higher in DPD expression-positive tumors than DPD expression-negative tumors. The level of DPD activity was correlated with DPD expression. Patients with DPD expression-positive tumors had a significantly (p<0.05) poorer prognosis in disease-free survival compared to those with DPD-negative tumors. When evaluated in patients treated with 5-FU or 5-FU derivatives, DPD expression was a significantly (p<0.05) poorer prognostic factor in disease-free and overall survival. Using a Cox proportional hazards model, nodal status, ER status, and DPD expression were independent prognostic factors for both disease-free and overall survival. In conclusion, DPD expression may function as a marker of DPD activity and may be a prognostic indicator for patients with breast cancer.
Article
The large number of active combination chemotherapy regimens for most cancers has led to the need for better information to guide the 'standard' treatment for each patient. In an attempt to individualise therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) encompass the search for answers to the hereditary basis for interindividual differences in drug response. This review will focus on the results of studies assessing the effects of polymorphisms in drug-metabolising enzymes and drug targets on the toxicity and response to commonly used chemotherapy drugs. In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted.
Article
The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24-28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome.
Article
Although women who carry BRCA1 or BRCA2 mutations have up to an 85% lifetime risk of breast cancer, the majority choose to forego prophylactic mastectomy, which has been proven to markedly lower breast cancer mortality, and opt for lifelong intensive surveillance. Whether surveillance lowers breast cancer mortality in these women is unknown. However, in a formal survey of 34 of these women, 82% indicated a strong belief in the ability of surveillance to find breast cancer at a stage when it is still curable. Since 1997 we have been conducting a study to compare the sensitivity of breast magnetic resonance imaging (MRI), ultrasound, mammography and clinical breast examination (CBE) in women at high risk for hereditary breast cancer. Breast cancer incidence rates have been even higher than predicted for this population. The addition of MRI and ultrasound to conventional surveillance with mammography and CBE significantly improves sensitivity, but at the expense of decreased specificity. Two years ago we began a formal study of distress and breast cancer anxiety. A sample of 25 new and ongoing participants in the surveillance study have completed the Hospital Anxiety and Depression Scale together with the Breast Cancer Worry Scale, up to six times per year over a 2-year period. To date there has been no evidence of any impact of intensive surveillance, including false-positive studies, on anxiety, depression or breast cancer worry.
Article
The same doses of medication cause considerable heterogeneity in efficacy and toxicity across human populations. Genetic factors are thought to represent important determinants of drug efficacy and toxicity. Pharmacogenetics focuses on the prediction of the response of tumor and normal tissue to standard therapy by genetic profiling and, thereby, to select the most appropriate medication at optimal doses for each individual patient. In the present review, we discuss the relevance of single nucleotide polymorphisms (SNP) in genes, whose gene products act upstream of the actual drug target sites, that is, drug transporters and drug metabolizing phase I and II enzymes, or downstream of them, that is, apoptosis-regulating genes and chemokines. SNPs in relevant genes, which encode for proteins that interact with anticancer drugs, were also considered, that is, enzymes of DNA biosynthesis and metabolism, DNA repair enzymes, and proteins of the mitotic spindle. A significant body of evidence supports the concept of predicting drug efficacy and toxicity by SNP genotyping. As the efficacy of cancer chemotherapy, as well as the drug-related toxicity in normal tissues is multifactorial in nature, sophisticated approaches such as genome-wide linkage analyses and integrate drug pathway profiling may improve the predictive power compared with genotyping of single genes. The implementation of pharmacogenetics into clinical routine diagnostics including genotype-based recommendations for treatment decisions and risk assessment for practitioners represents a challenge for the future.
Article
We discuss recently published studies that elucidate the pathogenesis of AIDS-associated lymphoma. Several recent reports have provided valuable new information on the role of gamma-herpesviruses in the pathogenesis of AIDS-associated lymphoma. In addition to this, significant new information has become available on how B cell activation-associated DNA-modifying events, involving activation-induced cytidine deaminase and DNA polymerase-eta, contribute to the molecular lesions that result in AIDS-associated lymphoma. In particular, new evidence that oncogenic viruses can directly induce activation-induced cytidine deaminase expression and oncogene mutation in human B cells is of central relevance to better understanding the pathogenesis of AIDS-associated lymphoma. New information provides insights into the contributions of immune dysfunction and oncogenic virus infection to pathogenesis of AIDS-associated lymphoma, and may lead to new potential targets for therapeutic intervention in these cancers.
Chemoradiother-apy after surgery compared with surgery alone for adenocarci-noma of the stomach or gastroesophageal junction
  • Macdonald Js
  • Smalley
  • Sr
  • J Benedetti
Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiother-apy after surgery compared with surgery alone for adenocarci-noma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730.
Distribution and inhibition
  • Ho
  • Townsend L Dh
Ho DH, Townsend L, Luna MA, et al.: Distribution and inhibition
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction
  • J S Macdonald
  • S R Smalley
  • J Benedetti
Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-730.
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction
  • Macdonald