OBJECTIVE: Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported. PATIENTS AND METHODS: The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method. RESULTS: Thirty-three patients (12.4%) were heterozygous (26 were TPMT*1/*3A, 5 TPMT*1/*2, 2 TPMT *1/*3C) and 1 was a compound heterozygote (*2/*3A). Normal and low normal TPMT activities substantially overlapped in wild-type and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient. CONCLUSION: Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism.

• MeSH
• asparaginasa terapeutické užití   MeSH
• cyklofosfamid terapeutické užití   MeSH
• cytarabin terapeutické užití   MeSH
• daunomycin terapeutické užití   MeSH
• erytrocytární membrána enzymologie   MeSH
• genetické asociační studie MeSH
• idiopatické střevní záněty krev   MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk farmakoterapie   genetika   MeSH
• merkaptopurin terapeutické užití   MeSH
• methotrexát terapeutické užití   MeSH
• methyltransferasy nedostatek   genetika   metabolismus   MeSH
• mladiství MeSH
• polymerázová řetězová reakce MeSH
• prednison terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• vinkristin terapeutické užití   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH

BACKGROUND: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. METHODS: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. RESULTS: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. CONCLUSION: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.

• MeSH
• dakarbazin aplikace a dávkování   analogy a deriváty   MeSH
• dítě MeSH
• dospělí MeSH
• etoposid aplikace a dávkování   MeSH
• fenofibrát aplikace a dávkování   MeSH
• inhibitory angiogeneze aplikace a dávkování   MeSH
• isotretinoin aplikace a dávkování   MeSH
• kojenec MeSH
• lidé MeSH
• metronomické podávání léků MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory farmakoterapie   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   MeSH
• pyrazoly aplikace a dávkování   MeSH
• registrace MeSH
• studie proveditelnosti MeSH
• sulfonamidy aplikace a dávkování   MeSH
• vitamin D aplikace a dávkování   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

OBJECTIVES: The development of colorectal cancer (CRC) is characterized by multiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a subset of 481 sequences longer than 200 bp, which are absolutely conserved between orthologous regions of human, rat and mouse genomes, and are actively transcribed. It has recently been proven in cancer systems that differentially expressed T-UCRs could alter the functional characteristics of malignant cells. Genome-wide profiling revealed that T-UCRs have distinct signatures in human leukemia and carcinoma. METHODS: In our study, we examined the expression levels of uc.43, uc.73, uc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal carcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR. T-UCR expression levels were also correlated with commonly used clinicopathological features of CRC. RESULTS: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were significantly decreased in CRC tissue, and uc.73 indicated a positive correlation with overall survival (p = 0.0315). The lower expression of uc.388 was associated with the distal location of CRC (p = 0.0183), but no correlation of any evaluated T-UCR with clinical stage, grade and tumor diameter was observed. CONCLUSION: Our preliminary results suggest that uc.73 and uc.388 could be potential diagnostic and prognostic biomarkers in CRC patients.

• MeSH
• dospělí MeSH
• kolorektální nádory genetika   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• nekódující RNA analýza   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

For many years, therapy for metastatic renal cell carcinoma (mRCC) was limited to a single line of cytokine therapy with either interferon or interleukin-2. Relatively recently, the novel targeted agents bevacizumab, sorafenib, sunitinib and temsirolimus have each demonstrated activity in patients with mRCC that is refractory to cytokine therapy. Based on phase III trial data of patients who have received no prior therapy for mRCC, targeted agents have now rapidly replaced cytokines or, in the case of bevacizumab, are used in combination with interferon as first-line therapy for mRCC. Thus, second-line therapy for mRCC needs to be re-evaluated. Available data indicate that patients whose disease is refractory to a targeted agent may obtain, in some cases, benefit from a different agent, inhibiting either the same or a different pathway. With the availability of relatively few drugs for the treatment of mRCC, it is important to consider how to ensure that patients are obtaining maximum benefit through optimal use of the agents available. The definition of whether second-line therapy is active and tolerable and which therapy should be used in this setting in individual patients, particularly taking into account prior therapy, will therefore be important in defining the general therapeutic strategy in patients with mRCC. Copyright 2009 S. Karger AG, Basel.

• MeSH
• financování organizované MeSH
• indoly terapeutické užití   MeSH
• interferon alfa terapeutické užití   MeSH
• interleukin-2 terapeutické užití   MeSH
• karcinom z renálních buněk farmakoterapie   patologie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky terapeutické užití   MeSH
• nádory ledvin farmakoterapie   patologie   MeSH
• pyrroly terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

OBJECTIVES: SNP309 polymorphism (T-G) at the promoter region of MDM2 has been reported to cause increased binding affinity of transcriptional activator Sp1 followed by increased MDM2 both in mRNA and protein level. This model was proposed in vitro in the small panel of cell lines that indicated an on average 8-fold higher level of MDM2 mRNA in cells bearing the GG genotype. METHODS: The incidence of SNP309 was determined in a cohort of 158 breast, 17 endometrium, 13 cervix and 45 ovarian cancer tissues by PCR-RFLP. The expression of p53 and MDM2 protein levels in the cohort was immunohistochemically investigated and statistically correlated with SNP309 polymorphism using Pearson chi(2) and t test. RESULTS: No significant difference was observed in the G allele incidence in breast cancer specimens compared to 149 noncancer controls. Furthermore, no statistically significant association of the G allele frequencies and p53 and MDM2 protein expression levels was observed. CONCLUSIONS: Our data clearly show neither association between SNP309 and cancer risk, nor the responsibility of G allele for increased MDM2 or decreased of p53 protein levels in human primary breast tumors.

• MeSH
• alely MeSH
• dospělí MeSH
• financování organizované MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory prsu genetika   metabolismus   MeSH
• nádory ženských pohlavních orgánů genetika   metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH

OBJECTIVES: Development and metastases of colorectal cancer (CRC) are characterized by multiple genetic alterations. MicroRNAs (miRNAs) are endogenously expressed regulatory noncoding RNAs. Previous, mainly preclinical studies showed altered expression levels of several miRNAs in CRC. METHODS: In our study, the expression levels of miR-21, miR-31, miR-143 and miR-145 in 29 primary colorectal carcinomas and 6 non-tumor adjacent tissue specimens were examined by real-time polymerase chain reaction. miRNA expression levels were also correlated with commonly used clinicopath-ologic features of CRC. RESULTS: Expression levels of analyzed miRNAs significantly differed among tumors and adjacent non-tumor tissues: miR-21 (p = 0.0001) and miR-31 (p = 0.0006) were upregulated, and miR-143 (p = 0.011) and miR-145 (p = 0.003) were downregulated in tumors. For the first time, a high expression of miR-21 was associated with lymph node positivity (p = 0.025) and the development of distant metastases (p = 0.009) in CRC patients. Thus, expression of miR-21 correlated with CRC clinical stage (p = 0.032). Furthermore, tumors >50 mm in maximal tumor diameter were characterized by lower expression of miR-143 (p = 0.006) and miR-145 (p = 0.003). We found no correlation between analyzed miRNAs and serum levels of carcinoembryonic antigen. CONCLUSION: Our results suggest possible roles of miR-21, miR-31, miR-143 and miR-145 in CRC. (c) 2008 S. Karger AG, Basel

• MeSH
• financování organizované MeSH
• klinické zkoušky jako téma MeSH
• kolorektální nádory genetika   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• srovnávací studie MeSH

Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well. Copyright (c) 2005 S. Karger AG, Basel.

• MeSH
• akutní lymfatická leukemie farmakoterapie   krev   metabolismus   MeSH
• antagonisté kyseliny listové aplikace a dávkování   škodlivé účinky   MeSH
• antimetabolity antitumorózní aplikace a dávkování   škodlivé účinky   MeSH
• dítě MeSH
• financování organizované MeSH
• homocystein krev   účinky léků   MeSH
• kyselina listová krev   účinky léků   MeSH
• lidé MeSH
• metabolické nemoci mozku chemicky indukované   metabolismus   MeSH
• methotrexát aplikace a dávkování   škodlivé účinky   MeSH
• mozek metabolismus   účinky léků   MeSH
• rozvrh dávkování léků MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH

• MeSH
• dítě MeSH
• dospělí MeSH
• kalcitonin krev   MeSH
• karcinom krev   MeSH
• lidé MeSH
• mladiství MeSH
• nádory štítné žlázy krev   MeSH
• radioimunoanalýza MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH