An increasing resistance of mammalian tumor cells to chemotherapy along with the severe side effects of commonly used cytostatics has raised the urgency in the search for new anti-cancer agents. Several drugs originally approved for indications other than cancer treatment have recently been found to have a cytostatic effect on cancer cells. These drugs could be expediently repurposed as anti-cancer agents, since they have already been tested for toxicity in humans and animals. The groups of newly recognized potential cytostatics discussed in this review include benzimidazole anthelmintics (albendazole, mebendazole, flubendazole), anti-hypertensive drugs (doxazosin, propranolol), psychopharmaceuticals (chlorpromazine, clomipramine) and antidiabetic drugs (metformin, pioglitazone). All these drugs have a definite potential to be used especially in combinations with other cytostatics; the chemotherapy targeting of multiple sites now represents a promising approach in cancer treatment. The present review summarizes recent information about the anti-cancer effects of selected drugs commonly used for other medical indications. Our aim is not to collect all the reported results, but to present an overview of various possibilities. Advantages, disadvantages and further perspectives regarding individual drugs are discussed and evaluated.

• MeSH
• anthelmintika terapeutické užití   MeSH
• antihypertenziva terapeutické užití   MeSH
• cytostatické látky terapeutické užití   MeSH
• hypoglykemika terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• přehodnocení terapeutických indikací léčivého přípravku * MeSH
• protinádorové látky terapeutické užití   MeSH
• psychotropní léky terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• anthelmintika MeSH
• antihypertenziva MeSH
• cytostatické látky MeSH
• hypoglykemika MeSH
• protinádorové látky MeSH
• psychotropní léky MeSH

Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest.

• Klíčová slova
• anti-cancer medications, cell-based medicinal products, dendritic cells, investigator-initiated clinical trial, manufacturing outcome variability, neuroblastoma, sarcoma,
• Publikační typ
• časopisecké články MeSH

Patients with metastatic urothelial carcinoma (mUC) are typically elderly and often have other comorbidities that require the use of concomitant medications. In our study we evaluated the association of concomitant use of antibiotics (ATBs), proton pump inhibitors (PPIs), corticosteroids, statins, metformin and insulin with patient outcomes and we validated the prognostic role of a concomitant drug score in mUC patients treated with enfortumab vedotin (EV) monotherapy. Data from 436 patients enrolled in the ARON-2EV retrospective study were analyzed according to the concomitant medications used at baseline. Finally, the patients were stratified into three risk groups according to the concomitant drug score based on ATBs, corticosteroids and PPIs. Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Inferior survival outcomes were observed in ATB users compared to non-users (OS: 7.3 months, 95%CI 5.0 - 12.3 vs 13.7 months, 95%CI 12.2 - 47.3, p = 0.001; PFS: 5.1 months 95%CI 3.3 - 17.7 vs 8.3 months, 95%CI 7.1 - 47.3, p = 0.001) and also in corticosteroid users compared to non-users (OS: 8.4 months, 95%CI 6.6 - 10.0 vs 14.2 months, 95%CI 12.7 - 47.3, p < 0.001; PFS: 6.0 months 95%CI 4.6 - 7.9 vs 8.9 months, 95%CI 7.2 - 47.3, p = 0.004). In the Cox multivariate analysis, the concomitant drug score was a significant factor predicting both OS (HR = 1.32 [95% CI 1.03 - 1.68], p = 0.026) and PFS (HR = 1.23 [95% CI 1.01 - 1.51], p = 0.044). Our findings suggest detrimental impact of concomitant use of ATBs and corticosteroids on survival outcomes and the prognostic utility of the concomitant drug score in previously treated mUC patients receiving EV.

• Klíčová slova
• ARON-2EV study, Antibiotics, Concomitant drug score, Concomitant medication, Corticosteroids, Enfortumab vedotin, NCT05290038, Urothelial cancer,
• MeSH
• antibakteriální látky terapeutické užití   MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• inhibitory protonové pumpy terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   sekundární   patologie   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální protilátky * terapeutické užití   MeSH
• nádory močového měchýře farmakoterapie   patologie   mortalita   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   patologie   mortalita   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• antibakteriální látky MeSH
• enfortumab vedotin MeSH Prohlížeč
• hormony kůry nadledvin MeSH
• inhibitory protonové pumpy MeSH
• monoklonální protilátky * MeSH

Quantitative Phase Imaging is becoming an important tool in the objective evaluation of cellular responses to experimental treatment. The technique is based on interferometric measurements of the optical thickness of cells in tissue culture reporting on the distribution of dry mass inside the cells. As the measurement of the optical thickness is interferometric, it is not subjected to the Abbe resolution limit, and the use of an incoherent-light source further increases the accuracy practically achieving 0.93nm in optical path difference corresponding to 4.6 femtograms/μm2. Holographic mode reduces the exposure in comparison to phase-shifting or phase-stepping interference microscopy and allows observation of faster dynamics. An attractive application is in the development of novel anti-cancer drugs and there is an important potential for pretesting chemotherapeutic drugs with biopsy material for personalized cancer treatment. The procedure involves the preparation of live cells in tissue culture, seeding them into suitable observation chambers, and time-lapse recording with an adjusted microscope. Subsequent image processing and statistical analysis are essential last steps producing the results, which include rapid measurements of cell growth in terms of dry-mass increase in individual cells, speed of cell motility and other dynamic morphometric parameters.

• Klíčová slova
• Cancer cells, Holographic quantitative phase imaging, Light microscopy, Measurements of cell growth and motility,
• MeSH
• holografie * metody   MeSH
• mikroskopie metody   MeSH
• počítačové zpracování obrazu metody   MeSH
• pohyb buněk MeSH
• protinádorové látky * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové látky * MeSH

Solid-phase microextraction (SPME) is an alternative method to dialysis and ultrafiltration for the determination of plasma protein binding (PPB) of drugs. It is particularly advantageous for complicated analytes where standard methods are not applicable. Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) is a lead compound of novel thiosemicarbazone anti-cancer drugs, which entered clinical trials in 2016. However, this agent exhibited non-specific binding on filtration membranes and had intrinsic chelation activity, which precluded standard PPB methods. In this study, using a simple and fast procedure, we prepared novel SPME fibers for extraction of DpC based on a metal-free, silicon string support, covered with C18 sorbent. Reproducibility of the preparation process was demonstrated by the percent relative standard deviation (RSD) of ≤ 9.2% of the amount of DpC extracted from PBS by several independently prepared fibers. The SPME procedure was optimized by evaluating extraction and desorption time profiles. Suitability of the optimized protocol was verified by examining reproducibility, linearity, and recovery of DpC extracted from PBS or plasma. All samples extracted by SPME were analyzed using an optimized and validated UHPLC-MS/MS method. The developed procedure was applied to the in vitro determination of PPB of DpC at two clinically relevant concentrations (500 and 1000 ng/mL). These studies showed that DpC is highly bound to plasma proteins (PPB ≥ 88%) and this did not differ significantly between both concentrations tested. This investigation provides novel data in the applicability of SPME for the determination of PPB of chelators, as well as useful information for the clinical development of DpC. Graphical abstract.

• Klíčová slova
• Anti-cancer agents, Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, Sample preparation, Solid-phase microextraction,
• MeSH
• adsorpce MeSH
• design vybavení MeSH
• křemík chemie   MeSH
• krevní proteiny metabolismus   MeSH
• krysa rodu Rattus MeSH
• mikroextrakce na pevné fázi přístrojové vybavení   metody   MeSH
• protinádorové látky metabolismus   MeSH
• pyridiny metabolismus   MeSH
• skot MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• thiosemikarbazony metabolismus   MeSH
• vazba proteinů MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone MeSH Prohlížeč
• křemík MeSH
• krevní proteiny MeSH
• protinádorové látky MeSH
• pyridiny MeSH
• thiosemikarbazony MeSH

BACKGROUND: The costs of oncology treatments are increasing, due to the rising prevalence of malignant diseases and the introduction of expensive novel anti-cancer agents. The new European Society for Clinical Oncology (ESMO) has recently developed a new parametric system to evaluate the clinical benefit of drugs. The Magnitude of Clinical Benefit Scale (ESMO-MCBS) compares the contribution of a novel drug based on overall and progression-free survival and quality of life with those of current treatment options. MATERIAL AND METHODS: An expert group of the Czech Oncological Society conducted an assessment based on published data and an ESMO-MCBS methodology for antineoplastic agents used for the treatment of solid tumors with limited reimbursement to Comprehensive Cancer Centers. We evaluated drugs categorized as "S" that were eligible for public health insurance as of January 1, 2017. RESULTS AND CONCLUSION: The ESMO-MCBS score is a promising new parameter for the evaluation of new anticancer drugs. The ESMO-MCBS method for assessing the clinical benefit of drugs is simple, robust, and reproducible. The advantage of the assessment is that it is not based on a single index but rather combines several dimensions of drug performance. This parameter will be gradually added to Czech cancer guidelines. Scores obtained in the majority of cases correspond to the observed benefit of a drug in routine clinical practice.Key words: tumors - farmacotherapy - assesment study as a subject - survival - protocols of anti-cancer therapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 3. 5. 2017Accepted: 20. 6. 2017.

• MeSH
• analýza nákladů a výnosů metody   MeSH
• lékařská onkologie ekonomika   MeSH
• lidé MeSH
• nádory farmakoterapie   ekonomika   MeSH
• protinádorové látky ekonomika   terapeutické užití   MeSH
• společnosti lékařské MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Turecko MeSH
• Názvy látek
• protinádorové látky MeSH

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug candidate MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority.

• Klíčová slova
• Candida, Cryptococcus, Leishmania, Plasmodium, Trypanosoma, drug, mitochondria,
• MeSH
• membránový potenciál mitochondrií MeSH
• Plasmodium falciparum MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• protinádorové látky * metabolismus   farmakologie   MeSH
• Trypanosoma brucei brucei * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové látky * MeSH

In our aging population the incidence of cancer is increasing in the elderly. We are thus facing a new challenge especially considering incidence of cardiovascular diseases (CVD) in this patients population. Overall survival of cancer patients has significantly improved therefore cancer has become in many cases a chronic disease. We are about to be treating patients who either may develop a new CVD or their current CVD may deteriorate. Cancer can cause various cardiovascular conditions locally (pressure in mediastinum, effusions) or systemically (increased risk of pulmonary embolism, arrhythmias, carcinoid heart disease). Medical cancer therapy can lead to congestive heart failure (CHF) per se, by anthracycline or antiHER2 therapy direct cardiac toxicity or by number of other cardiac conditions medical treatment can cause, such as accelerated arterial hypertension due to anti-angiogenic therapy (tyrosine-kinase inhibitors, bevacizumab) or even standard chemotherapy (alkylating agents, cisplatin) or overusing steroids in cancer patients. Atrial fibrillation (AFib) also contributes to CHF development. AFib in cancer patients may develop secondary to ischaemia in anaemic patients, metabolic disorders caused by cancer or treatment, pulmonary embolism, sepsis or even as a result of direct impact of cytotoxic treatment (cisplatin, ifosfamide, gemcitabine, 5-fluorouracil, etoposide). One of major risk factors for CHF is coronary artery disease (CAD), which is a very serious late sequel of cancer therapy mainly in long time cancer survivors (testicular cancer, childhood cancer, hematologic malignancies, breast cancer). CAD may develop secondary to thoracic irradiation, dyslipidemia caused by hormonal treatment or simply as results of endothelial dysfunction caused by alkylating agents. In summary, long time cancer survivors represent a subgroup of patients at great risk of developing CVD in any form. It is crucial to mention that these patients can develop typical CVD much earlier compared to standard population and therefore require special follow-up with active surveillance.Key words: anthracycline - atrial fibrillation - cardiac toxicity - heart failure - pulmonary embolism.

• MeSH
• antracykliny škodlivé účinky   MeSH
• fibrilace síní etiologie   MeSH
• karcinoidní nemoc srdce etiologie   MeSH
• kardiotoxicita MeSH
• kardiovaskulární nemoci etiologie   MeSH
• lidé MeSH
• nádory komplikace   terapie   MeSH
• nemoci koronárních tepen etiologie   MeSH
• nemoci srdce etiologie   MeSH
• přežívající MeSH
• protinádorové látky škodlivé účinky   MeSH
• radioterapie škodlivé účinky   MeSH
• rizikové faktory MeSH
• srdeční selhání etiologie   MeSH
• trastuzumab škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antracykliny MeSH
• protinádorové látky MeSH
• trastuzumab MeSH

The measurement of serum tumour markers is a simple and non-invasive method for assessing the response to systemic therapies in metastatic colorectal cancer (mCRC) and estimation of prognosis. The aim of our retrospective study was to evaluate the association of baseline serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase (TK) and tissue polypeptide specific antigen (TPS) with outcome of patients with mCRC treated with combination of chemotherapy and monoclonal antibodies against epidermal growth factor receptor (anti-EGFR mAbs) in the first line. In our study, the cohort included 102 patients treated with therapy based on anti-EGFR mAbs between years 2011 and 2017 at Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Czech Republic. Serum samples were collected within one month before the initiation of treatment. In multivariate Cox analysis that included serum tumour markers and clinical baseline parameters show that high baseline serum CA 19-9 was significantly associated with worse progression-free survival (HR=1.871, p=0.0330) and also overall survival (HR=3.903, p=0.0006). We have not demonstrated association of baseline levels of CEA, TK and TPS with patients' outcome. CA 19-9 is commonly used serum tumour marker which is simple and readily available and its candidate prognostic importance in the setting of anti-EGFR therapy deserves to be studied in prospective trials.

• Klíčová slova
• carbohydrate antigen 19-9, cetuximab, chemotherapy, colorectal cancer, panitumumab, serum carcinoembryonic antigen, thymidine kinase, tissue polypeptide specific antigen, tumor markers,
• Publikační typ
• časopisecké články MeSH

The purpose of this study was to use the proteomics approach, which is based on high resolution two-dimensional electrophoresis coupled with multivariate correspondence analysis and mass spectrometry, to classify objectively the biochemical basis of the anti-cancer activity of the synthetic cyclin-dependent kinase inhibitor, bohemine (BOH). The changes in the cell cycle and corresponding protein composition of the A549 human lung adenocarcinoma cell line after treatment with BOH were evaluated and proteins differentially expressed in the BOH treated A549 cells, compared to the untreated A549 counterparts, were selected. Thirteen of these candidate proteins associated with the drug effects in vitro were identified by mass spectrometry. Many of these proteins fall into one of three functional categories: i) metabolic pathways (glycolysis, nucleic acid synthesis and NADPH production), ii) stress response and protein folding, and iii) cytoskeleton and exocytosis. Changes in protein expression patterns corresponded to a higher resistance of A549 lung carcinoma cells to BOH when compared to the CEM leukaemia cell line. These protein changes reflect a fine balance of the resistant versus the susceptible phenotype in response to the drug. Since BOH is a selective cyclin-dependent kinase inhibitor, changes in the protein expression pattern can be more generally associated with cell cycle regulation as evidenced by inhibition of cell cycling in A549 cells. Our conclusions further underline the importance of cell cycle control in both the cellular signalling and metabolic pathways.

• MeSH
• 2D gelová elektroforéza MeSH
• buněčný cyklus MeSH
• časové faktory MeSH
• cytoskelet metabolismus   MeSH
• exocytóza MeSH
• fenotyp MeSH
• fytogenní protinádorové látky farmakologie   MeSH
• hmotnostní spektrometrie MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• paclitaxel farmakologie   MeSH
• počítačové zpracování obrazu MeSH
• proteinkinasa CDC2 antagonisté a inhibitory   MeSH
• proteom * MeSH
• protinádorové látky farmakologie   MeSH
• průtoková cytometrie MeSH
• puriny farmakologie   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bohemine MeSH Prohlížeč
• fytogenní protinádorové látky MeSH
• paclitaxel MeSH
• proteinkinasa CDC2 MeSH
• proteom * MeSH
• protinádorové látky MeSH
• puriny MeSH