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Heterogeneous catalysts based on magnetite nanoparticles, Fe3O4, were prepared by the chemical coprecipitation method using iron (III) chloride as a salt precursor. The physicochemical properties of the nanoparticles were determined by different techniques and the efficiency was evaluated for the degradation of the cytostatic drug, 5-fluorouracil (5-FU), in aqueous solution by photo-Fenton process under simulated solar radiation. The most influential parameters, namely pH of the solution, catalyst load, H2O2 dosage, and use of radiation, were studied and optimized in the degradation process. The optimal conditions to achieve a 100% degradation of 5-FU (10 mg L-1) and a high mineralization degree (76%) were established at the acidic pH of 3.0, 100 mg L-1 of catalyst loading, and 58 mM of H2O2 under simulated solar radiation. The contribution of iron leaching to the catalyst deactivation, the role of the dissolved iron ions on homogenous reactions, and the stability of the catalyst were assessed during consecutive reaction cycles.

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The aim of this study was to evaluate the biodecolorization and detoxification of the anticancer drug mitoxantron (MTX) by immobilized crude versatile peroxidase of Bjerkandera adusta CCBAS 930 (icVP/Ba). The concentrated crude VP was obtained from B. adusta CCBAS 930 culture on medium with MTX (µg/mL) addition, immobilized with 4% sodium alginate. MTX removal degree (decolorization), levels of phenolic compounds and free radicals were determined during MTX biotransformation. Moreover, the phytotoxicity (Lepidium sativum L.), biotoxicity (multi-species microbial assay, MARA), and genotoxicity (SOS Chromotest) of MTX were evaluated before and after the biological treatment. The use of icVP/Ba (95 U/mL) significantly shortened the bioremoval of 10 µg/mL MTX (95.57% after 72 h). MTX removal by icVP/Ba was correlated with an 85% and 90% decrease in the levels of phenolic compounds and free radicals, respectively. In addition, the use of icVP/Ba contributed to a decrease in the phyto-, bio-, and genotoxicity of MTX. This is the first study to describe the possibility of removing MTX using immobilized crude fungal peroxidase.

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Breast cancer is one of the most common malignant neoplasms, and despite the dynamic development of anticancer therapies, 5-year survival in the metastatic stage is still less than 30%. 6-Gingerol (1-[4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) is a substance contained in ginger, which exhibits anti-cancer properties. Paclitaxel is a cytostatic substance used to treat breast cancer, but its therapeutically effective dose has many adverse effects. The aim of the presented study was to assess the anticancer effect of 6-gingerol and the possibility of increasing the effectiveness of Paclitaxel in the death induction of wild type human breast cancer cells. MCF-7/WT cells were treated with drugs-6-gingerol and paclitaxel at selected concentrations. The mitochondrial activity assay, caspase 7 activity assay, ATP assay, microscopy studies, and RT-PCR assays were performed to evaluate the antitumor activity and mechanism of action of both compounds, alone and in combination. After 72 h of incubation, the mitochondrial activity showed that the combination of 5 nM Paclitaxel with 10 µM 6-Gingerol led to the same decrease in viability as the use of 20 nM Paclitaxel alone; 10 µM 6-Gingerol led to an enhancement of caspase 7 activity, with the highest activity observed after 24 h of incubation. A real-time PCR study showed that 6-Gingerol induces the simultaneous transcription of Bax with TP53 genes in large excess to BCL-2. In contrast, 5 nM Paclitaxel induces TP53 transcription in excess of BCL-2 and Bax. Our results suggest that 6-Gingerol may act as a cell death-inducing agent in cancer cells and, in combination with paclitaxel, and increase the effectiveness of conventional chemotherapy.

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Aquatic organisms are continuously exposed to emerging contaminants coming from urban effluents of wastewater treatment plants. The contamination of surface water by those effluents poses a number of environmental risks, and pharmaceuticals are part of this class of effluent contaminants. Various classes of pharmaceuticals are not treated by wastewater treatment plants and anticancer drugs are part of them. The chemotherapy drug methotrexate (MTX) is an emerging contaminant and its growing use with the increase in cancer cases worldwide raises potential risk to aquatic organisms exposed to effluent discharges. However, chemical analyses in exposed freshwater aquatic organisms for ecotoxicological studies are rarely available and no studies have been done yet to accompany ecotoxicological data of exposed filter-feeding organisms. The purpose of this study was to develop a specific and sensitive analytical LC-MS/MS method for the quantification of methotrexate uptake in mussels exposed at different concentrations of the drug. A solid/liquid extraction followed by solid phase extraction (SPE) using an MCX phase purification scheme was optimized. The optimal recovery of 65% and matrix effect of 38% allowed to achieve a limit of quantification of 0.25 ng g-1, with an accuracy of 99-106%, a precision of no more than 3% RSD, and linearity ranging from 0.25 to 25 ng g-1. This methodology was tested with mussels exposed for 96 h at different concentrations (4 to 100 µg L-1) of MTX. The data revealed tissue uptake at concentrations ranging from 0 to 2.53 ng g-1. This suggests that this drug has low uptake potential and this methodology could be used to examine tissue levels of this drug in organisms continuously exposed to urban pollution.

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Municipal effluents continuously release cytostatic drugs with unknown consequences in aquatic organisms. The purpose of the study was to examine the sublethal toxicity of 2 commonly-found cytostatic drugs 5-fluouracile (5-FLU) and methotrexate (MTX) to endemic Elliptio complanata freshwater mussels. The mussels were exposed of each drugs at 0, 4, 20 and 100 µg/L for 96 h t 15 °C. After the exposure period, glutathione S-transferase (GST) and dehydrofolate reductase (DHFR) activities, DNA damage and lipid peroxidation (LPO) were determined. The drugs were detected in mussel tissues with no evidence of accumulation with either drugs. The drug 5-FLU gave a larger spectrum of effects than MTX such as increased DHFR, decreased LPO and DNA strand breaks (repair activity) suggesting that the mussels were metabolically hindered and reduced DNA repair activity. The drug MTX only increased DHFR activity in the gonad. Hence, the data suggest that these drugs are biologically active in freshwater mussels and based on the reported maximum levels of these drugs in municipal effluents, the observed effects are likely in sessile freshwater mussel species downstream urban sources of pollution.

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The drugs used for treatment during chemotherapy are manufactured individually for each patient in specialised pharmacies. Thorough quality control to confirm the identity of the delivered active pharmaceutical ingredient and the final concentration of the prepared application solution is not standardized yet except for optical or gravimetric testing. However, solution stability problems, counterfeit drugs, and erroneous or deliberate underdosage may occur and negatively influence the quality of the product and could cause severe health risks for the patient. To take a step towards analytical quality control, an on-site analytical instrument using Raman and UV absorption spectroscopy was employed and the results were compared to high-performance liquid chromatography coupled to diode array detection. Within the scope of the technology evaluation, the uncertainty of measurement was determined for the analysis of the five frequently used cytostatic drugs 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan and paclitaxel. The Raman/UV technique (2.0-3.2% uncertainty of measurement; level of confidence: 95%) achieves a combined uncertainty of measurement comparable to HPLC-DAD (1.7-3.2% uncertainty of measurement; level of confidence: 95%) for the substances 5-fluorouracil, cyclophosphamide and gemcitabine. However, the uncertainty of measurement for the substances irinotecan and paclitaxel is three times higher when the Raman/UV technique is used. This is due to the fact that the Raman/UV technique analyses the undiluted sample; therefore, the sample has a higher viscosity and tendency to foam. Out of 136 patient-specific preparations analysed within this study, 96% had a deviation of less than 10% from the target content.

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Vascular disrupting agents (VDAs) are emerging anticancer agents, which show rising demand for combination with cytostatic drugs (CSDs), owing to inadequate tumor inhibition when applied singly. Nevertheless, the combination remains a challenge due to the different working sites of VDAs and CSDs and hypoxia-induced drug resistance after disrupting neovasculature by VDAs. Herein, we developed a shell-stacked nanoparticle (SNP) for coencapsulation of a VDA combretastatin A-4 phosphate (CA4P) and a proteasome inhibitor bortezomib (BTZ). The SNP could spatiotemporally deliver CA4P to tumor neovasculature and BTZ to tumor cells mediated by the site-specific stimuli-activated drug release. Moreover, the SNP also reversed the drug resistance caused by the overexpressed ABCG2 under CA4P-induced hypoxic conditions. The spatiotemporally targeted combination therapy significantly inhibited the growth of both the human A549 pulmonary adenocarcinoma xenograft model and patient-derived xenograft (PDX) model of colon cancer in mice, providing a promising strategy for treating advanced cancers.

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The recirculating split-flow batch reactor with a cell divided into anolyte and catholyte compartments for oxidation mixture of cytostatic drugs (CD) was tested. In this study, kinetics and mechanisms of electrochemical oxidization of two mixtures: 5-FU/CP and IF/CP were investigated. The order of the CD degradation rate in single drug solutions and in mixtures was found to be 5-FU < CP < IF. In the 5-FU/CP mixture, kapp of 5-FU increased, while kapp of CP decreased comparing to the single drug solutions. No effect on the degradation rate was found in the CP/IF mixture. The presence of a second drug in the 5-FU/CP mixture significantly altered mineralization and nitrogen removal efficiency, while these processes were inhibited in IF/CP. The experiments in the different electrolytes showed that •OH and sulphate active species can participate in the drug's degradation. The kapp of the drugs was accelerated by the presence of Cl- ions in the solution. Chlorine active species played the main role in the production of gaseous nitrogen products and increased the mineralisation. Good results were obtained for the degradation and mineralisation processes in mixtures of drugs in municipal wastewater-treated effluent, which is beneficial from the technological and practical point of view.

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Poland is one of the European countries with the highest level of production of dangerous medical waste. Although in Europe the volume of produced cytotoxic and cytostatic waste (used in chemotherapy by oncological patients) has been declining for several years, in Poland a reverse trend has been observed. As this waste puts the safety of medical workers and patients at risk, special handling procedures are required to limit the harmful effect of these drugs on human health. In view of the above, the aim of the work was to present the rules of conduct with cytotoxic and cytostatic drugs, and their waste, in Poland. Med Pr. 2019;70(3):377-91.

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In this study, the electrochemical degradation process of 5-fluorouracil (5-FU) in aqueous media was performed using a continuous flow reactor in an undivided cell (system I), and in a divided cell with a cationic membrane (Nafion® 424) (system II). In system I, 75% of 5-FU degradation was achieved (50 mg L-1) with a applied current density japp = 150 A m-2, volumetric flow rate qv = 13 L h-1, after 6 h of electrolysis (kapp = 0.004 min-1). The removal efficiency of 5-FU was higher (95%) when the concentration was 5 mg L-1 under the same conditions. Nitrates (22% of initial amount of N), fluorides (27%) and ammonium (10%) were quantified after 6 h of electrolysis. System II, 77% of 5-FU degradation was achieved (50 mg L-1) after 6 h of electrolysis (kapp = 0.004 min-1). The degradation rate of 5-FU was complete when the concentration was 5 mg L-1 under the same conditions. Nitrates (29% of initial amount of N), fluorides (25%) and ammonium (5%) were quantified after 6 h of electrolysis. In addition, the main organic byproducts identified by mass spectroscopy were aliphatic compound with carbonyl and carboxyl functionalities. Due to, the mineralization of 5-FU with acceptable efficiency of 88% found in system II (japp of 200 A m-2), this system seems to be more promising in the cytostatic drug removal. Moreover the efficiency of 5-FU removal in diluted solutions is better in system II than in system I.

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Triple-Negative Basal-Like tumors, representing 15 to 20% of breast cancers, are very aggressive and with poor prognosis. Targeted therapies have been developed extensively in preclinical and clinical studies to open the way for new treatment strategies. The present study has focused on developing 3D cell cultures from SUM1315 and MDA-MB-231, two triple-negative basal-like (TNBL) breast cancer cell lines, using the liquid overlay technique. Extracellular matrix concentration, cell density, proliferation, cell viability, topology and ultrastructure parameters were determined. The results showed that for both cell lines, the best conditioning regimen for compact and homogeneous spheroid formation was to use 1000 cells per well and 2% Geltrex®. This conditioning regimen highlighted two 3D cell models: non-proliferative SUM1315 spheroids and proliferative MDA-MB-231 spheroids. In both cell lines, the comparison of 2D vs 3D cell culture viability in the presence of increasing concentrations of chemotherapeutic agents i.e. cisplatin, docetaxel and epirubicin, showed that spheroids were clearly less sensitive than monolayer cell cultures. Moreover, a proliferative or non-proliferative 3D cell line property would enable determination of cytotoxic and/or cytostatic drug activity. 3D cell culture could be an excellent tool in addition to the arsenal of techniques currently used in preclinical studies.

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The present work is focused on the long-term stability and in vitro cellular internalization of newly designed biocompatible polyester nanocapsules prepared via nanoprecipitation approach with mean diameter <165 nm and narrow size distribution, dedicated to theranostic applications. We monitored the optical, morphological, and biological properties of the nanocarriers loaded by multifunctional cargo, i.e., paclitaxel (PTX) and a fluorescent marker: coumarin-6 (CR-6) or Nile Red (NR), by fluorescence and UV-vis spectroscopy (encapsulation efficiency), dynamic light scattering (average size expressed as hydrodynamic diameter, DH), zeta potential (ζ, colloidal stability), atomic force microscopy (AFM, imaging), and confocal laser scanning microscopy (CLSM, nanocapsule visualization, and cellular internalization in vitro by human breast cancer MCF-7/WT cells). The fabricated nanocapsules with optimal composition of oleic phase, i.e., coconut oil, palm oil, and Capmul MCM, as well as polymeric shell, i.e., polylactic acid (PLA), poly (ε-caprolactone) (PCL), and poly (lactide-co-glycolide) (PLGA), showed high loading capacity, long-term stability, and improved localization of the active cargo in studied tumor cells. Therefore, our results prove that the studied polyester oil core nanocapsules provide lifelong and biocompatible nanocarriers suitable for in vivo administration and for diagnostic applications.

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The efficacy of many chemotherapeutic agents relies on the preferential destruction of rapidly dividing cancer cells by inducing various kinds of DNA damage. The most deleterious type of DNA lesions are DNA double-strand breaks (DSB), which can be detected by immunofluorescence staining of phosphorylated histone protein H2AX (γH2AX). Furthermore, γH2AX has been suggested as clinical pharmacodynamic biomarker in chemotherapeutic cancer treatment. A great challenge in treating neoplastic diseases is the varying response behavior among cancer patients. Thus, intrinsic or drug-induced overexpression of efflux pumps often leads to multiple drug resistance (MDR) and treatment failure. In particular, inter-individual differences in expression levels of efflux pumps, such as the permeability glycoprotein (P-gp), were shown to correlate with cancer progression. Several efficient cytostatic drugs, including the DSB-inducing agent etoposide (ETP) are known P-gp substrates. In this respect, modulation of MDR by P-gp inhibitors, like the immunosuppressives cyclosporine A (CsA) and rapamycin (Rapa) have been described. Here, we investigated the application of γH2AX focus assay to monitor the impact of CsA and Rapa on ETP-induced cytotoxicity in human peripheral blood mononuclear cells. Evaluation of γH2AX foci was performed by the automated fluorescence microscopy and interpretation system AKLIDES. Compared to ETP treatment alone, our results revealed a significant rise in γH2AX focus number and percentage of DSB-positive cells after cells have been treated with ETP in the presence of either CsA or Rapa. In contrast, DSB levels of cells incubated with CsA or Rapa alone were comparable to focus number of untreated cells. Our results successfully demonstrated how automated γH2AX analysis can be used as fast and reliable approach to monitor drug resistance and the impact of MDR modulators during treatment with DSB-inducing cytostatics..

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Se realizó un estudio descriptivo, transversal y prospectivo de 201 pacientes con cáncer de mama atendidos en el Servicio de Quimioterapia del Hospital Oncológico Docente Provincial "Conrado Benítez García" de Santiago de Cuba durante un año (de junio del 2013 a igual mes del 2014), a fin de caracterizarles y determinar la presencia de neutropenia como reacción adversa al tratamiento. La información fue analizada estadísticamente mediante el cálculo porcentual y la prueba de la Χ², con lo cual se obtuvo que 82 pacientes padecieran neutropenia (40,7 %), en quienes predominó el grupo etario de 41-60 años (50,0 %), el estadio clínico II del tumor maligno (65,8 %) y un único episodio de neutropenia (90,2 %). En cuanto a las pacientes diagnosticadas con neutropenia, se registraron 91 episodios, con mayor frecuencia de los grados moderado (52,7 %) y leve (39,5 %), y una reacción favorable al factor estimulante de colonias de granulocitos humano en 81,8 % de ellas. Por último, se demostró la existencia de neutropenia como efecto adverso a los citostáticos en casi 50 % de las pacientes, así como el resultado beneficioso del factor estimulante en estas; sin embargo, no se halló asociación entre las diferentes combinaciones de citostáticos y los episodios y grados de neutropenia.

A descriptive, cross-sectional and prospective study of 201 patients with breast cancer assisted in the Chemotherapy Service of "Conrado Benítez García" Teaching Provincial Oncological Hospital in Santiago de Cuba was carried out during a year (from June, 2013 to the same month of 2014), in order to characterize them and to determine neutropenia as adverse reaction to the treatment. The information was analyzed statistically by means of the percentage calculation and the test Chi squared test, with which it was obtained that 82 patients suffered neutropenia (40.7%) in whom the age group 41- 60 years prevailed (50.0%), the clinical stage II of the malignant tumor (65.8%) and just one neutropenia episode (90.2%). As for the patients diagnosed with neutropenia, 91 episodes were registered, with higher frequency of the moderated degrees (52.7%) and mild (39.5%), and a favorable reaction to the stimulating factor of human granulocytes colonies 81.8% of them. Lastly, the neutropenia existence as adverse effect to the cytostatic drugs in almost 50% of the patients was demonstrated, as well as the beneficial result of the stimulating factor in them; however, there was no association between the different combinations of cytostatic drugs and the episodes and neutropenia degrees.

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Treatment of advanced soft tissue sarcoma usually includes dacarbazine (DTIC), an alkylating agent that methylates DNA and is active during all phases of the cell cycle. Common side effects of DTIC include nausea, vomiting, impaired liver and kidney function, myelosuppression, and pneumonia. There are no accounts, however, of histological and hematological changes caused by DTIC. We investigated acute hematological and morphological changes in different organs and in tumors that were caused by a single dose of DTIC. Adult Syrian golden hamsters were inoculated with a suspension of tumorigenic baby hamster kidney (BHK) cells by subcutaneous injection. On day 14 after inoculation, doses of 1.4, 1.6, 1.8 or 2.0 g/m(2) DTIC were injected intraperitoneally into the hamsters. Hamsters in the control group were injected with physiological saline in the same way. Seven days after drug or saline injection the animals were sacrificed and samples of blood, heart, kidney, liver, lungs, spleen, small intestine and tumor were excised, processed and analyzed. Mitoses were counted using an ocular extension with engraved frame. Anemia, thrombocytopenia and leukocytosis were found in the control group of hamsters with fibrosarcoma, whereas animals with fibrosarcoma treated with DTIC developed anemia, thrombocytopenia and leukopenia. Severe pneumonia and moderate hepatitis were detected in all DTIC treated groups. Effects of DTIC on tumor cells included rounding and enlargement of nuclei and rarefaction of chromatin. The number of mitoses was reduced with increasing doses of DTIC. Hepatitis, myelosuppression, pneumonia, and dose-related inhibition of tumor cell proliferation were observed after a single dose of DTIC.

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