The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.

• Klíčová slova
• Enhanced permeability and retention effect, HPMA, Nitric oxide donor, Polymer-based cytotoxic drugs, Solid tumour treatment, T-cell lymphoma,
• MeSH
• antibiotika antitumorózní aplikace a dávkování   MeSH
• buněčné linie MeSH
• donory oxidu dusnatého aplikace a dávkování   MeSH
• doxorubicin aplikace a dávkování   MeSH
• lidé MeSH
• lymfom T-buněčný farmakoterapie   MeSH
• myši inbrední C57BL MeSH
• nosiče léků aplikace a dávkování   MeSH
• polymery aplikace a dávkování   MeSH
• synergismus léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• donory oxidu dusnatého MeSH
• doxorubicin MeSH
• nosiče léků MeSH
• polymery MeSH

Polymer carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with incorporated organic nitrates as nitric oxide (NO) donors were designed with the aim to localise NO generation in solid tumours, thus highly increasing the enhanced permeability and retention (EPR) effect. The NO donors were coupled to the polymer carrier either through a stable bond or through a hydrolytically degradable, pH sensitive, bond. In vivo, the co-administration of the polymer NO donor and HPMA copolymer-bound cytotoxic drug (doxorubicin; Dox) resulted in an improvement in the treatment of murine EL4 T-cell lymphoma. The polymer NO donors neither potentiated the in vitro toxicity of the cytotoxic drug nor exerted any effect on in vivo model without the EPR effect, such as BCL1 leukaemia. Thus, an increase in passive accumulation of the nanomedicine carrying cytotoxic drug via NO-enhanced EPR effect was the operative mechanism of action. The most significant improvement in the therapy was observed in a combination treatment with such a polymer conjugate of Dox, which is characterised by increased circulation in the blood and efficient accumulation in solid tumours. Notably, the combination treatment enabled the development of an anti-tumour immune response, which was previously demonstrated as an important feature of HPMA-based polymer cytotoxic drugs.

• Klíčová slova
• Drug delivery, EL4 lymphoma, HPMA copolymers, anti-tumour immune response, enhanced EPR effect, polymer NO donor, polymer cytotoxic drugs, solid tumour treatment,
• MeSH
• antitumorózní látky aplikace a dávkování   metabolismus   MeSH
• donory oxidu dusnatého aplikace a dávkování   metabolismus   MeSH
• experimentální nádory farmakoterapie   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice aplikace a dávkování   metabolismus   MeSH
• nosiče léků aplikace a dávkování   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• polymery aplikace a dávkování   metabolismus   MeSH
• tumor burden účinky léků   fyziologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• donory oxidu dusnatého MeSH
• nosiče léků MeSH
• oxid dusnatý MeSH
• polymery MeSH

BACKGROUND: Solid pseudopapillary tumour (SPT) of the pancreas is a relatively rare entity which most commonly occurs in young women. In this paper we report our clinical experience together with the current knowledge on the diagnostics, treatment and prognosis of this rare tumour. METHODS: We reviewed hospital records of patients diagnosed with a solid pseudopapillary tumour of the pancreas between January 2002 and December 2011 at the Department of Surgery, University Hospital Hradec Králové, Czech Republic. Clinical, operative, pathological data were obtained on all the patients. RESULTS: Over the 10-year period of the study we performed 181 planned pancreatic resections in our department. Overall, the 30-day postoperative mortality rate in this series of patients was 2.2%. SPT was diagnosed in 4 cases. All the patients were women and the average age was 34 years. Preoperative endosonography with biopsy sample was performed in all the patients and the diagnosis of SPT was known in all the patients before the surgical procedure. CONCLUSIONS: The current knowledge of SPT is based only on case reports and small series. It typically occurs in young women and therefore the presence of a large pancreatic mass in a young woman may suggest a diagnosis of SPT. SPT has a low malignant potential and the prognosis is excellent following complete surgical resection in the majority of the cases.

• MeSH
• biopsie MeSH
• časové faktory MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití trendy   MeSH
• mladý dospělý MeSH
• nádory slinivky břišní diagnóza   mortalita   chirurgie   MeSH
• následné studie MeSH
• pankreas diagnostické zobrazování   patologie   chirurgie   MeSH
• pankreatektomie metody   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (Mw ~27kDa, Rh ~4nm) and non-degradable star (Mw ~250kDa, Rh ~13nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85mgDOX/kg) and lower for the star conjugate (22.5mgDOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased Rh that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments.

• Klíčová slova
• Anti-tumour activity, Doxorubicin, HPMA, Structure, Toxicity,
• MeSH
• akrylamidy chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• antibiotika antitumorózní * chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• dendrimery chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• doxorubicin chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• játra účinky léků   patologie   MeSH
• kostní dřeň účinky léků   patologie   MeSH
• maximální tolerovaná dávka MeSH
• molekulová hmotnost MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory krev   farmakoterapie   metabolismus   MeSH
• nosiče léků * chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• slezina účinky léků   patologie   MeSH
• střevní sliznice metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• antibiotika antitumorózní * MeSH
• dendrimery MeSH
• doxorubicin MeSH
• N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Prohlížeč
• nosiče léků * MeSH
• PAMAM Starburst MeSH Prohlížeč

Myoblastic myoma was first described in 1926. Immunohistochemical methods have proven the neuroectodermal origin of this tumour. It most frequently affects individuals between 30 and 60 years of age, with a significant female predominance. In most cases it is a benign solitary tumour, with multiple lesions found in 25% of cases. The malignant variant of the tumour is diagnosed in less than 3% of cases. This case report of a 30-year-old woman describes the appearance of a solid resistance between her breasts following delivery of her child, with similar findings on the neck and wrists. Histopathological examination confirmed the presence of a benign variant of myoblastic myoma.

• MeSH
• dospělí MeSH
• hodnocení rizik MeSH
• imunohistochemie MeSH
• jehlová biopsie MeSH
• lidé MeSH
• nádor z granulárních buněk patologie   chirurgie   MeSH
• nádory kůže patologie   chirurgie   MeSH
• následné studie MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

• MeSH
• acylkarnitin terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• bilirubin krev   MeSH
• Ehrlichův tumor farmakoterapie   patologie   MeSH
• experimentální nádory jater farmakoterapie   patologie   MeSH
• mitoxantron terapeutické užití   MeSH
• myši MeSH
• sérový albumin analýza   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acylkarnitin MeSH
• antitumorózní látky MeSH
• bilirubin MeSH
• mitoxantron MeSH
• sérový albumin MeSH

Various conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the drug carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesised. Structure of the conjugates differed in the type and the content of hydrophobic substituent (dodecyl, oleic acid and cholesterol moieties) introduced into the polymer structure. In aqueous solutions the conjugates self-assembled into high-molecular-weight supramolecular structures, such as polymeric micelles or stable hydrophilic nanoparticles 13-37 nm in diameter, depending on the type and the content of hydrophobic substituents. Treatment of mice bearing EL-4 T cell lymphoma with the conjugates in the therapeutic regime of drug administration (i.v.) resulted in significant tumour regression with up to 100% of long-term survivors, depending on the dose and the detailed structure of the carrier. The nanoparticles formed by the conjugate bearing cholesterol moiety exhibited prolonged blood circulation and enhanced tumour accumulation indicating an important role of the EPR effect in excellent anticancer activity of the conjugate.

• MeSH
• antibiotika antitumorózní chemie   farmakokinetika   farmakologie   MeSH
• doxorubicin analogy a deriváty   chemie   farmakokinetika   farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kyseliny polymethakrylové chemie   farmakokinetika   farmakologie   MeSH
• lidé MeSH
• methakryláty chemie   farmakokinetika   farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   MeSH
• nosiče léků chemie   farmakokinetika   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• kyseliny polymethakrylové MeSH
• methakryláty MeSH
• nosiče léků MeSH

Cardiotoxicity associated with conventional cytostatics is a known phenomenon and is related to their general cytotoxic effects. This damage to the myocardium is usually irreversible. Despite the attempts to optimize safety profile of targeted anticancer drugs during their development, evidence shows that these new treatment modalities also have cardiotoxic potential or may adversely affect vascular system. Over the last years, a significant number of these agents have been introduced in medical practice. Arterial hypertension, arrhythmias, left ventricular dysfunction and a heart failure are the most frequent cardiovascular adverse effects of targeted anticancer agents, but this toxicity seems to be reversible. To enable early interventions and to minimize these cardiovascular adverse effects, health care professionals have to be well-informed and familiar with the safety profiles of the drugs they administered, the patient's cardiovascular condition and co-morbidities, and they must regularly monitor their patients for potential adverse effects. The aim of this paper is to provide an overview of cardiotoxic effects caused by targeted anticancer drugs used in the treatment of solid tumours. We discuss pathophysiological mechanisms, diagnostics and treatment, risk factors and options for prevention.

• MeSH
• antitumorózní látky toxicita   MeSH
• cílená molekulární terapie metody   MeSH
• dysfunkce levé srdeční komory chemicky indukované   MeSH
• hypertenze chemicky indukované   MeSH
• inhibitory proteinkinas toxicita   MeSH
• lidé MeSH
• molekulová hmotnost MeSH
• monoklonální protilátky toxicita   MeSH
• nádory diagnóza   farmakoterapie   patofyziologie   MeSH
• nemoci srdce chemicky indukované   MeSH
• signální transdukce MeSH
• srdce účinky léků   MeSH
• srdeční arytmie chemicky indukované   MeSH
• srdeční selhání chemicky indukované   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibitory proteinkinas MeSH
• monoklonální protilátky MeSH

We have commenced a series of experiments to evaluate the effect of carnitine derivatives on the antineoplastic activity of mitoxantrone (MX) on various animal cancers. This report describes the therapeutic effect of MX in combination with l-carnitine (LCAR) on the growth of a solid form of Ehrlich tumour inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100mgkg(-1) on day 6 and 13 after tumour inoculation, 1h prior to the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6mgkg(-1). We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumour growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.

• MeSH
• algoritmy MeSH
• antitumorózní látky terapeutické užití   MeSH
• Ehrlichův tumor farmakoterapie   patologie   MeSH
• fixní kombinace léků MeSH
• injekce intravenózní MeSH
• injekce subkutánní MeSH
• karnitin terapeutické užití   MeSH
• mitoxantron terapeutické užití   MeSH
• myši MeSH
• přežití MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• fixní kombinace léků MeSH
• karnitin MeSH
• mitoxantron MeSH

BACKGROUND: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.

• Klíčová slova
• AXL, Cabozantinib, GIST, Gastrointestinal stromal tumour, Imatinib, KIT, MET, Resistance, Sunitinib, VEGFR,
• MeSH
• anilidy aplikace a dávkování   MeSH
• chemorezistence účinky léků   MeSH
• dospělí MeSH
• gastrointestinální nádory farmakoterapie   patologie   MeSH
• gastrointestinální stromální tumory farmakoterapie   sekundární   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• následné studie MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• pyridiny aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sunitinib aplikace a dávkování   MeSH
• záchranná terapie * 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
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anilidy MeSH
• cabozantinib MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• pyridiny MeSH
• sunitinib MeSH