The following correction has been made to this paper [...].

• Publication type
• Published Erratum MeSH

Cytostatikum doxorubcin enkapsulován do malých pegylovaných lipozomů (PLD) je indikován jako druhá volba v léčbě ovariálních nádorů a Kaposiho sarkomu. Vyznačuje se nižším stupněm vychytávání do RES a následně zvýšeným uptake do nádoru. Lipozomy s dlouhodobou cirkulací (k cílové distribuci) nabízejí dvojí výhodu: potlačují toxicitu (zejména závažnou kardiotoxicitu s nižší myelotoxicitou) a selektivní kumulaci do nádoru znamenající vyšší protinádorovou účinnost. Vzhledem ke zvláštní kinetice těchto lipozomů může však být jejich dlouhodobé přežívání rizikem pro toxicitu vůči sliznicím a kůži (projevuje se jako mukozitidy a syndrom ruka-noha). Dostatečná časová prodleva mezi saturací PLD v nádorové tkáni a jeho kumulací v kůži může být šancí pro eliminaci zbývající dávky cirkulující v plazmě (která má spíše malou terapeutickou hodnotu) využitím systému extrakorporální plazmatické filtrace. Náš projekt řeší zásadní otázku detoxikace organismu při použití léčiv cíleně distribuovaných nanočásticemi, jejich bezpečnou a účinnou aplikaci v léčbě onkologických nemocných.; An anti-cancer drug, doxorubicin, encapsulated in small-sized pegylated liposomes (PLD) is indicated for second-line treatment of ovarian cancer and AIDS-related Kaposi ́s sarcome. PLD shows a lower uptake by RES, and consequently, increased tumor uptake. Long-circulating lipozomes (as drug delivery systems) appear to offer a double advantage: toxicity buffering (mainly serious cardiotoxicity, less myelotoxicity) and selective tumor accumulation leading to an enhanced antitumour activity. Liposome longevity might be risky for mucocutaneous toxicities (mucositis and hand-foot syndrom) due to the unique pharmacokinetics of liposomes. A sufficient time gap between saturation of tumor tissue with PLD and accumulation in skin has been found which allows to eliminate a remaining dose circulating in the plasma by a system of extracorporeal plasma filtration. Our project solves the fundamental question of detoxification focused on drugs encapsulated to nanoparticles, their safe and effective clinical use in the treatment of cancer patients.

• MeSH
• Doxorubicin therapeutic use   MeSH
• Hemofiltration methods   MeSH
• Plasma MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Liposomes therapeutic use   MeSH
• Ovarian Neoplasms drug therapy   MeSH
• Nanoparticles therapeutic use   MeSH
• Check Tag
• Humans MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• gynekologie a porodnictví
• farmacie a farmakologie
• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

Cancer treatment has been greatly improved by the combined use of targeted therapies and novel biotechnological methods. Regarding the former, pegylated liposomal doxorubicin (PLD) has a preferential accumulation within cancer tumors, thus having lower toxicity on healthy cells. PLD has been implemented in the targeted treatment of sarcoma, ovarian, breast, and lung cancer. In comparison with conventional doxorubicin, PLD has lower cardiotoxicity and hematotoxicity; however, PLD can induce mucositis and palmo-plantar erythrodysesthesia (PPE, hand-foot syndrome), which limits its use. Therapeutical apheresis is a clinically proven solution against early PLD toxicity without hindering the efficacy of the treatment. The present review summarizes the pharmacokinetics and pharmacodynamics of PLD and the beneficial effects of extracorporeal apheresis on the incidence of PPE during chemoradiotherapy in cancer patients.

• Publication type
• Journal Article MeSH
• Review MeSH

Colorectal cancer (CRC) remains a serious health problem worldwide. Approximately half of patients will develop distant metastasis after CRC resection, usually with very poor prognosis afterwards. Because patient performance after distant metastasis surgery remains very heterogeneous, ranging from death within 2 years to a long-term cure, there is a clinical need for a precise risk stratification of patients to aid pre- and post-operative decisions. Furthermore, around 20% of identified CRC cases are at IV stage disease, known as a metastatic CRC (mCRC). In this review, we overview possible molecular and clinicopathological biomarkers that may provide prognostic and predictive information for patients with distant metastasis. These may comprise sidedness of the tumor, molecular profile and epigenetic characteristics of the primary tumor and arising metastatic CRC, and early markers reflecting cancer cell resistance in mCRC and biomarkers identified from transcriptome. This review discusses current stage in employment of these biomarkers in clinical practice as well as summarizes current experience in identifying predictive biomarkers in mCRC treatment.

• MeSH
• Epigenesis, Genetic * MeSH
• Colorectal Neoplasms * metabolism   pathology   therapy   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Biomarkers, Tumor biosynthesis   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH

The aim of this study was to evaluate cell diversity by considering how Ca(2+) signaling has been adapted in skeletal muscle cell function. We characterized single C2C12 myoblasts through intracellular Ca(2+) signaling kinetics after exposure to specific drugs and calcium blockers using fast fluorescence microspectrofluorimetry followed by ATP effect analysis, which confirmed the expression of functional purinergic adenosine and P2 receptors. Further, we found that glutamate sensitivity of C2C12 cells was mediated by ionotropic glutamate receptors; on the other hand, most cells were responsive to cyclopiazonic acid, which inhibits the sarco-endoplasmic reticulum Ca(2+)-ATPase pump. These results suggest that C2C12 cells possess functional L- and P/Q-type voltage-operated Ca(2+) channels, ryanodine receptors and functional sarcoplasmic reticulumCa(2+) stores (typical for muscle cells), adenosine and P2 purinergic receptors, as well as ionotropic glutamate receptors. The evaluation of intracellular Ca(2+) signaling is a promising approach towards a better understanding and control of the physiopathological properties of myogenic cells that could be used as a predictive factor in the selection of optimal cells for scaffold recellularization or for tissue engineered constructs used in stem cell therapy.

• MeSH
• Cell Line MeSH
• Intracellular Fluid physiology   MeSH
• Muscle Fibers, Skeletal physiology   MeSH
• Cells, Cultured MeSH
• Myoblasts physiology   MeSH
• Mice MeSH
• Calcium Signaling physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The extracellular matrix (ECM) consists of proteins, glycosaminoglycans and glycoproteins, that support the dynamic interactions between cells, including intercellular communication, cell attachment, cell differentiation, cell growth and migration. As such, the ECM represents an essential and very sensitive system within the tissue microenvironment that is involved in processes such as tissue regeneration and carcinogenesis. The aim of the present review is to evaluate its diversity through Ca(2+) signaling and its role in muscle cell function. Here, we discuss some methodological approaches dissecting Ca(2+) handling mechanisms in myogenic and non-myogenic cells, e.g. the importance of Ca(2+) and calpains in muscle dystrophy. We also consider the reconstruction of skeletal muscle by colonization of decellularized ECM with muscle-derived cells isolated from skeletal muscle. Therefore, it is necessary to establish new methodological procedures based on Ca(2+) signaling in skeletal muscle cells and their effect on ECM homeostasis, allowing the monitoring of skeletal muscle reconstruction and organ repair.

• MeSH
• Extracellular Matrix metabolism   MeSH
• Homeostasis physiology   MeSH
• Intracellular Fluid metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Humans MeSH
• Calcium Signaling physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Předmětem řešení projektu je problém cirkulace nanotechnologicky upravených protinádorových léků v období, kdy již nejsou účinná a mohou být zdrojem vedlejších nežádoucích projevů, které významně ovlivňují jak efektivitu léčby, tak „benefit cost“. Po dosažení Cmax v nádorové tkáni je další cirkulace liposomálního cytostatika neúčinná. Plazmatická hladina vede jen k vzniku nežádoucích vedlejších efektů (zejména zažívacího traktu a kůže), ale nemá léčebný efekt. Vhodným extrakorporálním eliminačním systémem je možno výrazně omezit akutní toxické účinky chemoterapie. Takovou léčbu pomocí rheohemaferézy (kaskádové filtrace, která je považována za nejvhodnější eliminační systém pro tuto potřebu) navrhujeme při léčbě pacientek s karcinomem ovarií pegylovaným liposomálním doxorubicinem. Nově chceme sledovat dosud neprobádané změny hematologických, imunologických a metabolických parametrů. Navrhovaný projekt je v plném souladu s vyhlášeným programem MZ ČR - 03. Onkologie.; The objective to be solved in this project is the issue of circulation of nanotechnologically modified anticancer drugs in the time when they have no effect and may be the source of adverse side-effects and thus influence significantly both the treatment efficacy and „benefit cost“. After Cmax is achieved in the tumour tissue further circulation of liposomal cytostatic drug is not effective. Plasma level leads only to the development of adverse efects but with no effect. With a suitable extracorporeal elimination system it is possible markedly limit acute toxic effects of chemotherapy. For the therapy with rheohemapheresis we suggest to use pegylated liposomal doxorubicine in female patients with ovarian cancer. Newly, we wish to monitore still unexplored changes of hematologic, immunologic and metabolic parameters. The proposed project is in consistence with the program of the Ministry of Health, Czech Republic - 03. Oncology.

• MeSH
• Cytostatic Agents adverse effects   therapeutic use   toxicity   MeSH
• Doxorubicin administration & dosage   pharmacokinetics   therapeutic use   MeSH
• Ovarian Neoplasms drug therapy   MeSH
• Nanotechnology MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Plasmapheresis MeSH
• Polyethylene Glycols MeSH

• Conspectus
• Farmacie. Farmakologie
• NML Fields
• farmacie a farmakologie
• onkologie
• gynekologie a porodnictví
• NML Publication type
• závěrečné zprávy o řešení grantu IGA MZ ČR

Cytostatic treatment is often negatively affected by dose-limited toxicities. Novel agents, including nanoparticle-based drug delivery systems (DDS), are becoming available to overcome this problem. Despite achieving a lesser toxicity in exchange for more favorable pharmacokinetic profiles, the use of DDS is often associated with a particular toxicity profile. The accumulation of DDS in tumor tissue is much faster than in normal tissues where toxic events occur. While only a small amount of DDS is delivered to the target tissue, and accumulated there, most of the administered dose remains in circulation. The removal of this fraction, which is no longer effective, is thought to reduce toxicity. Pegylated liposomal doxorubicin (PLD) has been proven to be effective in platinum-resistant ovarian carcinoma with the reduced risk for cardiotoxicity. Once saturation in tumor tissue is achieved, prolonged circulation seems ineffective, whereas other toxicity risks (palmar-plantar erythrody sesthesia and mucositis) have been reported. Therefore, extracorporeal elimination of circulating nanoparticles using plasma filtration would probably reduce this risk of toxicity. The elimination rate could be kinetically regulated, i.e. based on individual doxorubicin pharmacokinetic variables. Plasma filtration can significantly influence the exposure to PLD (plasma concentration-time profile-AUC of PLD) and would be a suitable, well tolerated method enabling individualized, more effective and safer chemotherapy.

• Keywords
• plasma filtration, liposomal doxorubicin,
• MeSH
• Doxorubicin * analogs & derivatives   pharmacokinetics   pharmacology   adverse effects   therapeutic use   MeSH
• Drug Delivery Systems * adverse effects   MeSH
• Humans MeSH
• Mucositis chemically induced   prevention & control   MeSH
• Neoplasms drug therapy   MeSH
• Polyethylene Glycols pharmacokinetics   pharmacology   adverse effects   therapeutic use   MeSH
• Antibiotics, Antineoplastic adverse effects   therapeutic use   MeSH
• Blood Component Removal * methods   MeSH
• Hand-Foot Syndrome etiology   prevention & control   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• Publication type
• Meeting Abstract MeSH

• MeSH
• Patient Compliance psychology   MeSH
• Precision Medicine trends   MeSH
• Quality of Life MeSH
• Medical Oncology * methods   trends   MeSH
• Humans MeSH
• Palliative Care * methods   MeSH
• Polypharmacy MeSH
• Check Tag
• Humans MeSH
• Female MeSH