New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rhof approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

• MeSH
• akrylamidy aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• antibiotika antitumorózní aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• micely * MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• polymery aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• propylenglykoly aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• tumor burden účinky léků   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Nanoparticle-based drug delivery systems can overcome the dose-limited toxicity of cytostatics. Pegylated doxorubicin-containing liposomes (PLD) are able to reduce cardiotoxicity. PLD quickly (in 2 days) attains therapeutic concentration in tumorous tissue (kinetic targeting), while its distribution in normal tissue, which is a cause of mucocutaneous toxicity (MCT), is delayed. We examined PLD extracorporeal removal effectivity, using plasma filtration (PF) to determine whether the drug could be withheld prior to its organ distribution responsible for MCT toxicity. METHODS: Nine patients suffering from platinum-resistant ovarian cancer were treated with a infusion of 50 mg/m2of PLD/cycle - for four cycles q4w. Over 44 (46)-47 (49) hours postinfusion, the patients (14 cycles in total) underwent PF using the cascade method. Doxorubicin blood concentration was monitored by the HPLC method during 116 h. Individual pharmacokinetic parameters of doxorubicin were estimated. RESULTS: Over 44 (46)-47 (49) hours postinfusion, a single one-volume plasma filtration removed 35 (22-45) % of the remaining doxorubicin amount in the body. Symptoms of MCT - PPE-like syndrome (grade 3) appeared in one patient. Only one adverse reaction (1/14-7%) - short-term malaise and nausea - was reported as being related to PF. CONCLUSION: PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach, which can be a useful tool for the increased efficacy and tolerability of therapy with PLD. There were no serious signs of drug toxicity and/or PF-related adverse events.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   škodlivé účinky   krev   farmakokinetika   MeSH
• chemorezistence MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   analogy a deriváty   krev   farmakologie   MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory vaječníků krev   diagnóza   farmakoterapie   MeSH
• polyethylenglykoly aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• příprava léků MeSH
• senioři MeSH
• tkáňová distribuce MeSH
• výměna plazmy metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: To examine the removal of pegylated liposomal doxorubicin (PLD) during plasmafiltration (PF) and determine whether the drug could be withheld prior to its organ distribution responsible for mucocutaneous toxicity. METHODS: Six patients suffering from platinum-resistant ovarian cancer were treated with a 1-h IV infusion 50 mg/m(2) of PLD/cycle-for three cycles q4w. Over 44 (46)-47(49) h postinfusion, five patients (14 cycles in total) underwent PF using a cascade PF method consisted of plasma separation by centrifugation and plasma treatment using filtration based one volume of plasma treatment, i.e., 3.18 L (±0.6 L) and plasma flow 1.0 L/h (0.91-1.48 L/h). Doxorubicin concentration in blood was monitored by a high-performance liquid chromatography method for 116 h postinfusion. Pharmacokinetic parameters determined from plasma concentration included volume of distribution, total body clearance, half-life of elimination, and area under the plasma concentration versus time. The amount of doxorubicin in the body eliminated by the patient and via extracorporeal treatment was evaluated. Toxicity was tested using CTCAE v4.0. RESULTS: The efficacy of PF and early responses to PLD/PF combination strategy were as follows: over 44(46) h postinfusion considered necessary for target distribution of PLD to tumor, patients eliminated 46 % (35-56 %) of the dose administered. Over 44(46)-47(49) h postinfusion, a single one-volume plasma filtration removed 40 % (22-45 %) (Mi5) of the remaining doxorubicin amount in the body. Total fraction eliminated attained 81 % (75-86 %). The most common treatment-related adverse events (grade 1-2) such as nausea (4/14 cycles-28 %) and vomiting (3/14 cycles-21 %) appeared during 44 h postinfusion. Hematological toxicity-anemia (5/14 cycles-35 %) was reported after cycle II termination. Symptoms of PPE-like syndrome (grade 1-2) appeared in one patient concomitantly with thrombophlebitis and malignant effusion. In this study, only one adverse reaction (1/14-7 %) as short-term malaise and nausea was reported by the investigator as probably related to PF. CONCLUSION: A single one-volume PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach. There were no serious signs of drug toxicity and/or PF-related adverse events. Kinetically guided therapy with pegylated liposomal doxorubicin combined with PF may be a useful tool to the higher efficacy and tolerability of therapy with PLD.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   škodlivé účinky   krev   farmakokinetika   MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   analogy a deriváty   krev   farmakokinetika   MeSH
• hemofiltrace škodlivé účinky   metody   MeSH
• kritické orgány MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolická clearance MeSH
• nádory vaječníků * farmakoterapie   patologie   MeSH
• nádory vejcovodů * farmakoterapie   patologie   MeSH
• nežádoucí účinky léčiv etiologie   prevence a kontrola   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• polyethylenglykoly aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• progrese nemoci MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem 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.

• 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
• střeva 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

Two conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the polymer carrier based on water-soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesized and their properties were compared, namely their behavior in vivo. The polymer carriers differed in dispersity due to different methods of synthesis; the carrier with relatively high dispersity (HD) was prepared by free radical polymerization (Mw=29,900 g/mol, D=1.75) and the carrier with low dispersity (LD) by controlled radical polymerization (Mw=30,000 g/mol, D=1.13). Both polymer-Dox conjugates showed prolonged blood circulation and tumor accumulation of the drug in comparison with the free drug; e.g. the tumor-to-blood ratio for the polymer-bound Dox was 3-5 times higher. The LD polymer-Dox conjugate exhibited moderately higher tumor accumulation than the HD one at a dose of 1x15 mg Dox (eq.)/kg. Also, their anti-tumor activity did not differ when injected at this dose. However, the increase of the dose to 1x25 mg Dox (eq.)/kg resulted in the enhanced therapeutic activity of the conjugates, especially of the LD one with 100% of long-term survivals. The dispersity of polymer drug carriers influenced the tumor accumulation rate, which affected the overall anti-cancer activity of polymer-drug conjugates.

• MeSH
• analýza přežití MeSH
• antibiotika antitumorózní chemie   farmakokinetika   farmakologie   MeSH
• doxorubicin chemie   farmakokinetika   farmakologie   MeSH
• experimentální nádory farmakoterapie   metabolismus   patologie   MeSH
• léky s prodlouženým účinkem MeSH
• methakryláty chemie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků MeSH
• polymery chemická syntéza   MeSH
• tkáňová distribuce MeSH
• volné radikály chemie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

• MeSH
• adherence k farmakoterapii MeSH
• antibiotika antitumorózní aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• doxorubicin aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   toxicita   MeSH
• inhibitory topoisomerasy II MeSH
• kardiovaskulární nemoci chemicky indukované   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kombinovaná farmakoterapie metody   využití   MeSH
• nádory prsu farmakoterapie   MeSH
• Publikační typ
• přednášky MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• farmakoterapie
• onkologie
• gynekologie a porodnictví
• NLK Publikační typ
• studie
• referáty

Difúzní B-velkobuněčný lymfom (DLBCL) je nejpočetněji zastoupenou jednotkou non-hodgkinských lymfomů. Jde o poměrně heterogenní onemocnění obsahující ve svém spektru řadu variant, podskupin a subtypů DLBCL s pestrými molekulárně-genetickými změnami, morfologickými rysy a také klinicky variabilním chováním a prognózou. Rituximab, první monoklonální protilátka použitá v rutinní protinádorové terapii, významně zlepšil prognózu nemocných s většinou subtypů DLBCL. I dnes však existuje velká skupina jak mladších, tak i starších nemocných, kteří nedostatečně reagují na iniciální léčbu či po dosažení remise u nich po čase dochází k relapsu a jsou vůči další terapii rezistentní. Těmto pacientům mohou přinést naději nové biologické a cílené léky, které jsou nyní testovány v klinických studiích.

Diffuse large B-cell lymphoma (DLBCL) is the most commonly represented unit among non-Hodgkin lymphomas. The disease is relatively heterogeneous, containing a number of DLBCL variants, subgroups and subtypes in its spectrum, with many different molecular- -genetic changes, morphological characteristics, as well as clinically variable behaviours and prognosis. Rituximab, the first monoclonal antibody used in anti-cancer therapy, has significantly improved the prognosis in patients with most DLBCL subtypes. Even today, however, we encounter a large group of both younger and elderly patients with insufficient response to initial treatment, or patients experiencing relapse some time after their remission who then become resistant to continued therapy. New hope for these patients might be seen in new biological and targeted drugs currently investigated in ongoing clinical studies.

• MeSH
• analýza přežití MeSH
• antibiotika antitumorózní aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• antigeny CD20 * aplikace a dávkování   terapeutické užití   MeSH
• antitumorózní látky alkylující aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• antitumorózní látky fytogenní aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• biologická terapie * MeSH
• cílená molekulární terapie MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   MeSH
• dospělí MeSH
• imunologické faktory MeSH
• imunosupresiva aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• inhibitory topoisomerasy II aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• mladiství MeSH
• modulátory tubulinu aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• myeloablativní agonisté aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• myší monoklonální protilátky aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• nežádoucí účinky léčiv MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• rituximab MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

In this study, we describe the synthesis, physico-chemical characterisation and results of the in vitro and in vivo evaluation of the biological behaviour of N-(2-hydroxypropyl)methacrylamide-based (HPMA) copolymer conjugates bearing doxorubicin (DOX) partly bound via a pH-sensitive hydrazone and partly via enzymatically degradable amide bonds, each contributing to a different anti-tumour mechanism of action of the polymer-doxorubicin conjugate. The following two types of HPMA copolymer drug carriers designed for passive tumour targeting were synthesised and compared: the linear non-degradable copolymer and the biodegradable high-molecular-weight (HMW) diblock copolymer. The HMW diblock copolymer carrier containing a degradable disulphide bond between the polymer blocks showed a rapid degradation in a buffer containing glutathione within the first few hours of incubation. In contrast to the conjugate with the amide bond-bound DOX requiring the presence of lysosomal enzymes to release DOX, the polymer-drug conjugate with the DOX bound via a hydrazone bond released DOX by pH-sensitive hydrolysis, which was significantly faster in a buffer of pH 5.0 (intracellular pH) than pH 7.4, mimicking the conditions in the bloodstream. The significant and comparable in vivo anti-tumour activity of the diblock HMW conjugate and an equimolar mixture of the conjugates differing in the DOX attachment method along with the development of cancer resistance during treatment with these conjugates demonstrated the high potential of these compounds in the development of new nanomedicines suitable for the treatment of solid tumours.

• MeSH
• akrylamidy chemie   MeSH
• antibiotika antitumorózní chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• doxorubicin chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• hydrazony chemie   MeSH
• koncentrace vodíkových iontů MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   MeSH
• nosiče léků chemie   farmakologie   MeSH
• stabilita léku MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied. METHODS: DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored. RESULTS: ORC in combination with DOX significantly decreased DOXOL plasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOL concentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST. ConclusIONS: In vivo, ORC was able to retard DOXOL formation but was not able to improve DOX efficacy in EST-bearing mice.

• MeSH
• antibiotika antitumorózní farmakokinetika   farmakologie   MeSH
• doxorubicin analogy a deriváty   farmakokinetika   farmakologie   MeSH
• Ehrlichův tumor farmakoterapie   patologie   MeSH
• ethanolaminy farmakologie   MeSH
• intravenózní podání MeSH
• isochinoliny farmakologie   MeSH
• játra metabolismus   MeSH
• lékové interakce MeSH
• myokard metabolismus   MeSH
• myši MeSH
• tkáňová distribuce MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The molecular weight and molecular architecture of soluble polymer drug carriers significantly influence the biodistribution and anti-tumour activities of their doxorubicin (DOX) conjugates in tumour-bearing mice. Biodistribution of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-DOX conjugates of linear and star architectures were compared in EL4 T-cell lymphoma-bearing mice. Biodistribution, including tumour accumulation, and anti-tumour activity of the conjugates strongly depended on conjugate molecular weight (MW), polydispersity, hydrodynamic radius (R(h)) and molecular architecture. With increasing MW, renal clearance decreased, and the conjugates displayed extended blood circulation and enhanced tumour accumulation. The linear conjugates with flexible polymer chains were eliminated by kidney clearance more quickly than the highly branched star conjugates with comparable MWs. Interestingly, the data suggested different mechanisms of renal filtration for star and linear conjugates. Only star conjugates with MWs below 50,000g.mo(-1) were removed by kidney filtration, while linear polymer conjugates with MWs near 70,000g.mol(-1), exceeding the generally accepted limit for renal elimination, were detected in the urine 36-96h after injection. Additionally, survival of tumour-bearing mice was strongly dependent on molecular weight and polymer conjugate architecture. Treatment of mice with the lower MW conjugate at a dose of 10mg DOX eq./kg resulted in 12% long-term surviving animals, while treatment with the corresponding star conjugate enabled 75% survival of animals.

• MeSH
• akrylamidy chemie   farmakokinetika   terapeutické užití   MeSH
• antibiotika antitumorózní chemie   farmakokinetika   MeSH
• doxorubicin chemie   farmakokinetika   terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• lymfom farmakoterapie   MeSH
• metabolická clearance MeSH
• molekulární struktura MeSH
• molekulová hmotnost MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• stabilita léku MeSH
• tkáňová distribuce MeSH
• transplantace nádorů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH