Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.

• Klíčová slova
• eye preservation treatment, intravitreal chemotherapy, retinoblastoma, vitreous seeding,
• MeSH
• alkylační protinádorové látky farmakologie   terapeutické užití   MeSH
• dítě MeSH
• injekce intravitreální MeSH
• lidé MeSH
• melfalan škodlivé účinky   MeSH
• nádory sítnice * chemicky indukované   farmakoterapie   MeSH
• retinoblastom * chemicky indukované   farmakoterapie   MeSH
• retrospektivní studie MeSH
• sklivec patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• melfalan MeSH

INTRODUCTION: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. AREAS COVERED: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. EXPERT OPINION: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.

• Klíčová slova
• Melflufen, melphalan flufenamide, relapsed/refractory multiple myeloma,
• MeSH
• alkylační protinádorové látky aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• fenylalanin aplikace a dávkování   škodlivé účinky   analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• melfalan aplikace a dávkování   škodlivé účinky   analogy a deriváty   farmakologie   MeSH
• míra přežití MeSH
• mnohočetný myelom farmakoterapie   patologie   MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• recidiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• fenylalanin MeSH
• melfalan MeSH
• melflufen MeSH Prohlížeč

PURPOSE: Primary cell lines are a valuable tool for evaluation of tumor behavior or sensitivity to anticancer treatment and appropriate dissociation of cells could preserve genomic profile of the original tissue. The main aim of our study was to compare the influence of two methods of glioblastoma multiforme (GBM) cell derivation (mechanic-MD; enzymatic-ED) on basic biological properties of thus derived cells and correlate them to the ones obtained from stabilized GBM cell line A-172. METHODS: Cell proliferation and migration (xCELLigence Real-Time Cell Analysis), expression of microRNAs and protein markers (RT-PCR and Western blotting), morphology (phase contrast and fluorescent microscopy), and accumulation of temozolomide (TMZ) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) inside the cells (LC-MS analysis) were carried out in five different samples of GBM (GBM1, GBM2, GBM32, GBM33, GBM34), with each of them processed by MD and ED types of isolations. The same analyses were done in the A-172 cell line too. RESULTS: Primary GBM cells obtained by ED or MD approaches significantly differ in biological behavior and properties of these cells. Unlike in primary MD GBM cells, higher proliferation, as well as migration, was observed in primary ED GBM cells, which were also associated with the acquired mesenchymal phenotype and higher sensitivity to TMZ. Finally, the same analyses of stabilized GBM cell line A-172 revealed several important differences in measured parameters. CONCLUSIONS: GBM cells obtained by MD and ED dissociation show considerable heterogeneity, but based on our results, MD approach should be the preferred method of primary GBM cell isolation.

• Klíčová slova
• cell isolation, glioblastoma multiforme, resistance, temozolomide,
• MeSH
• alkylační protinádorové látky farmakologie   MeSH
• chemorezistence MeSH
• glioblastom farmakoterapie   genetika   patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádory mozku farmakoterapie   genetika   patologie   MeSH
• pohyb buněk * účinky léků   MeSH
• proliferace buněk * účinky léků   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• screeningové testy protinádorových léčiv MeSH
• separace buněk metody   MeSH
• temozolomid farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• temozolomid MeSH

Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hippocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromodeoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60° sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.

• Klíčová slova
• Active avoidance, Adult neurogenesis, Discrimination, Generalization, Hippocampus, Reversal,
• MeSH
• alkylační protinádorové látky farmakologie   MeSH
• dakarbazin analogy a deriváty   farmakologie   MeSH
• gyrus dentatus účinky léků   MeSH
• krysa rodu Rattus MeSH
• neurogeneze účinky léků   MeSH
• neurony účinky léků   MeSH
• potkani Long-Evans MeSH
• prostorové učení účinky léků   MeSH
• reverzní učení účinky léků   MeSH
• temozolomid MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• dakarbazin MeSH
• temozolomid MeSH

The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts antiproliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). As homologous recombination repair (HRR)-deficient tumors are more susceptible to trabectedin, hyperthermia-mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8 or 43°C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type-dependent induction of apoptosis or senescence. Heat combination increased accumulation of γH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to γH2AX-positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA-transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear γH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency.

• Klíčová slova
• DNA repair, hyperthermia, sarcoma, trabectedin,
• MeSH
• alkylační protinádorové látky farmakologie   MeSH
• apoptóza účinky léků   účinky záření   MeSH
• biologické modely MeSH
• chemorezistence účinky záření   MeSH
• dioxoly farmakologie   MeSH
• histony metabolismus   MeSH
• indukovaná hypertermie * MeSH
• kaspasy metabolismus   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protein BRCA2 metabolismus   MeSH
• proteolýza účinky léků   účinky záření   MeSH
• rekombinační oprava DNA účinky léků   účinky záření   MeSH
• rekombinasa Rad51 metabolismus   MeSH
• sarkom metabolismus   patologie   terapie   MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• trabektedin MeSH
• transport proteinů MeSH
• vazba proteinů MeSH
• viabilita buněk účinky léků   účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• dioxoly MeSH
• histony MeSH
• kaspasy MeSH
• protein BRCA2 MeSH
• rekombinasa Rad51 MeSH
• tetrahydroisochinoliny MeSH
• trabektedin MeSH

Interaction of nine human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with six platinum complexes was studied using pooled human microsomes. The compounds used were cisplatin, oxaliplatin, carboplatin, transplatin, and trans-[PtCl2(NH3) (Am)], where Am=2-methylbutylamine or sec-butylamine. No significant inhibition of all CYP activities by carboplatin was observed. With cisplatin and oxaliplatin, a minor inhibition of CYP2C9 enzyme (75% of control at 400 miromol/l of these complexes) was seen; cisplatin also inhibited slightly the CYP2B6 activity (85% of control). With respect to plasma levels of cisplatin obtained in clinical applications, these effects are probably not important. In contrast, clinically ineffective transplatin, inhibited the CYP2B6 as well as CYP2C9 activities significantly (to 50-35% of control at 100 micromol/l); also, an inhibition of CYP2E1 activity was found here (to 70% at 100 micromol/l). Two other derivatives of transplatin (new antitumor agents with trans geometry), inhibited CYP activities more strongly reaching nearly a complete inhibition of the respective CYP activities at concentration of 200 micromol/l. Half maximal inhibitory concentration values were found in the range of tens of micromol/l indicating that there is a possibility of potential interactions of these compounds with drugs metabolized by CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2B6, CYP2A6, and CYP1A2. Interestingly, clinically non-significant inhibition was found with the CYP2C9 and CYP2C8 indicating low probability of interactions with, for example, warfarin. The results document that the new antitumor agents based on the transplatin should be more thoroughly tested for interactions with liver microsomal drug-metabolizing cytochromes P450.

• MeSH
• aktivace enzymů účinky léků   MeSH
• alkylační protinádorové látky chemie   farmakokinetika   farmakologie   MeSH
• biotransformace účinky léků   MeSH
• inhibitory cytochromu P450 * MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• organoplatinové sloučeniny chemie   farmakokinetika   farmakologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• inhibitory cytochromu P450 * MeSH
• organoplatinové sloučeniny MeSH
• systém (enzymů) cytochromů P-450 MeSH