Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

• MeSH
• dvojitá slepá metoda MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfocyty * MeSH
• nádory slinivky břišní krev   mortalita   MeSH
• neuroendokrinní nádory krev   mortalita   MeSH
• neutrofily * MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Malignant melanoma (MM) is the most aggressive and uneasily treatable form of skin cancer. Up to 90% of deaths because of skin tumours are estimated to be caused by this malignancy. Spontaneous regression is described as a partial or complete disappearance of cancer. It can be defined if the clinical and histological diagnosis of malignancy is verified and any therapeutic intervention potentially inducing mechanisms leading to regression has not been applied. Regression occurs more frequently in melanoma than in other types of tumours; it is reported to be six times higher than in other malignancies. Up to 50% of primary MM is reported to undergo spontaneous regression. However, spontaneous regression of the metastatic form of tumour is a rare phenomenon observed in only 0.23% of cases. The most frequently mentioned factors leading to spontaneous regression of MM are operative trauma, infection, vaccination (BCG and rabies vaccines) and immunological factors. Other well-documented circumstances associated with regression of metastatic MM include blood transfusion and various endocrine factors.

• MeSH
• lidé MeSH
• melanom imunologie   MeSH
• melanomové antigeny imunologie   MeSH
• nádory kůže imunologie   MeSH
• spontánní regrese nádoru imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Polymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer-RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer-RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer-DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs.

• MeSH
• akrylamidy aplikace a dávkování   farmakologie   MeSH
• chemorezistence MeSH
• doxorubicin aplikace a dávkování   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• neuroblastom farmakoterapie   metabolismus   MeSH
• P-glykoprotein antagonisté a inhibitory   biosyntéza   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• ritonavir aplikace a dávkování   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• synergismus léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This review deals with the role of microorganisms in spontaneous regression of a tumour. Spontaneous cancer regression is a phenomenon that has been described for many centuries. One of the most well known methods of inducing spontaneous regression of cancer is the application of Coley's toxin (heat-killed Streptococcus pyogenes and Serratia marcescens), which has been used for the successful treatment of sarcomas, carcinomas, lymphomas, myelomas and melanomas. In clinical practice, the use of Bacillus Calmette-Guérin vaccine for the treatment of superficial urinary bladder cancer is the most common instance of the application of microorganisms for the treatment of cancer. This review provides further information on other tested bacteria--Clostridium spp., Bifidobacterium spp., Lactobacillus spp. and Salmonella spp.--in this field of study. Among new age methods, bactofection, alternative gene therapy, combination bacteriolytic therapy and bacteria-directed enzyme prodrug therapy are some of the potential cancer treatment modalities that use microorganisms. We have also provided information about the interconnection among microorganisms, immune system response, and the possible mechanisms involved in the spontaneous regression of tumours.

• MeSH
• bakteriální toxiny dějiny   terapeutické užití   MeSH
• BCG vakcína terapeutické užití   MeSH
• Bifidobacterium genetika   metabolismus   MeSH
• Clostridium genetika   metabolismus   MeSH
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny starověku MeSH
• fyziologie bakterií * MeSH
• genetická terapie MeSH
• kombinovaná terapie MeSH
• Lactobacillus genetika   metabolismus   MeSH
• lidé MeSH
• nádory imunologie   mikrobiologie   terapie   MeSH
• Salmonella genetika   metabolismus   MeSH
• spontánní regrese nádoru MeSH
• Check Tag
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny starověku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

In the present study, we investigated the anticancer action of the trithiolato arene ruthenium complex, [(η-p-MeC6H4Pr)2Ru2(μ-S-p-C6H4OH)3]Cl, named diruthenium-2, both in vitro and in vivo. The mechanism of antiproliferative, cytotoxic, and DNA-damaging activity, and the effect on expressions of cell cycle regulatory proteins were investigated using a WST-1-based proliferation assay, lactate dehydrogenase leakage assay, comet assay, flow cytometry, and western blot analysis. In-vivo anticancer activity was evaluated using Ehrlich tumor-bearing NMRI mice. Diruthenium-2 inhibited the growth of all cancer cell lines used, the most sensitive being gastric (AGS), breast cancer (BT-549, MCF-7, MDA-MB-231), and leukemic (HL-60, MOLT-4) cells. In MCF-7 cells, it caused a G1/S cell cycle arrest, along with an increase in the expression of protein p21 and cyclin B1. We also observed increased levels of MRN complex proteins, which, together with the results from the comet assay, indicate the formation of DNA double-strand breaks. In tumor-bearing mice, diruthenium-2 at doses of 3 and 5 mg/kg inhibits the growth of solid Ehrlich tumor, although weaker than cisplatin. However, it did not prolong the post-therapeutic survival. Our results suggest the in-vitro potential of diruthenium-2 should be further evaluated in studies using other in-vivo models.

• MeSH
• HL-60 buňky MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• leukemie farmakoterapie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   MeSH
• nádory žaludku farmakoterapie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• ruthenium chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This study aimed to test the antiproliferative effect of three benzimidazole anthelmintics in intestinal cancer cells and to investigate whether these drugs, which inhibit tubulin polymerization, can potentiate the efficacy of the microtubule-stabilizing drug paclitaxel (PTX). Four intestinal cancer cell lines, SW480, SW620, HCT8, and Caco2, with different origins and growth characteristics were used. The antiproliferative effect of albendazole (ABZ), ricobendazole (RBZ), flubendazole (FLU), and their combinations with PTX was tested using three different end-point viability assays, cell cycle distribution analysis, and the x-CELLigence System for real-time cell analysis. ABZ and FLU inhibited cell proliferation significantly in a concentration-dependent and time-dependent manner through cell arrest in the G2/M phase. RBZ was not effective at any concentration tested. The cell lines differed in sensitivity to FLU and ABZ, with HCT8 being the most sensitive, showing IC₅₀ values for ABZ and FLU that reached 0.3 and 0.9 μmol/l, respectively. Combinations of PTX+ABZ and PTX+FLU decreased cell viability more effectively when compared with treatment with individual drugs alone. The anthelmintic benzimidazole drugs ABZ and FLU show a significant cytostatic effect and potentiate the efficacy of PTX in intestinal cancer cells.

• MeSH
• adenokarcinom farmakoterapie   MeSH
• albendazol analogy a deriváty   farmakologie   MeSH
• anthelmintika farmakologie   MeSH
• chemorezistence účinky léků   MeSH
• fytogenní protinádorové látky farmakologie   MeSH
• G2 fáze účinky léků   MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• mebendazol analogy a deriváty   farmakologie   MeSH
• mikrotubuly účinky léků   MeSH
• modulátory tubulinu farmakologie   MeSH
• nádorové buněčné linie MeSH
• paclitaxel farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• stabilita proteinů účinky léků   MeSH
• střevní nádory farmakoterapie   MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Doxorubicin belongs to anthracycline cytotoxic drugs and it is widely used as a major therapeutic agent in the treatment of various types of tumors. However,its therapeutic use is limited by the development of myelosuppression and cardiotoxicity after a specific cumulative dose is reached. The aim of this study was to investigate the effect of flavonoids, either natural or synthetic on doxorubicin-mediated formation of oxidative stress implicated in doxorubicin toxicity. Doxorubicin caused a concentration-dependent increase in the formation of hydroxyl radicals in minipig liver microsomes used as an in-vitro model system. When bacterial membranes heterologously expressing human NADPH cytochrome-P450 oxidoreductase were incubated with doxorubicin, formation of the superoxide radical under aerobic conditions and the doxorubicin–semiquinone radical under anaerobic conditions was detected. Forty different flavonoids were tested for their potency to prevent NADPH-induced or Fe2+-induced peroxidation of lipids in the microsomal system. According to the results, seven flavonoids were selected for evaluation of their potency to inhibit doxorubicin-dependent formation of hydroxyl radicals assessed by electron spin resonance. Myricetin, fisetin, and kaempferol were found to produce a significant protective effect against hydroxyl radicals in the minipig liver microsomal system. In conclusion, this study shows the use of a novel cost-effective in-vitro model system for preselection of antioxidants for testing of their protective effects against toxicity of anthracyclines and potentially other oxidative stress-inducing chemicals.

• MeSH
• benzochinony metabolismus   MeSH
• doxorubicin farmakologie   toxicita   MeSH
• elektronová paramagnetická rezonance MeSH
• flavonoidy farmakologie   MeSH
• hydroxylový radikál metabolismus   MeSH
• jaterní mikrozomy účinky léků   metabolismus   MeSH
• lidé MeSH
• modely u zvířat MeSH
• NADPH-cytochrom c-reduktasa metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• prasata MeSH
• protinádorová antibiotika farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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 farmakokinetika   farmakologie   chemie   MeSH
• biotransformace účinky léků   MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy enzymologie   účinky léků   MeSH
• lékové interakce MeSH
• lidé MeSH
• organoplatinové sloučeniny farmakokinetika   farmakologie   chemie   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
• práce podpořená grantem MeSH

The platinum(II)-based complex cisplatin is one of the most frequently used antitumour agents; however, a high incidence of harmful side effects and the frequent emergence of acquired resistance are the major clinical problems. The novel platinum(IV)-based complex LA-12 exhibits a high efficacy against cancer cell lines, including cisplatin-insensitive cells, but the mechanisms by which LA-12 perturbs cell growth are unclear. We tested the effects of LA-12 on the p53 response and demonstrate that LA-12 induces unique changes in the profile of gene expression compared with cisplatin and doxorubicin. Furthermore, the ability of LA-12 to disrupt cellular proliferation is greatly enhanced by the expression of p53 and p53/47 indicating both p53-dependent and p53-independent effects of LA-12. Exposure of the human cancer cell lines H1299, A2780, BT549 and BT474 to LA-12 alters the expression of p53 and p53/47 in both a time-dependent and dose-dependent manner. Treatment of cells with a low concentration of the drug results in accumulation of p53 and p53/47 concomitant with their posttranslational modification, whereas a high dose results in the disappearance of both the forms of p53. The distinct p53 activation profile of LA-12 compared with cisplatin and doxorubicin provides a molecular explanation for the ability of this drug to treat cisplatin-resistant cells and indicates its potential usefulness as an alternative antitumour agent in first-line therapy or as a second-line therapy in patients with acquired cisplatin resistance.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• buněčný cyklus účinky léků   MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• doxorubicin MeSH
• financování organizované MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• posttranslační úpravy proteinů MeSH
• proliferace buněk účinky léků   MeSH
• protein - isoformy genetika   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• průtoková cytometrie MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

We have examined the ability of actinomycin D to induce apoptosis in human peripheral blood lymphocytes. Run-On assays were performed to specify the primary molecular damage, reverse transcription-PCR, Western blots and flow cytometry studies were performed to ascertain which proteins of the apoptosis machinery were affected to cause actinomycin D-induced cell death. Expression of 23 apoptosis-related genes was investigated. The down-regulation of ribosomal RNA synthesis caused by actinomycin D induced a mitochondria-dependent apoptosis. Although the expression of the majority of examined genes remained indifferent against actinomycin D activity, the cellular level of p53 protein increased, subsequently upregulating both Puma mRNA and protein. Puma-mediated mitochondrial apoptosis was accompanied by nucleolin cleavage and Bcl-2 mRNA destabilization. The stability of the cellular level of Bcl-2 protein independent of a mRNA decrease suggests that protection of Bcl-2 protein against proteasomal degradation can moderate the apoptotic process. In peripheral blood lymphocytes cultured in vitro, the apoptosis induced by a low concentration of actinomycin D (10 nmol/l) is dependent on p53 and Puma activation. This apoptotic pathway is demonstrated in peripheral blood lymphocytes for the first time. A different apoptotic pathway induced in peripheral blood lymphocytes using this drug has, however, been previously revealed by other authors. The combination of cell specificity and dose-dependent effects can likely play a decisive role in apoptosis observed in peripheral blood lymphocytes after genotoxic drug application.

• MeSH
• apoptóza účinky léků   MeSH
• daktinomycin aplikace a dávkování   farmakologie   MeSH
• down regulace MeSH
• financování organizované MeSH
• lidé MeSH
• lymfocyty účinky léků   MeSH
• messenger RNA metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• poškození DNA účinky léků   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• protinádorová antibiotika aplikace a dávkování   farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• protoonkogenní proteiny metabolismus   MeSH
• průtoková cytometrie MeSH
• ribozomální DNA účinky léků   MeSH
• upregulace účinky léků   MeSH
• viabilita buněk MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH