In recent years, a lot of scientific interest has focused on cancer immunotherapy. Although chronic inflammation has been described as one of the hallmarks of cancer, acute inflammation can actually trigger the immune system to fight diseases, including cancer. Toll-like receptor (TLR) ligands have long been used as adjuvants for traditional vaccines and it seems they may also play a role enhancing efficiency of tumor immunotherapy. The aim of this perspective is to discuss the effects of TLR stimulation in cancer, expression of various TLRs in different types of tumors, and finally the role of TLRs in anti-cancer immunity and tumor rejection.

• Klíčová slova
• anti-cancer immunity, immuno-oncology, immunotherapy, toll-like receptors, tumor rejection,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• imunita * MeSH
• lidé MeSH
• ligandy MeSH
• nádory etiologie   metabolismus   patologie   terapie   MeSH
• orgánová specificita genetika   imunologie   MeSH
• regulace genové exprese u nádorů MeSH
• toll-like receptory agonisté   genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• ligandy MeSH
• toll-like receptory MeSH

Positive effects of repeated administration of diclofenac, an inhibitor of prostaglandin synthesis, in terms of prevention of tumor development and stimulation of hematopoiesis have been observed in C3H mice transplanted subcutaneously with G:5:113 fibrosarcoma cells. Fourteen-day treatment with diclofenac (3.75 microg/kg/day) started from day 5 after tumor cell transplantation. Measurements of tumors and hematological examinations were performed on day 30. The results strongly suggest the possibility that inhibitors of prostaglandin synthesis (non-steroidal anti-inflammatory drugs) may be used in oncological practice where the observed effects are highly desirable.

• MeSH
• antiflogistika nesteroidní farmakologie   terapeutické užití   MeSH
• diklofenak farmakologie   terapeutické užití   MeSH
• experimentální sarkom farmakoterapie   MeSH
• fibrosarkom farmakoterapie   MeSH
• hematopoéza účinky léků   MeSH
• myši inbrední C3H MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• preklinické hodnocení léčiv MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• diklofenak MeSH

Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including non-canonical functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from "cold" to "hot", and potentially augment immune check-point blockade therapies. This combination modality demonstrated to significantly reduce tumor growth in syngeneic melanoma tumor models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed profound changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically "cold" tumors and subsequently improve ongoing immune check-point blockade therapies.

• MeSH
• antiflogistika terapeutické užití   MeSH
• antigeny CD274 imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   imunologie   MeSH
• imunologická tolerance účinky léků   MeSH
• inhibitory histondeacetylas terapeutické užití   MeSH
• makrofágy účinky léků   imunologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory farmakoterapie   imunologie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antiflogistika MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• Cd274 protein, mouse MeSH Prohlížeč
• Hdac6 protein, mouse MeSH Prohlížeč
• histondeacetylasa 6 MeSH
• inhibitory histondeacetylas MeSH
• protinádorové látky imunologicky aktivní MeSH

A novel anti-tumor platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand displaying oral activity was prepared and its oral activity was evaluated. The murine ADJ/PC6 plasmacytoma and human A2780 ovarian carcinoma tumor model were used to evaluate the in vivo anti-tumor activity of a single dose and also of repeated doses with comparison to the activity of cisplatin and of the platinum(IV) complex satraplatin. The acute toxicity of LA-12 in mice is relatively low (maximum tolerated dose 1000 mg/kg), and the effective dose is comparable to that of cisplatin and higher than that of satraplatin. The therapeutic index derived from this is very high (250). In the human tumor model, two repeated dose schedule regimens were evaluated. LA-12 exerted a significantly higher anti-tumor activity than other substances, i.e. cisplatin and satraplatin, in repeated doses on the murine ADJ/PC6 plasmacytoma tumor model. The dailyx5 repeated dose regimen was selected for further evaluation.

• MeSH
• adenokarcinom farmakoterapie   MeSH
• amantadin aplikace a dávkování   analogy a deriváty   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• aplikace orální MeSH
• inbrední kmeny myší MeSH
• léky antitumorózní - screeningové testy metody   MeSH
• lidé MeSH
• maximální tolerovaná dávka MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory vaječníků farmakoterapie   MeSH
• organoplatinové sloučeniny aplikace a dávkování   MeSH
• plazmocytom farmakoterapie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

Camptothecin (CPT), an alkaloid, was first discovered from plants and has potent anti-tumor activity. Since then, CPT analogs (namely Irinotecan and Topotecan) have been approved by the FDA for cancer treatments. Curcumin, on the other hand, is a widely used photosensitizer in photodynamic therapy (PDT) treatment. In our previous work, we have reported a straightforward strategy to construct a drug self-delivery system in which two-molecular species Irinotecan and Curcumin can self-assembly into a complex of ion pairs, namely ICN, through intermolecular non-covalent interactions. We found that ICN has slightly better chemotherapy efficacy than its individual components with much fewer side effects. In this paper, we aim to combine the chemotherapy and the PDT of ICN to further improve its anti-tumor performance. The efficient cellular uptake of ICNs was observed by confocal microscopy. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the generation of singlet oxygen species. We found that the cell viability was 9% with both chemotherapy and PDT, and 31% with chemotherapy alone for the case with an ICN concentration of 10 μM, which demonstrated that the anti-tumor efficacy against the HT-29 cancer cell line was enhanced substantially with the combination therapy strategy. The study with an in vivo mouse model has further verified that the chemo-PDT dual therapy can inhibit tumor growth by 84% and 18.8% comparing with the control group and the chemotherapy group, respectively. Our results demonstrated that the new strategy using self-assembly and carrier-free nanoparticles with their chemo-PDT dual therapy may provide new opportunities to develop future combinatorial therapy methods in treating cancer.

• Klíčová slova
• Anti-tumor efficacy, Combination therapy, Drug delivery system, Photodynamic therapy,
• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• apoptóza účinky léků   účinky záření   MeSH
• buňky HT-29 MeSH
• diarylheptanoidy chemie   MeSH
• fotochemoterapie metody   MeSH
• intracelulární prostor účinky léků   metabolismus   účinky záření   MeSH
• kamptothecin chemie   farmakologie   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• diarylheptanoidy MeSH
• kamptothecin MeSH

The Internet-based system DIOS addresses the issues of anti-tumor chemotherapy and its evaluation. The repository of chemotherapeutic regimens (CHRs) stored in XML structured format constitutes the core of the system. Several applications have been created based on this repository, in order to allow users to browse current CHRs and procedures of planning and evaluation of chemotherapy based on the dose intensity concept. This freely available system uses technology based on the XML standard and XSLT transformations.

• MeSH
• internet * MeSH
• karboplatina aplikace a dávkování   farmakokinetika   MeSH
• lidé MeSH
• plánování péče o pacienty MeSH
• počítačová farmakoterapie metody   MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   farmakokinetika   MeSH
• rozvrh dávkování léků MeSH
• systémy pro podporu klinického rozhodování organizace a řízení   MeSH
• telemedicína metody   organizace a řízení   MeSH
• uživatelské rozhraní počítače * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• karboplatina MeSH

BACKGROUND: Discontinuation of anti-TNF therapy in patients with inflammatory bowel diseases (IBD) in remission remains a controversial issue. The aims of our study were to assess the proportion of patients who relapse after cessation of biological treatment, and to identify potential risk factors of disease relapse. METHODS: Consecutive IBD patients who discontinued anti-TNF therapy in steroid-free clinical and endoscopic remission were prospectively followed. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. RESULTS: Seventy-eight IBD patients (Crohn's disease, CD 61; ulcerative colitis, UC 17) were included and followed for a median of 30 months (range 7-47). A total of 32 (53%) CD patients and nine (53%) UC patients relapsed by the end of the follow-up with a median time to relapse of 8 months (range 1-25) in CD patients and 14 months (range 4-37) in UC patients, respectively. The cumulative probabilities of maintaining remission at 6, 12, and 24 months were 82%, 59%, and 51% in CD patients, and 77%, 77%, and 64% in UC patients, respectively. Survival of CD patients who were in deep remission (clinical and endoscopic healing; faecal calprotectin <150 mg/kg; CRP ≤5 mg/l) was not better compared with those who did not fulfill these criteria. In multivariate models, only colonic CD protected patients from disease relapse. CONCLUSIONS: Approximately half of the IBD patients relapsed within 2 years after anti-TNF discontinuation. In CD patients, no difference between those who were or were not in deep remission was found. Colonic localization protected patients from relapse.

• Klíčová slova
• Crohn's disease, anti-TNF, treatment discontinuation, ulcerative colitis,
• MeSH
• adalimumab škodlivé účinky   terapeutické užití   MeSH
• antiflogistika nesteroidní škodlivé účinky   terapeutické užití   MeSH
• C-reaktivní protein metabolismus   MeSH
• časové faktory MeSH
• Crohnova nemoc farmakoterapie   patologie   MeSH
• dospělí MeSH
• feces chemie   MeSH
• gastrointestinální endoskopie MeSH
• indukce remise MeSH
• infliximab škodlivé účinky   terapeutické užití   MeSH
• leukocytární L1-antigenní komplex analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• nenasazení léčby MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• recidiva MeSH
• rizikové faktory MeSH
• senioři MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• ulcerózní kolitida farmakoterapie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adalimumab MeSH
• antiflogistika nesteroidní MeSH
• C-reaktivní protein MeSH
• infliximab MeSH
• leukocytární L1-antigenní komplex MeSH
• TNF-alfa MeSH

The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.

• MeSH
• amantadin analogy a deriváty   terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• chemorezistence MeSH
• cisplatina škodlivé účinky   MeSH
• ligandy MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   patologie   prevence a kontrola   MeSH
• nádory tračníku farmakoterapie   patologie   prevence a kontrola   MeSH
• nádory vaječníků farmakoterapie   patologie   prevence a kontrola   MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• transplantace heterologní MeSH
• viabilita buněk účinky léků   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
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• ligandy MeSH
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

Herein, new biodegradable star polymer-doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable polymer conjugates in a broad range of molecular weights (200-1000g/mol) while still maintaining low polydispersity (~1.7). The polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight polymer carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star polymer-Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a M(w) of HPMA copolymers of 200,000 to 600,000g/mol is optimal for polymer carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.

• MeSH
• antibiotika antitumorózní chemie   metabolismus   farmakokinetika   terapeutické užití   MeSH
• biokompatibilní materiály chemie   metabolismus   MeSH
• dendrimery chemie   metabolismus   MeSH
• doxorubicin chemie   metabolismus   farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• lymfom farmakoterapie   MeSH
• methakryláty chemie   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie 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
• biokompatibilní materiály MeSH
• dendrimery MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• PAMAM Starburst MeSH Prohlížeč

Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.

• Klíčová slova
• Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone, anti-cancer agents, di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, metabolism, pharmacokinetics,
• MeSH
• antitumorózní látky metabolismus   farmakokinetika   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• tandemová hmotnostní spektrometrie MeSH
• thiosemikarbazony metabolismus   farmakokinetika   farmakologie   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antitumorózní látky MeSH
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Prohlížeč
• thiosemikarbazony MeSH