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Sample records for active anti-cancer immunotherapy

  1. The promising alliance of anti-cancer electrochemotherapy with immunotherapy.

    Calvet, Christophe Y; Mir, Lluis M

    2016-06-01

    Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects. PMID:26993326

  2. Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

    van den Engel Natasja K

    2011-08-01

    Full Text Available Abstract Background Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg transgenic mouse. Methods Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST. Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls. Results LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4+CD25+FoxP3+ T cells (Tregs. Conclusions Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.

  3. Potential Anti-cancer Activity of Furanodiene

    Zhen-zhen Ba; Yan-ping Zheng; Hui Zhang; Xiu-yan Sun; Dong-hai Lin

    2009-01-01

    Objective: To study the anti-tumor activities of furanodiene (C15H20O), a primary sesquiterpene compound isolated from the essential oil of the rhizome of Curcuma wenyujin YH Chen et C. Ling(Wen Ezhu), in vitro and in vivo.Methods: In vitro MTT assay was used to further study the effects of time and dosage on anti-proliferation of furanodiene against the sensitive Hela, Hep-2,HL-60, U251 cells, based on the cytotoxic effects of furanodiene on 12 human malignant tumor cell lines with the essential oil of Wen Ezhu as control., and the half-inhibitory concentration (IC50) was observed. In vivo uterine cervix (U14) tumor cell was selected and the conventional assay method of anti-tumor activity was employed. Furanodiene liposome was administered intraperitoneally, and tumor-inhibitory rate, thymus and spleen indexes were observed.Results: The inhibitive effects on cell proliferation were shown in all of the twelve cell lines and the cytotoxic effects of furanodiene against Hela, Hep-2, HL-60, U251 cells were observed after 12 h of administration, the effect could last for at least 48 h in a dose dependent manner, and the IC50 values were 0.6, 1.7, 1.8, 7.0 μg/ml, respectively. Furanodiene was also found to show inhibitive effects on the proliferation of uterine cervix (U14) tumor induced in mice. The tumor inhibition rates were 36.09% (40 mg/kg), 41.55% (60 mg/kg), 58.29% (80 mg/kg), respectively.Conclusion: Furanodiene is one of primary anti-cancer active components in the essential oil of Wen Ezhu, and also a very effective agent against uterine cervix cancer, and has protection effect on the immune function.

  4. Anti-cancer activities of diospyrin, its derivatives and analogues

    Sagar, Sunil

    2010-09-01

    Natural products have played a vital role in drug discovery and development process for cancer. Diospyrin, a plant based bisnaphthoquinonoid, has been used as a lead molecule in an effort to develop anti-cancer drugs. Several derivatives/analogues have been synthesized and screened for their pro-apoptotic/anti-cancer activities so far. Our review is focused on the pro-apoptotic/anti-cancer activities of diospyrin, its derivatives/analogues and the different mechanisms potentially involved in the bioactivity of these compounds. Particular focus has been placed on the different mechanisms (both chemical and molecular) thought to underlie the bioactivity of these compounds. A brief bioinformatics analysis at the end of the article provides novel insights into the new potential mechanisms and pathways by which these compounds might exert their effects and lead to a better realization of the full therapeutic potential of these compounds as anti-cancer drugs. © 2010 Elsevier Masson SAS. All rights reserved.

  5. ANTI-CANCER ACTIVITY OF NIGELLA SATIVA

    Salomi, M.J.; Panikkar, K.R.; Kesavan, M.; Donata, K.; Rajagopalan, K.

    1989-01-01

    An extract of Smilax china, Hemidesmus indicus and Nigella Sativa on the ratio 3:2:1, prepared by boiling in water and concentrated could completely cure cases of oral canger diagnosed by modern methods. Cytotoxic studies with the three components showed activity in Nigella sativa at a concentration of 25 microgram equivalent of the dry powder against Dalton's lymphoma ascites cells. Animal experiments indicated the retarded growth of ascites as compared to the controls with a longivity of 90%.

  6. Anti-cancer activity of compounds from Cassia garrettiana heartwood

    Supreeya Yuenyongsawad

    2014-04-01

    Full Text Available The ethanol extract of Cassia garrettiana heartwood showed marked inhibitory activity against several cancer cell lines including HT-29, HeLa, MCF-7 and KB cells. Therefore, its extract and compounds were investigated for their anticancer effect using the Sulforhodamine B (SRB assay. The ethanol extract of C. garrettiana heartwood was separated to give five compounds which are chrysophanol (1, piceatannol (2, aloe-emodin (3, emodin (4 and cassigarol E (5. Of the tested samples, chrysophanol (1 showed the highest anti-cancer activity against KB cells (IC50 = 0.045 g/mL, aloe emodin (3 was the most active against HT-29 (IC50 = 0.29 g/mL, emodin (4 was against HeLa cells (IC50 = 0.82 g/mL, and cassigarol E (5 was active against MCF-7 (IC50 = 0.021 g/mL, whereas piceatannol (2 was inactive in all tested cell lines. This is the first report of anti-cancer effect against HT-29, HeLa, MCF-7 and KB cells of C. garrettiana heartwood.

  7. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark

    Eo, Hyun Ji; Park, Jae Ho; Park, Gwang Hun; Lee, Man Hyo; Lee, Jeong Rak; Koo, Jin Suk; Jeong, Jin Boo

    2014-01-01

    Background Root bark of mulberry (Morus alba L.) has been used in herbal medicine as anti-phlogistic, liver protective, kidney protective, hypotensive, diuretic, anti-cough and analgesic agent. However, the anti-cancer activity and the potential anti-cancer mechanisms of mulberry root bark have not been elucidated. We performed in vitro study to investigate whether mulberry root bark extract (MRBE) shows anti-inflammatory and anti-cancer activity. Methods In anti-inflammatory activity, NO was...

  8. Anti-cancer activity of bromelain nanoparticles by oral administration.

    Bhatnagar, Priyanka; Patnaik, Soma; Srivastava, Amit K; Mudiam, Mohan K R; Shukla, Yogeshwer; Panda, Amulya K; Pant, Aditya B; Kumar, Pradeep; Gupta, Kailash C

    2014-12-01

    Oral administration of anti-cancer drugs is an effective alternative to improve their efficacy and reduce undesired toxicity. Bromelain (BL) is known as an effective anti-cancer phyto-therapeutic agent, however, its activity is reduced upon oral administration. In addressing the issue, BL was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) to formulate nanoparticles (NPs). Further, the NPs were coated with Eudragit L30D polymer to introduce stability against the gastric acidic conditions. The resultant coated NPs were characterized for BL entrapment, proteolytic activity and mean particle size. The stability and release pattern of NPs were evaluated under simulated gastrointestinal tract (GIT) pH conditions. Cytotoxicity studies carried out in human cell lines of diverse origin have shown significant dose advantage (-7-10 folds) with NPs in reducing the IC50 values compared with free BL. The cellular uptake of NPs in MCF-7, HeLa and Caco-2 cells monolayer was significantly enhanced several folds as compared to free BL. Altered expression of marker proteins associated with apoptosis and cell death (P53, P21, Bcl2, Bax) also confirmed the enhanced anti-carcinogenic potential of formulated NPs. Oral administration of NPs reduced the tumor burden of Ehrlich ascites carcinoma (EAC) in Swiss albino mice and also increased their life-span (160.0 ± 5.8%) when compared with free BL (24 ± 3.2%). The generation of reactive oxygen species, induction of apoptosis and impaired mitochondrial membrane potential in EAC cells treated with NPs confirmed the suitability of Eudragit coated BL-NPs as a promising candidate for oral chemotherapy. PMID:26000370

  9. Anti-cancer activities of Ganoderma lucidum: active ingredients and pathways

    Chi H.J. Kao; Jesuthasan, Amalini C; Karen S. Bishop; Marcus P. Glucina; Ferguson, Lynnette R

    2013-01-01

    ABSTRACTGanoderma lucidum, commonly referred to as Lingzhi, has been used in Asia for health promotion for centuries. The anti-cancer effects of G. lucidum have been demonstrated in both in vitro and in vivo studies. In addition, the observed anti-cancer activities of Ganoderma have prompted its usage by cancer patients alongside chemotherapy.The main two bioactive components of G. lucidum can be broadly grouped into triterpenes and polysaccharides. Despite triterpenes and polysaccharides bei...

  10. Potential Anti-Cancer Activities and Mechanisms of Costunolide and Dehydrocostuslactone

    Xuejing Lin

    2015-05-01

    Full Text Available Costunolide (CE and dehydrocostuslactone (DE are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application.

  11. Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity.

    Han, Li-Chen; Stanley, Paul A; Wood, Paul J; Sharma, Pallavi; Kuruppu, Anchala I; Bradshaw, Tracey D; Moses, John E

    2016-08-21

    Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues. PMID:27443386

  12. Anti-cancer efficacy of silybin derivatives -- a structure-activity relationship.

    Chapla Agarwal

    Full Text Available Silybin or silibinin, a flavonolignan isolated from Milk thistle seeds, is one of the popular dietary supplements and has been extensively studied for its antioxidant, hepatoprotective and anti-cancer properties. We have envisioned that potency of silybin could be further enhanced through suitable modification/s in its chemical structure. Accordingly, here, we synthesized and characterized a series of silybin derivatives namely 2,3-dehydrosilybin (DHS, 7-O-methylsilybin (7OM, 7-O-galloylsilybin (7OG, 7,23-disulphatesilybin (DSS, 7-O-palmitoylsilybin (7OP, and 23-O-palmitoylsilybin (23OP; and compared their anti-cancer efficacy using human bladder cancer HTB9, colon cancer HCT116 and prostate carcinoma PC3 cells. In all the 3 cell lines, DHS, 7OM and 7OG demonstrated better growth inhibitory effects and compared to silybin, while other silybin derivatives showed lesser or no efficacy. Next, we prepared the optical isomers (A and B of silybin, DHS, 7OM and 7OG, and compared their anti-cancer efficacy. Isomers of these three silybin derivatives also showed better efficacy compared with respective silybin isomers, but in each, there was no clear cut silybin A versus B isomer activity preference. Further studies in HTB cells found that DHS, 7OM and 7OG exert better apoptotic activity than silibinin. Clonogenic assays in HTB9 cells further confirmed that both the racemic mixtures as well as pure optical isomers of DHS, 7OM and 7OG were more effective than silybin. Overall, these results clearly suggest that the anti-cancer efficacy of silybin could be significantly enhanced through structural modifications, and identify strong anti-cancer efficacy of silybin derivatives, namely DHS, 7OM, and 7OG, signifying that their efficacy and toxicity should be evaluated in relevant pre-clinical cancer models in rodents.

  13. IN VITRO AND IN VIVO ANTI CANCER ACTIVITY OF METHANOLIC EXTRACT OF TECOMA STANS FLOWERS

    S.Kameshwaran

    2012-03-01

    Full Text Available Tecoma stans flowers have been traditionally used for many ailments including cancer. In the present study, anti cancer activity of methanolic flower extract of T.stans (METS was evaluated using both in vitro and in vivo methods. METS was subjected to preliminary qualitative phytochemical investigations by using standard procedures. In vitro antitumor activity of METS was evaluated by the MTT assay method using Vero and HEP‐2 cell lines. Then the extract subjected to in vivo anti cancer activity using Ehrlich ascites carcinoma (EAC tumor model. The activity was assessed Increase in life span, average increase in body weight, changes in food intake, tumor volume, tumor weight, viable cell count, non viable cell count, PCV, Total cell count and hematological studies. The potency of the extract was compared with standard 5-flurouracil (20 mg/kg i.p.. In in vitro anti cancer activity METS exhibited significant cytotoxic activity against both cell lines even at different concentrations. Oral administration of METS at the dose of 200 and 400 mg/Kg, significantly (p < 0.001 increased the survival time, non viable cell count and decreased the average body weight and food intake, viable cell count of the tumor bearing mice. After 14 days of inoculation, METS was able to reverse the changes in the hematological parameters, protein and PCV consequent to tumor inoculation.The results indicate that METS possess significant antitumor activity on dose dependent manner.

  14. Alloimmune activation promotes anti-cancer cytotoxicity after rat liver transplantation.

    Stéphanie Lacotte

    Full Text Available Liver transplantation for hepatocellular carcinoma (HCC results in a specific condition where the immune response is potentially directed against both allogeneic and cancer antigens. We have investigated the level of anti-cancer immunity during allogeneic immune response. Dark Agouti-to-Lewis and Lewis-to-Lewis rat liver transplantations were performed and the recipients anti-cancer immunity was analysed at the time of alloimmune activation. The occurrence of rejection in the allogeneic recipients was confirmed by a shorter survival (p<0.01, increased liver function tests (p<0.01, the presence of signs of rejection on histology, and a donor-specific ex vivo mixed lymphocyte reaction. At the time of alloimmune activation, blood mononuclear cells of the allogeneic group demonstrated increased anti-cancer cytotoxicity (p<0.005, which was related to an increased natural killer (NK cell frequency (p<0.05 and a higher monocyte/macrophage activation level (p<0.01. Similarly, liver NK cell anti-cancer cytotoxicity (p<0.005, and liver monocyte/macrophage activation levels (p<0.01 were also increased. The alloimmune-associated cytotoxicity was mediated through the NKG2D receptor, whose expression was increased in the rejected graft (p<0.05 and on NK cells and monocyte/macrophages. NKG2D ligands were expressed on rat HCC cells, and its inhibition prevented the alloimmune-associated cytotoxicity. Although waiting for in vivo validation, alloimmune-associated cytotoxicity after rat liver transplantation appears to be linked to increased frequencies and levels of activation of NK cells and monocyte/macrophages, and is at least in part mediated through the NKG2D receptor.

  15. NOVEL HYDROXAMIC ACIDS HAVING HISTONE DEACETYLASE INHIBITING ACTIVITY AND ANTI-CANCER COMPOSITION COMPRISING THE SAME AS AN ACTIVE INGREDIENT

    2013-01-01

    The present invention relates to a pharmaceutical composition for anticancer including novel hydroxamic acid with histone deacetylase inhibiting activity as an active ingredient. Hydroxamic acid compound of the present invention has inhibitory activity of histone deacetylase (HDAC) and shows...... cytotoxicity to a variety of cancer cells, being useful in strong anti-cancer drug....

  16. Immunotherapy

    ... Help raise $300,000 this month to find cures. Loading... Immunotherapy Immunotherapy SHARE: Print Glossary Immunotherapy, also ... destroy the antigens. In most circumstances, the body's natural immune system seems unable to identify cancer as ...

  17. Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity.

    Jeffrey J Roix

    Full Text Available Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.

  18. Trypanocidal activity of the proteasome inhibitor and anti-cancer drug bortezomib

    Wang Xia

    2009-07-01

    Full Text Available Abstract The proteasome inhibitor and anti-cancer drug bortezomib was tested for in vitro activity against bloodstream forms of Trypanosoma brucei. The concentrations of bortezomib required to reduce the growth rate by 50% and to kill all trypanosomes were 3.3 nM and 10 nM, respectively. In addition, bortezomib was 10 times more toxic to trypanosomes than to human HL-60 cells. Moreover, exposure of trypanosomes to 10 nM bortezomib for 16 h was enough to kill 90% of the parasites following incubation in fresh medium. However, proteasomal peptidase activities of trypanosomes exposed to bortezomib were only inhibited by 10% and 30% indicating that the proteasome is not the main target of the drug. The results suggest that bortezomib may be useful as drug for the treatment of human African trypanosomiasis.

  19. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-03-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.

  20. Synthesis, Characterization and Anti-Cancer Activity of Hydrazide Derivatives Incorporating a Quinoline Moiety.

    Bingul, Murat; Tan, Owen; Gardner, Christopher R; Sutton, Selina K; Arndt, Greg M; Marshall, Glenn M; Cheung, Belamy B; Kumar, Naresh; Black, David StC

    2016-01-01

    Identification of the novel (E)-N'-((2-chloro-7-methoxyquinolin-3-yl)methylene)-3-(phenylthio)propanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19-26 were prepared from the corresponding quinoline hydrazones and substituted carboxylic acids using EDC-mediated peptide coupling reactions. Further modification of the parent compound 18 was achieved by replacement of the quinoline moiety with other aromatic systems. All the newly synthesized compounds were evaluated for their anti-cancer activity against the SH-SY5Y and Kelly neuroblastoma cell lines, as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Analogues 19 and 22 significantly reduced the cell viability of neuroblastoma cancer cells with micromolar potency and significant selectivity over normal cells. The quinoline hydrazide 22 also induced G₁ cell cycle arrest, as well as upregulation of the p27(kip1) cell cycle regulating protein. PMID:27428941

  1. Synthesis, Characterization and Anti-Cancer Activity of Hydrazide Derivatives Incorporating a Quinoline Moiety

    Murat Bingul

    2016-07-01

    Full Text Available Identification of the novel (E-N′-((2-chloro-7-methoxyquinolin-3-ylmethylene-3-(phenylthiopropanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19–26 were prepared from the corresponding quinoline hydrazones and substituted carboxylic acids using EDC-mediated peptide coupling reactions. Further modification of the parent compound 18 was achieved by replacement of the quinoline moiety with other aromatic systems. All the newly synthesized compounds were evaluated for their anti-cancer activity against the SH-SY5Y and Kelly neuroblastoma cell lines, as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Analogues 19 and 22 significantly reduced the cell viability of neuroblastoma cancer cells with micromolar potency and significant selectivity over normal cells. The quinoline hydrazide 22 also induced G1 cell cycle arrest, as well as upregulation of the p27kip1 cell cycle regulating protein.

  2. Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines.

    Thigulla, Yadagiri; Akula, Mahesh; Trivedi, Prakruti; Ghosh, Balaram; Jha, Mukund; Bhattacharya, Anupam

    2016-01-21

    The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 μM). PMID:26592542

  3. Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity.

    Petiwala, Sakina M; Johnson, Jeremy J

    2015-10-28

    Recently, rosemary extracts standardized to diterpenes (e.g. carnosic acid and carnosol) have been approved by the European Union (EU) and given a GRAS (Generally Recognized as Safe) status in the United States by the Food and Drug Administration (FDA). Incorporation of rosemary into our food system and through dietary selection (e.g. Mediterranean Diet) has increased the likelihood of exposure to diterpenes in rosemary. In consideration of this, a more thorough understanding of rosemary diterpenes is needed to understand its potential for a positive impact on human health. Three agents in particular have received the most attention that includes carnosic acid, carnosol, and rosmanol with promising results of anti-cancer activity. These studies have provided evidence of diterpenes to modulate deregulated signaling pathways in different solid and blood cancers. Rosemary extracts and the phytochemicals therein appear to be well tolerated in different animal models as evidenced by the extensive studies performed for approval by the EU and the FDA as an antioxidant food preservative. This mini-review reports on the pre-clinical studies performed with carnosic acid, carnosol, and rosmanol describing their mechanism of action in different cancers. PMID:26170168

  4. Anti-cancer Activities of Ginseng Extract Fermented with Phellinus linteus

    Lee, Jong-Jin; Kwon, Ho-Kyun; Jung, In-Ho; Cho, Yong-Baik; Kim, Kyu-Joong; Kim, Jong-Lae

    2009-01-01

    In the present study, the anti-cancer effects of ginseng fermented with Phellinus linteus (GFPL) extract were examined through in vitro and in vivo assays. GFPL was produced by co-cultivating ginseng and Phellinus linteus together. Ginsenoside Rg3, Rh1 and Rh2 are important mediators of anti-angiogenesis and their levels in GFPL were enriched 24, 19 and 16 times, respectively, more than that of ginseng itself through the fermentation. GFPL exhibited distinct anti-cancer effects, including gro...

  5. Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship

    Agarwal, Ch.; Wadhwa, R.; Deep, G.; Biedermann, David; Gažák, Radek; Křen, Vladimír; Agarwal, R.

    2013-01-01

    Roč. 8, č. 3 (2013), e00074. E-ISSN 1932-6203 R&D Projects: GA MŠk(CZ) ME10027 Institutional support: RVO:61388971 Keywords : Silybin * silibinin * anti-cancer efficacy Subject RIV: CE - Biochemistry Impact factor: 3.534, year: 2013

  6. Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

    Maciej Serda

    Full Text Available Thiosemicarbazones (TSCs are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

  7. Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

    Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Simůnek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

  8. The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides.

    Szwej, Emilia; Devocelle, Marc; Kenny, Shane; Guzik, Maciej; O'Connor, Stephen; Nikodinovic-Runic, Jasmina; Radivojevic, Jelena; Maslak, Veselin; Byrne, Annete T; Gallagher, William M; Zulian, Qun Ren; Zinn, Manfred; O'Connor, Kevin E

    2015-06-20

    Conjugation of DP18L peptide with (R)-3-hydroxydecanoic acid, derived from the biopolymer polyhydroxyalkanoate, enhances its anti-cancer activity (O'Connor et al., 2013. Biomaterials 34, 2710-2718). However, it is unknown if other (R)-3-hydroxyalkanoic acids (R3HAs) can enhance peptide activity, if chain length affects enhancement, and what effect R3HAs have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HAs is carbon chain length dependent. In all but one example the R3HA conjugated peptides were more active against cancer cells than the unconjugated peptides. However, R3HAs with 9 and 10 carbons were most effective at improving DP18L activity. DP18L peptide variant DP17L, missing a hydrophobic amino acid (leucine residue 4) exhibited lower efficacy against MiaPaCa cells. Circular dichroism analysis showed DP17L had a lower alpha helix content and the conjugation of any R3HA ((R)-3-hydroxyhexanoic acid to (R)-3-hydroxydodecanoic acid) to DP17L returned the helix content back to levels of DP18L. However (R)-3-hydroxyhexanoic did not enhance the anti-cancer activity of DP17L and at least 7 carbons were needed in the R3HA to enhance activity of D17L. DP17L needs a longer chain R3HA to achieve the same activity as DP18L conjugated to an R3HA. As a first step to assess the synthetic potential of polyhydroxyalkanoate derived R3HAs, (R)-3-hydroxydecanoic acid was synthetically converted to (±)3-chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells. PMID:25820126

  9. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

    Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

    2014-01-01

    Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

  10. In vitro anti-cancer activity of two ethno-pharmacological healing plants from Guatemala Pluchea odorata and Phlebodium decumanum.

    Gridling, Manuela; Stark, Nicole; Madlener, Sibylle; Lackner, Andreas; Popescu, Ruxandra; Benedek, Birgit; Diaz, Rene; Tut, Foster M; Nha Vo, Thanh Phuong; Huber, Daniela; Gollinger, Michaela; Saiko, Philipp; Ozmen, Ali; Mosgoeller, Wilhelm; De Martin, Rainer; Eytner, Ruth; Wagner, Karl-Heinz; Grusch, Michael; Fritzer-Szekeres, Monika; Szekeres, Thomas; Kopp, Brigitte; Frisch, Richard; Krupitza, Georg

    2009-04-01

    Many traditional healing plants successfully passed several hundred years of empirical testing against specific diseases and thereby demonstrating that they are well tolerated in humans. Although quite a few ethno-pharmacological plants are applied against a variety of conditions there are still numerous plants that have not been cross-tested in diseases apart from the traditional applications. Herein we demonstrate the anti-neoplastic potential of two healing plants used by the Maya of the Guatemala/Belize area against severe inflammatory conditions such as neuritis, rheumatism, arthritis, coughs, bruises and tumours. Phlebodium decumanum and Pluchea odorata were collected, dried and freeze dried, and extracted with five solvents of increasing polarity. We tested HL-60 and MCF-7 cells, the inhibition of proliferation and the induction of cell death were investigated as hallmark endpoints to measure the efficiency of anti-cancer drugs. Western blot and FACS analyses elucidated the underlying mechanisms. While extracts of P. decumanum showed only moderate anti-cancer activity and were therefore not further analysed, particularly the dichloromethane extract of P. odorata inhibited the cell cycle in G2-M which correlated with the activation of checkpoint kinase 2, and down-regulation of Cdc25A and cyclin D1 as well as inactivation of Erk1/2. In HL-60 and MCF-7 cells this extract was a very strong inducer of cell death activating caspase-3 followed by PARP signature type cleavage. The initiating death trigger was likely the stabilization of microtubules monitored by the rapid acetylation of alpha-tubulin, which was even more pronounced than that triggered by taxol. The dichloromethane extract of P. odorata contains apolar constituents which inhibit inflammatory responses and exhibit anti-cancer activity. The strong proapoptotic potential warrants further bioassay-guided fractionation to discover and test the active principle(s). PMID:19287970

  11. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    Longo Martins, Murillo; Ignazzi, Rosanna; Eckert, Juergen;

    2016-01-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer...... drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with...

  12. Content determination of benzyl glucosinolate and anti-cancer activity of its hydrolysis product inCarica papaya L.

    Ze-You Li; Yong Wang; Wen-Tao Shen; Peng Zhou

    2012-01-01

    Objective:To determine the content of benzyl glucosinolate(BG)in the pulp and the seed and investigate the anti-cancer activity of its hydrolysis product inCarica papaya L.Methods:Determination ofBG was performed on an HypersilBDS C18 column at the wavelength of214 nm with0.1% trifluoroacetic acid (TFA)aqueous solution (A) and 0.1%TFA acetonitrile (B)as the mobile phase. In vitro activity test was adopted with cultured human lung cancerH69 cellin vitro to investigate the inhibition rate of cell proliferation of benzyl isothiocyanate(BITC)againstH69 cell.Results: The pulp has more BG before the maturation of papaya and it nearly disappeared after papaya matured, while the seed containsBG at every stage. Activity test demonstrated that the a higher concentration ofBITC would have better inhibition rate of cell proliferation onH69 cell, and the IC50 was6.5 μmol/L.Conclusions:BG also can be produced in the pulp of papaya and it will be stored in the seed after the fruit has been matured. The hydrolysis product ofBG has certain cancer-prevention anti-cancer activities for human.

  13. Could B7-H4 serve as a target to activate anti-cancer immunity?

    Wang, Lijuan; Heng, Xueyuan; Lu, Yong; Cai, Zhen; Yi, Qing; Che, Fengyuan

    2016-09-01

    It has been over 13years since the identification of B7-H4, the co-stimulatory molecule of B7 family members. While B7-H4 mRNA is widely distributed protein expression seems to be limited on tissues. Various cytokines and inflammatory mediators induce the expression of B7-H4. However, the specific regulatory mechanisms of B7-H4 remain to be defined. Recently, it has been shown that B7-H4 executes an inhibitory function in the T-cell response via reduced expansion, cell cycle arrest, decreased cytokine secretion and induced apoptosis of activated T-cells. Furthermore, B7-H4 suppresses the function of antigen presenting cells (APCs) and promotes the proliferation and development of regulatory T-cells (Treg). Moreover, a growing body of literature demonstrates that various cancers express B7-H4 and that the expression levels of B7-H4 correlate with cancer size, histological type, pathologic stage, grade, infiltration, lymph node metastasis, cancer progression, recurrence and death. The over-expression of B7-H4 in cancer may be related to an increased resistance to immune responses. The aim of this review is to supply an overview of the advances in the regulation and function of B7-H4. Additionally, many studies have suggested that B7-H4 is a molecular target for therapeutic intervention in cancer and that targeting B7-H4 may have promising potential for improving the efficacy of immunotherapy for cancer patients. PMID:27258187

  14. Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

    Serda, Maciej; Kalinowski, Danuta S.; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Jan G Małecki; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Šimůnek, Tomáš; Richardson, Des R.; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di...

  15. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

    Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Dicker, David T.; Allen, Joshua E.; El-Deiry, Wafik S.

    2014-01-01

    We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers. PMID:25587031

  16. [Dendritic cells in cancer immunotherapy].

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  17. Influence of platelet-activating factor, lyso-platelet-activating factor and edelfosine on Langmuir monolayers imitating plasma membranes of cell lines differing in susceptibility to anti-cancer treatment: the effect of plasmalogen level

    Flasiński, Michał; Hąc-Wydro, Katarzyna; Wydro, Paweł; Dynarowicz-Łątka, Patrycja

    2014-01-01

    Three structurally related but differing in biological activities single-chained ether phospholipids (PAF (platelet-activating factor) and lyso-PAF) and an anti-cancer drug (edelfosine (ED)) were investigated in Langmuir monolayers imitating natural membranes. The aim of the undertaken experiments was to study the influence of these lipids on monolayers mimicking plasma membranes of cell lines differing in susceptibility to the anti-cancer activity of ED, i.e. promyelocytic leukaemia cells (H...

  18. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  19. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Brian J. Ahn

    2013-11-01

    Full Text Available Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  20. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas

  1. Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells.

    Kim, Aeyung; Im, Minju; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-01-01

    Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly. PMID:26020238

  2. Protocatechualdehyde possesses anti-cancer activity through downregulating cyclin D1 and HDAC2 in human colorectal cancer cells

    Jeong, Jin Boo [Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742 (United States); Lee, Seong-Ho, E-mail: slee2000@umd.edu [Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742 (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Protocatechualdehyde (PCA) suppressed cell proliferation and induced apoptosis in human colorectal cancer cells. Black-Right-Pointing-Pointer PCA enhanced transcriptional downregulation of cyclin D1 gene. Black-Right-Pointing-Pointer PCA suppressed HDAC2 expression and activity. Black-Right-Pointing-Pointer These findings suggest that anti-cancer activity of PCA may be mediated by reducing HDAC2-derived cyclin D1 expression. -- Abstract: Protocatechualdehyde (PCA) is a naturally occurring polyphenol found in barley, green cavendish bananas, and grapevine leaves. Although a few studies reported growth-inhibitory activity of PCA in breast and leukemia cancer cells, the underlying mechanisms are still poorly understood. Thus, we performed in vitro study to investigate if treatment of PCA affects cell proliferation and apoptosis in human colorectal cancer cells and define potential mechanisms by which PCA mediates growth arrest and apoptosis of cancer cells. Exposure of PCA to human colorectal cancer cells (HCT116 and SW480 cells) suppressed cell growth and induced apoptosis in dose-dependent manner. PCA decreased cyclin D1 expression in protein and mRNA level and suppressed luciferase activity of cyclin D1 promoter, indicating transcriptional downregulation of cyclin D1 gene by PCA. We also observed that PCA treatment attenuated enzyme activity of histone deacetylase (HDAC) and reduced expression of HDAC2, but not HDAC1. These findings suggest that cell growth inhibition and apoptosis by PCA may be a result of HDAC2-mediated cyclin D1 suppression.

  3. Protocatechualdehyde possesses anti-cancer activity through downregulating cyclin D1 and HDAC2 in human colorectal cancer cells

    Highlights: ► Protocatechualdehyde (PCA) suppressed cell proliferation and induced apoptosis in human colorectal cancer cells. ► PCA enhanced transcriptional downregulation of cyclin D1 gene. ► PCA suppressed HDAC2 expression and activity. ► These findings suggest that anti-cancer activity of PCA may be mediated by reducing HDAC2-derived cyclin D1 expression. -- Abstract: Protocatechualdehyde (PCA) is a naturally occurring polyphenol found in barley, green cavendish bananas, and grapevine leaves. Although a few studies reported growth-inhibitory activity of PCA in breast and leukemia cancer cells, the underlying mechanisms are still poorly understood. Thus, we performed in vitro study to investigate if treatment of PCA affects cell proliferation and apoptosis in human colorectal cancer cells and define potential mechanisms by which PCA mediates growth arrest and apoptosis of cancer cells. Exposure of PCA to human colorectal cancer cells (HCT116 and SW480 cells) suppressed cell growth and induced apoptosis in dose-dependent manner. PCA decreased cyclin D1 expression in protein and mRNA level and suppressed luciferase activity of cyclin D1 promoter, indicating transcriptional downregulation of cyclin D1 gene by PCA. We also observed that PCA treatment attenuated enzyme activity of histone deacetylase (HDAC) and reduced expression of HDAC2, but not HDAC1. These findings suggest that cell growth inhibition and apoptosis by PCA may be a result of HDAC2-mediated cyclin D1 suppression.

  4. The design and synthesis of novel N-heterocyclic compounds, and their evaluation of anti-cancer and anti-viral activity

    More, Vijaykumar

    2014-01-01

    2010 - 2011 The thesis entitled “The design and synthesis of novel N-heterocyclic compounds, and their evaluation of anti-cancer and anti-viral activity" is divided into three chapters. The title of the thesis clearly reflects the importance of nitrogen heterocycles compounds: in fact they are extremely pivotal structural motifs responsible for eliciting various biological activities in natural products and synthetic medicines. This has attracted the medicinal chemists towards the synth...

  5. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke

    Van Kanegan, Michael J.; Dunn, Denise E.; Kaltenbach, Linda S.; Bijal Shah; Dong Ning He; Daniel D. McCoy; Peiying Yang; Jiangnan Peng; Li Shen; Lin Du; Cichewicz, Robert H.; Newman, Robert A; Lo, Donald C.

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-0...

  6. Modulating chromatin structure and DNA accessibility by deacetylase inhibition enhances the anti-cancer activity of silver nanoparticles.

    Igaz, Nóra; Kovács, Dávid; Rázga, Zsolt; Kónya, Zoltán; Boros, Imre M; Kiricsi, Mónika

    2016-10-01

    Histone deacetylase (HDAC) inhibitors are considered as novel therapeutic agents inducing cell cycle arrest and apoptotic cell death in various cancer cells. Inhibition of deacetylase activity results in a relaxed chromatin structure thereby rendering the genetic material more vulnerable to DNA targeting agents that could be exploited by combinational cancer therapy. The unique potential of silver nanoparticles (AgNPs) in tumor therapy relies on the generation of reactive radicals which trigger oxidative stress, DNA damage and apoptosis in cancer cells. The revolutionary application of AgNPs as chemotherapeutical drugs seems very promising, nevertheless the exact molecular mechanisms of AgNP action in combination with other anti-cancer agents have yet to be elucidated in details before clinical administrations. As a step towards this we investigated the combinational effect of HDAC inhibition and AgNP administration in HeLa cervical cancer cells. We identified synergistic inhibition of cancer cell growth and migration upon combinational treatments. Here we report that the HDAC inhibitor Trichostatin A enhances the DNA targeting capacity and apoptosis inducing efficacy of AgNPs most probably due to its effect on chromatin condensation. These results point to the potential benefits of combinational application of HDAC inhibitors and AgNPs in novel cancer medication protocols. PMID:27434153

  7. Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

    Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Our results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.

  8. Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 (NFE2L2) anti-oxidative stress/anti-inflammatory pathways

    Wu Qing; Saw Constance; Kong Ah-Ng Tony

    2010-01-01

    Abstract This article reviews recent basic and clinical studies of ginseng, particularly the anti-cancer effects and the potential chemopreventive actions by activating the transcriptional factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2)-mediated anti-oxidative stress or anti-inflammatory pathways. Nrf2 is a novel target for cancer prevention as it regulates the antioxidant responsive element (ARE), a critical regulatory element in the promoter region of genes encoding cel...

  9. Anti cancer activity on Graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anti-cancerous leads.

    Paul, Jeno; Gnanam, R; Jayadeepa, R M; Arul, L

    2013-01-01

    Nature is the world's best chemist: Many naturally occurring compounds have very complicated structures that present great challenges to chemists wishing to determine their structures or replicate them. The plant derived herbal compounds have a long history of clinical use, better patient tolerance and acceptance. Their high ligand binding affinity to the target introduce the prospect of their use in chemo preventive applications; in addition they are freely available natural compounds that can be safely used to prevent various ailments. Plants became the basis of traditional medicine system throughout the world for thousands of years and continue to provide mankind with new remedies. Here, we present a research study on a medicinal plant, Graviola, a native of North America but rarely grown in India. It has a wide potent anticancerous agents coined as Acetogenins which play a key role towards many varieties of cancer, Acetogenins are potent inhibitors of NADH oxidase of the plasma membranes of cancer cells. Potent leads were taken for the study through literature survey, major types of cancer targets were identified, the natureceuticals and the cancer protein were subjected to docking analysis, further with the help of the dock score and other descriptor properties top ranked molecules were collected, commercial drug was also selected and identified as a Test compound for the study. Later, the phytochemicals were subjected to toxicity analysis. Those screened compounds were then considered for active site analysis and to find the best binding site for the study. R Programming library was used to find the best leads. Phytochemicals such as Anonaine, Friedelin, Isolaureline, Annonamine, Anomurine, Kaempferol, Asimilobine, Quercetin, Xylopine were clustered and the highly clustered compounds such as Annonamine , Kaempferol termed to be a potential lead for the study. Further study on experimental analysis may prove the potentiality of these compounds. In the

  10. Potential Anti-cancer and Anti-bacterial Activities of Philippine Echinoderm Extracts

    Rodyl J. Layson

    2014-11-01

    Full Text Available In high-throughput search for bioactive compounds under resource-limited settings from Philippine echinoderms, the aqueous, methanol, chloroform and hexane extracts of seven Philippine echinoderms namely Holothuria nobilis (sea cucumber, Bohadscia marmorata (sea cucumber, Stichopus chloronatus (sea cucumber, Holothuria axiologa (sea cucumber, Linckia laevigata (starfish, Oreaster nodusus (starfish and Ophiocoma ochoenleinii (brittle star were screened for antitumor and antibacterial activity. Antitumor activity was determined using brine shrimp lethality assay while antibacterial assay was performed using turbidimetric method. Both assays utilized 96-well microtiter plates to facilitate speed and ease in screening. The chloroform extract of H. nobilis gave a positive result on antitumor activity while almost all sample extracts showed antibacterial activity against E. coli.

  11. DNA-Binding, Photocleavage, and Photodynamic Anti-cancer Activities of Pyridyl Corroles.

    Liang, Zhen-Hua; Liu, Hai-Yang; Zhou, Rong; Zhang, Zao; Ali, Atif; Han, Bing-Jie; Liu, Yun-Jun; Xiao, Xin-Yan

    2016-08-01

    The DNA-binding, photocleavage, and antitumor activity of three free base pyridyl corroles 1, 2, and 3 have been investigated. The binding affinity toward CT-DNA decreases with increasing number of pentafluorophenyl, whereas the photocleavage activity toward pBR322 DNA becomes more efficient. Singlet oxygen was demonstrated as active species responsible for DNA cleavage. These corroles exhibited high cytotoxicity against three tested cancer cells (Hela, HapG2, and A549) and the cytotoxicity could be further enhanced under irradiation. Intracellular reactive oxygen species level was also monitored using HeLa Cells upon the combined treatment of corroles and light. These corroles could be absorbed by HeLa cells at low concentration. They can induce the decrease of mitochondrial membrane potential and apoptosis of tumor cells under irradiation. PMID:26895317

  12. Synthesis of isatin thiosemicarbazones derivatives: In vitro anti-cancer, DNA binding and cleavage activities

    Ali, Amna Qasem; Teoh, Siang Guan; Salhin, Abdussalam; Eltayeb, Naser Eltaher; Khadeer Ahamed, Mohamed B.; Majid, A. M. S. Abdul

    New derivatives of thiosemicarbazone Schiff base with isatin moiety were synthesized L1-L6. The structures of these compounds were characterized based on the spectroscopic techniques. Compound L6 was further characterized by XRD single crystal. The interaction of these compounds with calf thymus (CT-DNA) exhibited high intrinsic binding constant (kb = 5.03-33.00 × 105 M-1) for L1-L3 and L5 and (6.14-9.47 × 104 M-1) for L4 and L6 which reflect intercalative activity of these compounds toward CT-DNA. This result was also confirmed by the viscosity data. The electrophoresis studies reveal the higher cleavage activity of L1-L3 than L4-L6. The in vitro anti-proliferative activity of these compounds against human colon cancer cell line (HCT 116) revealed that the synthesized compounds (L3, L6 and L2) exhibited good anticancer potency.

  13. Plant derived substances with anti-cancer activity: from folklore to practice

    Marcelo eFridlender; Yoram eKapulnik; Hinanit eKoltai

    2015-01-01

    Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70-95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early 19th century. This trend led to the discovery of different active compounds that are derived from plants. I...

  14. Plant derived substances with anti-cancer activity: from folklore to practice

    Fridlender, Marcelo; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70–95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early nineteenth century. This trend led to the discovery of different active compounds that are derived from pla...

  15. Identification and analysis of the active phytochemicals from the anti-cancer botanical extract Bezielle.

    Vivian Chen

    Full Text Available Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it.

  16. Anti-cancer activities of pH- or heat-modified pectin

    Lionel eLeclere

    2013-10-01

    Full Text Available Despite enormous efforts that have been made in the search for novel drugs and treatments, cancer continues to be a major public health problem. Moreover, the emergence of resistance to cancer chemotherapy often prevents complete remission. Researchers have thus turned to natural products mainly from plant origin to circumvent resistance. Pectin and pH- or heat-modified pectin have demonstrated chemopreventive and antitumoral activities against some aggressive and recurrent cancers. The focus of this review is to describe how pectin and modified pectin display these activities and what are the possible underlying mechanisms. The failure of conventional chemotherapy to reduce mortality as well as serious side effects makes natural products, such as pectin-derived products, ideal candidates for exerting synergism in combination with conventional anticancer drugs.

  17. Anti-cancer activities of pH- or heat-modified pectin

    Leclere, Lionel; Van Cutsem, Pierre; Michiels, Carine

    2013-01-01

    Despite enormous efforts that have been made in the search for novel drugs and treatments, cancer continues to be a major public health problem. Moreover, the emergence of resistance to cancer chemotherapy often prevents complete remission. Researchers have thus turned to natural products mainly from plant origin to circumvent resistance. Pectin and pH- or heat-modified pectin have demonstrated chemopreventive and antitumoral activities against some aggressive and recurrent cancers. The focus...

  18. Engineering of polyphenol metabolism in tomatoes to enhance anti-cancer activities

    Bulling, Katharina

    2013-01-01

    Anthocyanins are polyphenolic plant pigments that are responsible for much of the attractive colour displays found in many flowers, fruit and vegetables. Anthocyanins are divided into different classes based on the number of hydroxyl groups on their phenyl B-ring and subsequent side chain modifications. It has been shown in our laboratory that the introduction of the regulatory genes Delila and Rosea1 activates the biosynthetic pathway leading to accumulation of trihydroxylated anthocyanin...

  19. Synthesis, Characterization, and Anti-Cancer Activity of Some New N′-(2-Oxoindolin-3-ylidene-2-propylpentane hydrazide-hydrazones Derivatives

    Ayman El-Faham

    2015-08-01

    Full Text Available Eight novel N′-(2-oxoindolin-3-ylidene-2-propylpentane hydrazide-hydrazone derivatives 4a–h were synthesized and fully characterized by IR, NMR (1H-NMR and 13C-NMR, elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2 and leukaemia (Jurkat, as well as in normal cell lines derived from human embryonic kidney (HEK293 using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 μM as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32–50 μM. Among the tested compounds, 4a showed specificity against leukaemia (Jurkat cells, with an IC50 value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.

  20. The Anti-Cancer Potency and Mechanism of a Novel Tumor-Activated Fused Toxin, DLM

    Dejun Sun

    2015-02-01

    Full Text Available Melittin, which acts as a membrane-disrupting lytic peptide, is not only cytotoxic to tumors, but also vital to normal cells. Melittin had low toxicity when coupled with target peptides. Despite significant research development with the fused toxin, a new fused toxin is needed which has a cleavable linker such that the fused toxin can release melittin after protease cleavage on the tumor cell surface. We describe a novel fused toxin, composed of disintegrin, uPA (urokinase-type plasminogen activator-cleavable linker, and melittin. Disintegrin is a single strand peptide (73 aa isolated from Gloydius Ussuriensis venom. The RGD (Arg-Gly-Asp site of disintegrin dominates its interaction with integrins on the surface of the tumor cells. uPA is over-expressed and plays an important role in tumor cell invasiveness and metastatic progression. The DLM (disintegrin-linker-melittin linker is uPA-cleavable, enabling DLM to release melittin. We compared binding activity of our synthesized disintegrin with native disintegrin and report that DLM had less binding activity than the native form. uPA-cleavage was evaluated in vitro and the uPA-cleavable linker released melittin. Treating tumors expressing uPA with DLM enhanced tumor cell killing as well as reduced toxicity to erythrocytes and other non-cancerous normal cells. The mechanism behind DLM tumor cell killing was tested using a DNA ladder assay, fluorescent microscopy, flow cytometry, and transmission electron microscopy. Data revealed tumor cell necrosis as the mechanism of cell death, and the fused DLM toxin with an uPA-cleavable linker enhanced tumor selectivity and killing ability.

  1. The in Vitro Structure-Related Anti-Cancer Activity of Ginsenosides and Their Derivatives

    Liang Liu

    2011-12-01

    Full Text Available Panax ginseng has long been used in Asia as a herbal medicine for the prevention and treatment of various diseases, including cancer. The current study evaluated the cytotoxic potency against a variety of cancer cells by using ginseng ethanol extracts (RSE, protopanaxadiol (PPD-type, protopanaxatriol (PPT-type ginsenosides fractions, and their hydrolysates, which were prepared by stepwise hydrolysis of the sugar moieties of the ginsenosides. The results showed that the cytotoxic potency of the hydrolysates of RSE and total PPD-type or PPT-type ginsenoside fractions was much stronger than the original RSE and ginsenosides; especially the hydrolysate of PPD-type ginsenoside fractions. Subsequently, two derivatives of protopanaxadiol (1, compounds 2 and 3, were synthesized via hydrogenation and dehydration reactions of compound 1. Using those two derivatives and the original ginsenosides, a comparative study on various cancer cell lines was conducted; the results demonstrated that the cytotoxic potency was generally in the descending order of compound 3 > 20(S-dihydroprotopanaxadiol (2 > PPD (1 > 20(S-Rh2 > 20(R-Rh2 ≈ 20(R-Rg3 ≈ 20(S-Rg3. The results clearly indicate the structure-related activities in which the compound with less polar chemical structures possesses higher cytotoxic activity towards cancer cells.

  2. Water soluble polysaccharides from Spirulina platensis: extraction and in vitro anti-cancer activity.

    Kurd, Forouzan; Samavati, Vahid

    2015-03-01

    Polysaccharides from Spirulina platensis algae (SP) were extracted by ultrasound-assisted extraction procedure. The optimal conditions for ultrasonic extraction of SP were determined by response surface methodology. The four parameters were, extraction time (X1), extraction temperature (X2), ultrasonic power (X3) and the ratio of water to raw material (X4), respectively. The experimental data obtained were fitted to a second-order polynomial equation. The optimum conditions were extraction time of 25 min, extraction temperature 85°C, ultrasonic power 90 W and ratio of water to raw material 20 mL/g. Under these optimal conditions, the experimental yield was 13.583±0.51%, well matched with the predicted models with the coefficients of determination (R2) of 0.9971. Then, we demonstrated that SP polysaccharides had strong scavenging activities in vitro on DPPH and hydroxyl radicals. Overall, SP may have potential applications in the medical and food industries. PMID:25583023

  3. Enhanced Anti-Cancer Effect of Snake Venom Activated NK Cells on Lung Cancer Cells by Inactivation of NF-κB

    Kollipara, Pushpa Saranya; Won, Do Hee; Hwang, Chul Ju; Jung, Yu Yeon; Yoon, Heui Seoung; Park, Mi Hee; Song, Min Jong; Song, Ho Sueb; Hong, Jin Tae

    2014-01-01

    In the present study, we investigated anti-cancer effect of snake venom activated NK cells (NK-92MI) in lung cancer cell lines. We used snake venom (4 μg/ml) treated NK-92MI cells to co-culture with lung cancer cells. There was a further decrease in cancer cell growth up to 65% and 70% in A549 and NCI-H460 cell lines respectively, whereas 30–40% was decreased in cancer cell growth by snake venom or NK-92MI alone treatment. We further found that the expression of various apoptotic proteins suc...

  4. Advances in identification and application of tumor antigen inducing anti-cancer responses

    2003-01-01

    @@ Tumor antigen is one of the important bases of tumor immunotherapy[1]. With the discovery of novel tumor antigens, interest in specific immunotherapy for treatment of malignancies has increased substantially. Nowadays more and more scientists paid close attention to various tumor antigens with their roles or/and applications in anti-cancer immune responses, immune tolerance, tumor markers, tumor immunotherapy and so on. Here we discussed the classification of tumor antigens and summarized the technologies of identification and application of tumor antigens.

  5. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

    Shao-Xing Dai; Wen-Xing Li; Fei-Fei Han; Yi-Cheng Guo; Jun-Juan Zheng; Jia-Qian Liu; Qian Wang; Yue-Dong Gao; Gong-Hua Li; Jing-Fei Huang

    2016-01-01

    There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed t...

  6. Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. : Active Tau immunotherapy

    Troquier, Laëticia; Caillierez, Raphaëlle; Burnouf, Sylvie; Fernandez-Gomez, Francisco,; Grosjean, Marie-Eve; Zommer, Nadège; Sergeant, Nicolas; Schraen-Maschke, Susanna; Blum, David; Buee, Luc

    2012-01-01

    Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 i...

  7. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

    Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

    2016-05-01

    There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

  8. Are isothiocyanates potential anti-cancer drugs?

    Xiang WU; Qing-hua ZHOU; Ke XU

    2009-01-01

    Isothiocyanates are naturally occurring small molecules that are formed from glucosinolate precursors of cruciferous vegetables. Many isothiocyanates, both natural and synthetic, display anticarcinogenic activity because they reduce activation of carcinogens and increase their detoxification. Recent studies show that they exhibit anti-tumor activity by affecting multiple pathways including apoptosis, MAPK signaling, oxidative stress, and cell cycle progression. This review summarizes the current knowledge on isothiocyanates and focuses on their role as potential anti-cancer agents.

  9. Anti-cancer potential of South Asian plants

    Rahman, Mohammad Mijanur; Khan, Md Asaduzzaman

    2013-01-01

    Phyto-chemicals are increasingly being used in the treatment of cancer because of their availability, potential anti-cancer activity with less adverse effects when compared with chemotherapy. The variation of climate and geography in South Asian countries provides a nursing environment for the growth of versatile plant species, that are repeatedly drawing attention of the scientific community. In this review, we have focused on the anti-cancer potential of thirty plants, which are commonly fo...

  10. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

    Van Kanegan, Michael J; Dunn, Denise E; Kaltenbach, Linda S; Shah, Bijal; He, Dong Ning; McCoy, Daniel D; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H; Newman, Robert A; Lo, Donald C

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD. PMID:27172999

  11. Anti-cancer effects of p21WAF1/CIP1 transcriptional activation induced by dsRNAs in human hepatocellular carcinoma cell lines

    Zhi-ming WU; Gang CHEN; Chun DAI; Ying HUANG; Cui-fang ZHENG; Qiong-zhu DONG; Guan WANG; Xiao-wen LI; Xiao-fei ZHANG; Bin LI

    2011-01-01

    Aim: To investigate the anti-cancer effects of p21WAF1/CIP1 transcriptional activation induced by dsRNAs in hepatocellular carcinoma (HCC) cell lines.Methods: HCC cell lines BEL7402, SMMC-7721, MHCC97L, MHCC97H, and MHCCLM3 were used. HCC ceils were treated with dsP21322 (50 nmol/L), dsControl (50 nmol/L), siP21 (50 nmol/L), or mock transfection. The expression of p21 was detected using quantitative PCR and Western blot. The effects of RNA activation on HCC cells were determined using cell viability assays, apoptosis analyses and clonogenic survival assays. Western blot was also conducted to detect the expression of Bcl-xL, survivin, cleaved caspase-3,cleaved caspase-9 and cleaved PARP.Results: At 72 to 120 h following the transfection, dsP21-322 markedly inhibited the viability of HCC cells and clone formation. At the same times, dsP21-322 caused a significant increase in HCC cell apoptosis, as demonstrated with cytometric analysis. The phenomena were correlated with decreased expression levels of the anti-apoptotic proteins Bcl-xL, surviving, and increased expression of cleaved caspase-3, cleaved caspase-9 and cleaved PARP.Conclusion: RNA-induced activation of p21 gene expression may have significant therapeutic potential for the treatment of hepatocellular carcinoma and other cancers.

  12. Anti-Cancer Potential of a Novel SERM Ormeloxifene

    Gara, Rishi Kumar; Sundram, Vasudha; Chauhan, Subhash C.; Jaggi, Meena

    2014-01-01

    Ormeloxifene is a non-steroidal Selective Estrogen Receptor Modulator (SERM) that is used as an oral contraceptive. Recent studies have shown its potent anti-cancer activities in breast, head and neck, and chronic myeloid leukemia cells. Several in vivo and clinical studies have reported that ormeloxifene possesses an excellent therapeutic index and has been well-tolerated, without any haematological, biochemical or histopathological toxicity, even with chronic administration. A reasonably long period of time and an enormous financial commitment are required to develop a lead compound into a clinically approved anti-cancer drug. For these reasons and to circumvent these obstacles, ormeloxifene is a promising candidate on a fast track for the development or repurposing established drugs as anti-cancer agents for cancer treatment. The current review summarizes recent findings on ormeloxifene as an anti-cancer agent and future prospects of this clinically safe pharmacophore. PMID:23895678

  13. In vitro investigation of the potential immunomodulatory and anti-cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamomum).

    Majdalawieh, Amin F; Carr, Ronald I

    2010-04-01

    Although the immunomodulatory effects of many herbs have been extensively studied, research related to possible immunomodulatory effects of various spices is relatively scarce. Here, the potential immunomodulatory effects of black pepper and cardamom are investigated. Our data show that black pepper and cardamom aqueous extracts significantly enhance splenocyte proliferation in a dose-dependent, synergistic fashion. Enzyme-linked immunosorbent assay experiments reveal that black pepper and cardamom significantly enhance and suppress, respectively, T helper (Th)1 cytokine release by splenocytes. Conversely, Th2 cytokine release by splenocytes is significantly suppressed and enhanced by black pepper and cardamom, respectively. Experimental evidence suggests that black pepper and cardamom extracts exert pro-inflammatory and anti-inflammatory roles, respectively. Consistently, nitric oxide production by macrophages is significantly augmented and reduced by black pepper and cardamom, respectively. Remarkably, it is evident that black pepper and cardamom extracts significantly enhance the cytotoxic activity of natural killer cells, indicating their potential anti-cancer effects. Our findings strongly suggest that black pepper and cardamom exert immunomodulatory roles and antitumor activities, and hence they manifest themselves as natural agents that can promote the maintenance of a healthy immune system. We anticipate that black pepper and cardamom constituents can be used as potential therapeutic tools to regulate inflammatory responses and prevent/attenuate carcinogenesis. PMID:20210607

  14. Immunotherapy of Brain Cancer.

    Roth, Patrick; Preusser, Matthias; Weller, Michael

    2016-01-01

    The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors. PMID:27260656

  15. Searching in mother nature for anti-cancer activity: anti-proliferative and pro-apoptotic effect elicited by green barley on leukemia/lymphoma cells.

    Elisa Robles-Escajeda

    Full Text Available Green barley extract (GB was investigated for possible anti-cancer activity by examining its anti-proliferative and pro-apoptotic properties on human leukemia/lymphoma cell lines. Our results indicate that GB exhibits selective anti-proliferative activity on a panel of leukemia/lymphoma cells in comparison to non-cancerous cells. Specifically, GB disrupted the cell-cycle progression within BJAB cells, as manifested by G2/M phase arrest and DNA fragmentation, and induced apoptosis, as evidenced by phosphatidylserine (PS translocation to the outer cytoplasmic membrane in two B-lineage leukemia/lymphoma cell lines. The pro-apoptotic effect of GB was found to be independent of mitochondrial depolarization, thus implicating extrinsic cell death pathways to exert its cytotoxicity. Indeed, GB elicited an increase of TNF-α production, caspase-8 and caspase-3 activation, and PARP-1 cleavage within pre-B acute lymphoblastic leukemia Nalm-6 cells. Moreover, caspase-8 and caspase-3 activation and PARP-1 cleavage were strongly inhibited/blocked by the addition of the specific caspase inhibitors Z-VAD-FMK and Ac-DEVD-CHO. Furthermore, intracellular signaling analyses determined that GB treatment enhanced constitutive activation of Lck and Src tyrosine kinases in Nalm-6 cells. Taken together, these findings indicate that GB induced preferential anti-proliferative and pro-apoptotic signals within B-lineage leukemia/lymphoma cells, as determined by the following biochemical hallmarks of apoptosis: PS externalization, enhanced release of TNF-α, caspase-8 and caspase-3 activation, PARP-1 cleavage and DNA fragmentation Our observations reveal that GB has potential as an anti-leukemia/lymphoma agent alone or in combination with standard cancer therapies and thus warrants further evaluation in vivo to support these findings.

  16. Targeted anti-cancerous therapies

    Crowning decades of efforts in fundamental and applied research, the first generation of targeted anti cancerous drugs is now on the market. Drugs coming from a new approach, conceived from molecular knowledge of cancer and directed against beforehand identified targets. In theory: a miracle of precision and technical success. In practice: a new sources of questions and new problems. (N.C.)

  17. Synthesis and structure-activity relationship of N-(2-arylethyl) isoquinoline derivatives as anti-cancer agents%N-芳乙基异喹啉衍生物的合成及其抗肿瘤活性研究

    汪燕翔; 赵午莉; 毕重文; 李阳彪; 邵荣光; 宋丹青

    2012-01-01

    A series of novel N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their anti-cancer activities. Among these analogs, compound 9a exhibited the potential anti-cancer activities on HepG2 and HCT116 cells with IC50 values of 2.52 and 1.99 μg·mL-1, respectively. Cell cycle was blocked at S phase of HepG2 cells treated with 9a by flow cytometry detection. Our results provided a basis for the development of a new series of anti-cancer candidates.%本研究采用一种简便的新方法设计合成了一系列全新结构的N-芳乙基异喹啉衍生物,并对其体外抗肿瘤活性进行了评价.其中化合物9a表现出较强的抗肿瘤活性,对人肝癌HepG2和大肠癌HCT116细胞的IC50值分别为2.52和1.99 μg·mL-1.初步作用机制显示,9a可以将HepG2细胞周期阻滞于S期,使细胞增殖受阻,达到抗肿瘤效果.

  18. Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue

    Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue was studied on the transplanted MM46 tumor of female C3H/He mice after radiotherapy. MM46 tumor cells were inoculated into the right hind paws of mice. On the 5th day, irradiation with the dose irradiated tumor tissue (2000 rad on the fifth day), were injected into the left hind paws of the tumor-bearing mice. Effectiveness of this active specific immunotherapy against tumor was evaluated by the regression of tumor and survival rate of mice. Tumor was markedly regressed and survival rate was significantly increased by the active specific immunitherapy

  19. An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV and anti-cancer activities.

    Ran He

    Full Text Available We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4 are significantly more potent in inhibiting human cytomegalovirus (CMV replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574, lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound.

  20. Nanopharmaceutical Approach for Enhanced Anti-cancer Activity of Betulinic Acid in Lung-cancer Treatment via Activation of PARP: Interaction with DNA as a Target -Anti-cancer Potential of Nano-betulinic Acid in Lung Cancer-

    Jayeeta Das

    2016-03-01

    Full Text Available Objectives: This study examined the relative efficacies of a derivative of betulinic acid (dBA and its poly (lactide- co-glycolide (PLGA nano-encapsulated form in A549 lung cancer cells in vivo and in co-mutagen [sodium arsenite (SA + benzo]undefined[a]pyrene (BaP]-induced lung cancer in mice in vivo. Methods: dBA was loaded with PLGA nanoparticles by using the standard solvent displacement method. The sizes and morphologies of nano-dBA (NdBA were determined by using transmission electron microscopy (TEM, and their intracellular localization was verified by using confocal microscopy. The binding and interaction of NdBA with calf thymus deoxyribonucleic acid (CT-DNA as a target were analyzed by using conventional circular dichroism (CD and melting temperature (Tm profile data. Apoptotic signalling cascades in vitro and in vivo were studied by using an enzyme-linked immunosorbent assay (ELISA; the ability of NdBA to cross the blood-brain barrier (BBB was also examined. The stage of cell cycle arrest was confirmed by using a fluorescence-activated cell-sorting (FACS data analysis. Results: The average size of the nanoparticles was ~ 110 nm. Confocal microscopy images confirmed the presence of NdBA in the cellular cytoplasm. The bio-physical properties of dBA and NdBA ascertained from the CD and the Tm profiles revealed that NdBA had greater interaction with the target DNA than dBA did. Both dBA and NdBA arrested cell proliferation at G0/G1, NdBA showing the greater effect. NdBA also induced a greater degree of cytotoxicity in A549 cells, but it had an insignificant cytotoxic effect in normal L6 cells. The results of flow cytometric, cytogenetial and histopathological studies in mice revealed that NdBA caused less nuclear condensation and DNA damage than dBA did. TEM images showed the presence of NdBA in brain samples of NdBA fed mice, indicating its ability to cross the BBB. Conclusion: Thus, compared to dBA, NdBA appears to have greater

  1. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K. P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  2. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells.

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p HCT-116 cells and elevated (p HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  3. Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs.

    Wang, Hao-Meng; Zhang, Li; Liu, Jiang; Yang, Zhao-Liang; Zhao, Hong-Ye; Yang, Yao; Shen, Di; Lu, Kui; Fan, Zhen-Chuan; Yao, Qing-Wei; Zhang, Yong-Min; Teng, Yu-Ou; Peng, Yu

    2015-03-01

    Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by (1)H NMR, (13)C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5'-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis. PMID:25590864

  4. Syntheses, characterization, and anti-cancer activities of pyridine-amide based compounds containing appended phenol or catechol groups

    Afsar Ali; Deepak Bansal; Nagendra K Kaushik; Neha Kaushik; Neha Kaushik; Eun Ha Choi; Rajeev Gupta

    2014-07-01

    Several pyridine-amide compounds appended with phenol/catechol groups are synthesized. These compounds consist of protected or deprotected phenol/catechol groups and offer pyridine, amide, and phenol/catechol functional groups. All compounds have been well-characterized by various spectroscopic methods, elemental analysis, thermal studies, and crystallography. The biological activities of all compounds were investigated while a few compounds significantly decreased the metabolic viability, growth and clonogenicity of T98G cells in dose dependent manner. Accumulation of ROS was observed in T98G cells, which displayed a compromised redox status as evident from increased cellular Caspase 3/7 activity and formation of micronuclei. The in silico pharmacokinetic studies suggest that all compounds have good bioavailability, water solubility and other drug-like parameters. A few compounds were identified as the lead molecules for future investigation due to their: (a) high activity against T98G brain, H-460 lung, and SNU-80 thyroid cancer cells; (b) low cytotoxicity in non-malignant HEK and MRC-5 cells; (c) low toxic risks based on in silico evaluation; (d) good theoretical oral bioavailability according to Lipinski ‘rule of five’ pharmacokinetic parameters; and (e) better drug-likeness and drug-score values.

  5. LYMPHOCYTE PHENOTYPE IN PATIENTS WITH SKIN MELANOMA AFTER IMMUNOTHERAPY OF ACTIVATED LYMPHOCYTES

    E. V. Abakushina

    2015-01-01

    Full Text Available The major medical problem in the treatment of skin melanoma is improvement methods of treatment, increasing their effectiveness and safety. In this study, adoptive immunotherapy, using lymphocytes activated in vitro, was performed in 15 patients with metastatic melanoma. Evaluated the phenotype of peripheral blood lymphocytes and activation markers (HLA-DR, CD25, CD314, CD38, CD69 before and 3-4 weeks after immunotherapy. It is shown that for these patients is characterized by increasing the number of CD25+ and Treg lymphocytes in the bloodstream, which has not changed after immunotherapy. Adoptive immunotherapy in combination with chemotherapy resulted in a decrease of absolute number of lymphocyte, B- and T-lymphocytes, T helper cells, NKT-cells, CD314+ lymphocytes, CD38+ lymphocytes and immature T-lymphocytes (CD3+CD38+ (р < 0,05. However, there was a positive dynamic to increase the percentage of NK-cells to 32% and CD69+NK-cells to 21% and significant increase in expression of HLA-DR on all lymphocytes (p < 0.05. Adoptive immunotherapy characterized by the absence of side effects and can be recommended as accompanying to basic radiation and chemotherapy.

  6. Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

    Rastogi, Namrata; Duggal, Shivali; Singh, Shailendra Kumar; Porwal, Konica; Srivastava, Vikas Kumar; Maurya, Rakesh; Bhatt, Madan L.B.; Mishra, Durga Prasad

    2015-01-01

    Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer. PMID:26621832

  7. A Survey of Marine Natural Compounds and Their Derivatives with Anti-Cancer Activity Reported in 2012

    Wamtinga Richard Sawadogo

    2015-04-01

    Full Text Available Although considerable effort and progress has been made in the search for new anticancer drugs and treatments in the last several decades, cancer remains a major public health problem and one of the major causes of death worldwide. Many sources, including plants, animals, and minerals, are of interest in cancer research because of the possibility of identifying novel molecular therapeutics. Moreover, structure-activity-relationship (SAR investigations have become a common way to develop naturally derived or semi-synthetic molecular analogues with improved efficacy and decreased toxicity. In 2012, approximately 138 molecules from marine sources, including isolated compounds and their associated analogues, were shown to be promising anticancer drugs. Among these, 62% are novel compounds. In this report, we review the marine compounds identified in 2012 that may serve as novel anticancer drugs.

  8. Biological investigation of the platinum(II)-[*I]iodohistamine complexes of potential synergistic anti-cancer activity

    Cisplatin chemotherapy in combination with external irradiation or with low-dose continuos internal radiotherapy produces significant supra-additive treatment effects towards several tumor cells. The purpose of our research is to develop a new class of platinum-based anticancer drugs containing moieties of synergistic potency such as platinum core and a radiotherapeutic isotope which, delivered directly to the tumorous cells by a specifically designed vectors, should produce a local enhancement of therapeutic dose. Thus, we have synthesized a new platinum-iodohistamine complex and its radioactive analogues labeled with I-125 and I-131. In the present study some biological properties of those compounds have been investigated. The in vitro screening study pointed out that non-radioactive platinum-iodohistamine complex possesses high cytostatic activity against COLO-205 cells, and moderate activity against HL-60 cell line. No cytotoxicity was observed against MOLT-4 and L-1210 cells, as well as against VERO normal cells. The biodistribution of intravenously administered radioactive platinum-[131I]-iodohistamine complex to normal rats revealed the highest accumulation in the liver (c.a. 40%ID). Intraperitoneal injections of the complex to tumor-bearing C3H mice resulted in scattering of the dose in the organs (mainly in GIT, liver, kidney). The retention of radioactive complex in neoplastic tissue was 3-4 times higher than in normal muscular tissue, although exhibited the tendency to decrease with time post injection. The results of the present study show promising features of the newly developed platinum-iodohistamine complexes and justify prospective investigation of in vivo anticancer potency on animal models of solid tumors

  9. Functional nanoemulsion-hybrid lipid nanocarriers enhance the bioavailability and anti-cancer activity of lipophilic diferuloylmethane

    Sun, Lili; Wan, Kun; Hu, Xueyuan; Zhang, Yonghong; Yan, Zijun; Feng, Jiao; Zhang, Jingqing

    2016-02-01

    The purpose of this study was to assess the enhanced physicochemical characteristics, in vitro release behavior, anti-lung cancer activity, gastrointestinal absorption, in vivo bioavailability and bioequivalence of functional nanoemulsion-hybrid lipid nanocarriers containing diferuloylmethane (DNHLNs). The DNHLNs were first fabricated by loading water-in-oil nanoemulsions into hybrid lipid nanosystems using nanoemulsion-thin film-sonication dispersion technologies. The in situ absorption and in vitro and in vivo kinetic features of DNHLNs were measured using an in situ unidirectional perfusion method, a dynamic dialysis method and a plasma concentration-time profile-based method, respectively. The cytotoxic effects of DNHLNs in lung adenocarcinoma A549 cells were examined using MTT colorimetric analysis. The absorptive constants and permeabilities of DNHLNs in four gastrointestinal sections increased by 1.43-3.23 times and by 3.10-7.76 times that of diferuloylmethane (DIF), respectively. The relative bioavailability of DNHLNs to free DIF was 855.02%. DNHLNs inhibited cancer cell growth in a time- and dose-dependent manner. DNHLNs markedly improved the absorption and bioavailability of DIF after oral administration. DNHLNs had stronger inhibitory effects on the viability of A549 cells than that of free DIF. DNHLNs might be potentially promising nanocarriers for DIF delivery via the oral route to address unmet clinical needs.

  10. Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities.

    Uesato, Shinichi; Matsuura, Yoshihiro; Matsue, Saki; Sumiyoshi, Takaaki; Hirata, Yoshiyuki; Takemoto, Suzuho; Kawaratani, Yasuyuki; Yamai, Yusuke; Ishida, Kyoji; Sasaki, Tsutomu; Enari, Masato

    2016-04-15

    Although several p53-Mdm2-binding disruptors have been identified to date, few studies have been published on p53-Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200-300 selectively inhibited the p53-Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53-Mdmx interaction over the p53-Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53-Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100mg/kg and 150mg/kg, respectively, in 40days. PMID:27010502

  11. Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence

    Ridnour Lisa A

    2011-09-01

    Full Text Available Abstract Background Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s by which they occur. Methods We have examined the matrix metalloproteinase (MMP protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-Aβ antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with Aβ vaccination for 4 months. Results There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-Aβ immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.

  12. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells

    Zhongyuan Zhang; Kiichiro Teruya; Toshihiro Yoshida; Hiroshi Eto; Sanetaka Shirahata

    2013-01-01

    Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE) from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as ...

  13. Immunotherapy: A useful strategy to help combat multidrug resistance

    Curiel, Tyler J.

    2012-01-01

    Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune ta...

  14. Enhancement of delayed hypersensitivity reaction with varieties of anti- cancer drugs. A common biological phenomenon

    1981-01-01

    Delayed hypersensitivity reaction in mice was commonly enhanced with various anti-cancer agents administered as single or intermittent high doses but not consecutive divided doses. The effect of anti-cancer agents on the delayed hypersensitivity reaction was thought to be due to elimination of suppressor T cell activity.

  15. The anti-cancer activities of Vernonia amygdalina extract in human breast cancer cell lines are mediated through caspase-dependent and p53-independent pathways.

    Fang Cheng Wong

    Full Text Available Breast cancer is currently the leading cause of cancer-related deaths among women globally. Notably, medicinal plant extracts may be a potential source for treatments of breast cancer. Vernonia amygdalina (VA is a woody shrub reported to have not only diverse therapeutic effects but also anti-cancer properties. However, current research about the mechanisms of the anti-cancer potential of VA has been limited. This study aimed to investigate the mechanisms of action of VA that underlie its anti-cancer effects in human breast cancer cell lines (MCF-7 and MDA-MB-231 cells. Results from MTT assay revealed that VA inhibits the proliferation of MCF-7 and MDA-MB-231, in a time- and dose-dependent manner. The underlying mechanism of this growth inhibition involved the stimulation of cell-type specific G1/S phase cell cycle arrest in only MCF-7 cells, and not in MDA-MB-231 cells. While the growth arrest was associated with increased levels of p53 and p21, and a concomitant decrease in the levels of cyclin D1 and cyclin E, it was shown that VA causes cell cycle arrest through a p53-independent pathway as tested by the wild type p53 inhibitor, pifithrin-α. Furthermore, this study revealed that VA induces apoptosis in the two cell lines, as indicated by the increase in Annexin V-positive cells and sub-G1 population, and that this VA-induced apoptosis occurred through both extrinsic and intrinsic apoptotic pathways. The apoptosis in MCF-7 cells was also likely to be caspase-dependent and not p53 transcriptional-dependent. Given that approximately 70% of diagnosed breast cancers express ER-α, a crucial finding was that VA inhibits the expression of ER-α and its downstream player, Akt, highlighting the potential clinical significance of VA. Moreover, VA exhibits synergism when combined with doxorubicin, suggesting that it can complement current chemotherapy. Overall, this study demonstrates the potential applications of VA as an anti-cancer drug for breast

  16. Neoadjuvant immunotherapy enhances radiosensitivity through natural killer cell activation.

    Chi, Chau-Hwa; Wang, Yu-Shan; Yang, Chieh-Han; Chi, Kwan-Hwa

    2010-02-01

    We investigated whether natural killer (NK) cells in the tumor microenvironment have a radiosensitization effect. The radiosensitization effect of combined CpG and Herceptin((R)) (Genentech, Inc., South San Francisco, CA) (CpG/Herceptin), given before or after radiation, was evaluated by using a murine colon cancer cell line overexpressing human HER2/neu, CT26HER2/neu. In vitro radiosensitization effects were investigated by coculture of CT26HER2/neu with splenocytes, CpG, and Herceptin before applying radiation. Tumor cells, cocultured with CpG-pretreated splenocytes and Herceptin, were more vulnerable to radiation damage. In BALB/c mice injected with CT26HER2/neu, CpG/Herceptin administered before radiotherapy was associated with a better retardation of tumor growth than when administered after radiotherapy. The radiosensitization effect was significantly abrogated by NK-cell depletion, indicating that NK cells play an essential role in it. Further, surviving mice treated with CpG or CpG/Herceptin and reverse transcriptase were resistant to renewed tumor challenge, suggesting the presence of an induced immune response to the tumor. Neoadjuvant immunotherapy with CpG/Herceptin may improve response to radiotherapy of HER2/neu-expressing tumors. PMID:20187795

  17. Anti-cancer Lead Molecule

    Sagar, Sunil

    2014-04-17

    Derivatives of plumbagin can be selectively cytotoxic to breast cancer cells. Derivative `A` (Acetyl Plumbagin) has emerged as a lead molecule for testing against estrogen positive breast cancer and has shown low hepatotoxicity as well as overall lower toxicity in nude mice model. The toxicity of derivative `A` was determined to be even lower than vehicle control (ALT and AST markers). The possible mechanism of action identified based on the microarray experiments and pathway mapping shows that derivative `A` could be acting by altering the cholesterol-related mechanisms. The low toxicity profile of derivative `A` highlights its possible role\\'as future anti-cancer drug and/or as an adjuvant drug to reduce the toxicity of highly toxic chemotherapeutic\\'drugs

  18. Optimizing complement-activating antibody-based cancer immunotherapy: a feasible strategy?

    Maio Michele

    2004-06-01

    Full Text Available Abstract Passive immunotherapy with monoclonal antibodies (mAb targeted to specific tumor-associated antigens is amongst the most rapidly expanding approaches to biological therapy of cancer. However, until now a limited number of therapeutic mAb has demonstrated clinical efficacy in selected neoplasia. Results emerging from basic research point to a deeper characterization of specific biological features of neoplastic cells as crucial to optimize the clinical potential of therapeutic mAb, and to identify cancer patients who represent the best candidates to antibody-based immunotherapy. Focus on the tissue distribution and on the functional role of membrane complement-regulatory proteins such as Protectin (CD59, which under physiologic conditions protects tissues from Complement (C-damage, might help to optimize the efficacy of immunotherapeutic strategies based on C-activating mAb.

  19. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells

    Zhongyuan Zhang

    2013-01-01

    Full Text Available Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as cell cycle modifications in MDA-MB-231 and MCF-7 cells. FE enhanced apoptosis in cancer cells that responded to treatment with three chemotherapeutic drugs with downregulation of the anti-apoptotic proteins Bcl-xL and Mcl-1. The combination treatments led to an obvious decrease in the phosphorylation of ERK and Akt in MDA-MB-231 cells, but increased the phosphorylation of ERK in MCF-7 cells. In addition, we observed that combination treatments enhanced intracellular ROS levels and reduced glutathione (GSH levels in breast cancer cells, suggesting that induction of oxidative stress was an important event in the cell death induced by the combination treatments.

  20. Synthesis, characterization and biological evaluation of anti-cancer indolizine derivatives via inhibiting β-catenin activity and activating p53.

    Moon, Seong-Hee; Jung, Youngeun; Kim, Seong Hwan; Kim, Ikyon

    2016-01-01

    Diversity-oriented construction of new indolizine scaffolds was accomplished by utilizing domino Knoevenagel condensation/intramolecular aldol cyclization. Biological evaluation revealed anticancer activity of these compounds through inhibition of β-catenin and activation of p53. PMID:26608553

  1. PEGylation in anti-cancer therapy: An overview

    Prajna Mishra; Bismita Nayak; R. K. Dey

    2016-01-01

    Advanced drug delivery systems using poly(ethylene glycol) (PEG) is an important development in anti-cancer therapy. PEGylation has the ability to enhance the retention time of the therapeutics like proteins, enzymes small molecular drugs, liposomes and nanoparticles by protecting them against various degrading mechanisms active inside a tissue or cell, which consequently improves their therapeutic potential. PEGylation effectively alters the pharmacokinetics (PK) of a variety of drugs and dr...

  2. Intracellular delivery of NF-κB small interfering RNA for modulating therapeutic activities of classical anti-cancer drugs in human cervical cancer cells

    Anthony Stanislaus

    2013-12-01

    Full Text Available Cervical cancer is the second most common cancer and fourth leading cause of cancer-related deaths among women. Advanced stage of the disease is treated with radiation therapy and chemotherapy with poor therapeutic outcome and adverse side effects. NFκB, a well-known transcription factor in the control of immunity and inflammation, has recently emerged as a key regulator of cell survival through induction of antiapoptotic genes. Many human cancers, including cervical carcinoma, constitutively express NF-κB and a blockade in expression of its subunit proteins through targeted knockdown of the gene transcripts with small interfering RNAs (siRNA could be an attractive approach in order to sensitize the cancer cells towards the widely used anti-cancer drugs. However, the inefficiency of the naked siRNA to cross the plasma membrane and its sensitiveness to nuclease-mediated degradation are the major challenges limiting the siRNA technology in therapeutic intervention. pH-sensitive carbonate apatite has been established as an efficient nano-carrier for intracellular delivery of siRNA, due to its strong electrostatic interaction with the siRNA, the desirable size distribution of the resulting siRNA complex for effective endocytosis and the ability of the endocytosed siRNA to be released from the degradable particles and escape the endosomes, thus leading to the effective knockdown of the target gene of cyclin B1 or ABCB1. Here, we report that carbonate apatite-facilitated delivery of the siRNA targeting NF-κB1 and NF-κB2 gene transcripts in HeLa, a human cervical adenocar- cinoma cell line expressing NF-κB, led to a synergistic effect in enhancement of chemosensitivity to doxorubicin, but apparently not to cisplatin or paclitaxel.

  3. Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds.

    Baharum, Zainal; Akim, Abdah Md; Hin, Taufiq Yap Yun; Hamid, Roslida Abdul; Kasran, Rosmin

    2016-02-01

    Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert anti-cancer effects have become an important area of health- and biomedicine-related research. This review provides an updated overview of T. cacao in terms of its potential anti-cancer compounds and their extraction, in vitro bioassay, purification, and identification. This article also discusses the advantages and disadvantages of the techniques described and reviews the processes for future perspectives of analytical methods from the viewpoint of anti-cancer compound discovery. PMID:27019680

  4. LGR5 expressing cells of hair follicle as potential targets for antibody mediated anti-cancer laser therapy

    Popov, Boris V.

    2013-02-01

    Near infrared laser immunotherapy becomes now a new promising research field to cure the patients with cancers. One of the critical limitation in medical application of this treatment is availability of the specific markers for delivery of laser-sensitive nanoparticles. When coupled to antibodies to the cancer stem cells markers these nanoparticles may be delivered to the cancer tissue and mediate the laser induced thermolysis of the cancer stem cells that initiate and drive growth of cancer. This paper addresses the Lgr5 cell surface marker mediating the Wnt/β-catenin signal transduction as a potential target for anti-cancer laser immunotherapy of skin cancers.

  5. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery. PMID:27229857

  6. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property [v1; ref status: indexed, http://f1000r.es/15s

    Asfar S Azmi

    2013-06-01

    Full Text Available “Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  7. Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy.

    Xiong, Zhengming; Ampudia-Mesias, Elisabet; Shaver, Rob; Horbinski, Craig M; Moertel, Christopher L; Olin, Michael R

    2016-09-01

    There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy. PMID:27485078

  8. BRAIN CANCER IMMUNOTHERAPY (REVIEW)

    Yashin К.S.; Medyanik I.А.

    2014-01-01

    The review analyzes Russian and foreign reports concerned with a rapidly developing brain cancer treatment technique — immunotherapy. There has been presented a current view on the basic concept of antitumor immunity, on the problem of immune system interaction with a tumor in general and under the conditions of an immunologically privileged nervous system, shown the theoretical background of efficiency of immunotherapy used against brain cancer (the capability of tumor antigens and activated...

  9. Reengineered tricyclic anti-cancer agents.

    Kastrinsky, David B; Sangodkar, Jaya; Zaware, Nilesh; Izadmehr, Sudeh; Dhawan, Neil S; Narla, Goutham; Ohlmeyer, Michael

    2015-10-01

    The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling. PMID:26372073

  10. 22种常见抗肿瘤中草药的抗氧化活性研究%Antioxidant Activity of 22 Chinese Herbal Medicines for Anti-cancer

    张新国; 刘英娟; 曹心张; 张春生; 匡彦蓓

    2015-01-01

    Objective:In this study ,22 Chinese herbal medicines for anti -cancer were developed for the study of its an-tioxidant activity .Methods:The antioxidant activities of samples were evaluated by DPPH method;phenols , flavonoids contents and total reducing power were estimated by using the Folin -Ciocalteu reagent , aluminum salt colorimetric method and ferric-reducing antioxidant power assay ( FRAP) .Results:The results confirmed that 90 .09%of the medi-cine had characterized the antioxidant activity with more than 50%, which included eight kinds of plant materials such as Rhizoma Curcumae , Rhizoma Polygoni Cuspidati , Wild Skullcaps , Radix Paeoniae Alba , Fern , Salviamiltiorrhiza , Radix Dipsaci Asperoidis , Curcuma longa demonstrated better antioxidant activity ( activity >90%) .Wild Skullcaps demonstrated the best antioxidant activity with the lowest IC 50 value of 0.05g/L, the highest phenolic and flavonoid con-tents of 5240μg/L and 83210μg/L.Conclusion:Each sample for anti -cancer has a strong antioxidant activity except for the Coix seed and Poria , which confirms natural antioxidant and antitumor effect has a certain correlation , but its mechanism needs further research .In this study , it is possible to find antioxidants and antioxidant -based anticancer drugs develop from broad anti -tumor natural resources providing an experimental basis .%目的:本研究以常见的22种具有抗肿瘤活性的中药材为对象,对其抗氧化活性进行研究。方法:以DPPH自由基清除率为指标,测定各试样的抗氧化活性;通过FRAP法,Folin-Ciocaheu法以及铝盐显色法,比较其总还原力,总酚含量以及黄酮含量。结果:抗氧化活性大于50%的药材占到了90.09%,其中莪术、虎杖、野生黄芩、白芍、凤尾草、丹参、川断、姜黄等8种药材DPPH的清除作用均超过了90%,显示了较强的抗氧化作用,且野生黄芩的IC50最低(IC50=0.05g/L),抗氧化能力

  11. Influence of ecological factors on the production of active substances in the anti-cancer plant Sinopodophyllum hexandrum (Royle T.S. Ying.

    Wei Liu

    Full Text Available The quality of traditional Chinese herbal medicine, which plays a very important role in the health system of China, is determined by the active substances produced by the plants. The type, content, and proportion of these substances may vary depending on ecological factors in areas where the plants are grown. Sinopodophyllum hexandrum (Royle T.S. Ying, an endangered plant species with great medical value, was investigated in eight production locations representative of its natural geographical distribution range in China. The correlation between the contents of the active ingredients extracted from the roots and rhizomes of S. hexandrum and the ecological factors were evaluated step-by-step using a series of computational biology methodologies. The results showed that ecological factors had significant effects on the contents but not on the types of the active ingredients in eight production locations. The primary ecological factors influencing the active substances included the annual average precipitation, July mean temperature, frost-free period, sunshine duration, soil pH, soil organic matter, and rapidly available potassium in the soil. The annual average precipitation was the most important determinant factor and was significantly and negatively correlated with the active ingredient contents (P < 0.001. In contrast, organic matter was the most important limiting factor and was significantly and positively correlated with the active substances. These ecological factors caused 98.13% of the total geographical variation of the active ingredient contents. The climate factors contributed more to the active ingredient contents than did the soil factors. It was concluded that from the view of the contents of the secondary metabolites and ecological factors of each growing location, in Jingyuan, Ningxia Province, and Yongdeng, Gansu Province, conditions were favorable to the production of podophyllotoxin and lignans, whereas in Shangri-La, Yunnan

  12. Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities.

    Filali, Insaf; Bouajila, Jalloul; Znati, Mansour; Bousejra-El Garah, Fatima; Ben Jannet, Hichem

    2015-06-01

    In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC50 = 10.4 µM) was obtained for harmine 1 and cytotoxic activities (IC50 = 0.2 µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC50 = 29.2 and 55.5 µM, respectively). PMID:25068731

  13. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  14. Antitumor and Adjuvant Activity of λ-carrageenan by Stimulating Immune Response in Cancer Immunotherapy.

    Luo, Min; Shao, Bin; Nie, Wen; Wei, Xia-Wei; Li, Yu-Li; Wang, Bi-Lan; He, Zhi-Yao; Liang, Xiao; Ye, Ting-Hong; Wei, Yu-Quan

    2015-01-01

    λ-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of λ-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of λ-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, λ-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-α in tumor, most of which was secreted by infiltrating macrophages. Moreover, λ-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that λ-carrageenan was with a good safety profile. Thus, λ-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID:26098663

  15. Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti-cancer activity in human triple negative breast carcinoma cells.

    Ahir, Manisha; Bhattacharya, Saurav; Karmakar, Soumendu; Mukhopadhyay, Ayan; Mukherjee, Sudeshna; Ghosh, Swatilekha; Chattopadhyay, Sreya; Patra, Prasun; Adhikary, Arghya

    2016-01-01

    Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug-resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-κB favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent. PMID:26520043

  16. Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid).

    Bibby, M. C.; Double, J A; Phillips, R. M.; Loadman, P.M.

    1987-01-01

    LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM...

  17. Influence of Ecological Factors on the Production of Active Substances in the Anti-Cancer Plant Sinopodophyllum hexandrum (Royle) T.S. Ying

    Liu, Wei; Liu, Jianjun; Yin, Dongxue; Zhao, Xiaowen

    2015-01-01

    The quality of traditional Chinese herbal medicine, which plays a very important role in the health system of China, is determined by the active substances produced by the plants. The type, content, and proportion of these substances may vary depending on ecological factors in areas where the plants are grown. Sinopodophyllum hexandrum (Royle) T.S. Ying, an endangered plant species with great medical value, was investigated in eight production locations representative of its natural geographi...

  18. Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

    Yang, Hung-Yu; Hsu, Ya-Fen; Chiu, Pei-Ting; Ho, Shiau-Jing; Wang, Chi-Han; Chi, Chih-Chin; Huang, Yu-Han; Lee, Cheng-Feng; Li, Ying-Shiuan; Ou, George; Hsu, Ming-Jen

    2013-01-01

    Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID:24312323

  19. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    Michael G. Morash; Douglas, Susan E.; Anna Robotham; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. ...

  20. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    Morash, Michael G.; Douglas, Susan E.; Anna Robotham; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of actio...

  1. Exosomes from myeloid derived suppressor cells carry biologically active proteins

    Burke, Meghan; Choksawangkarn, Waeowalee; Edwards, Nathan; Ostrand-Rosenberg, Suzanne; Fenselau, Catherine

    2013-01-01

    Myeloid-derived suppressor cells (MDSC) are present in most cancer patients where they inhibit natural anti-tumor immunity and are an obstacle to anti-cancer immunotherapies. They mediate immune suppression through their production of proteins and soluble mediators that prevent the activation of tumor-reactive T lymphyocytes, polarize macrophages towards a tumor-promoting phenotype, and facilitate angiogenesis. The accumulation and suppressive potency of MDSC is regulated by inflammation with...

  2. Anti-Cancer Activity of Solanum nigrum (AESN through Suppression of Mitochondrial Function and Epithelial-Mesenchymal Transition (EMT in Breast Cancer Cells

    Ying-Jang Lai

    2016-04-01

    Full Text Available Chemotherapy is the main approach for treating advanced and recurrent carcinoma, but the clinical performance of chemotherapy is limited by relatively low response rates, drug resistance, and adverse effects that severely affect the quality of life of patients. An association between epithelial-mesenchymal transition (EMT and chemotherapy resistance has been investigated in recent studies. Our recent studies have found that the aqueous extract of Solanum nigrum (AESN is a crucial ingredient in some traditional Chinese medicine formulas for treating various types of cancer patients and exhibits antitumor effects. We evaluated the suppression of EMT in MCF-7 breast cancer cells treated with AESN. The mitochondrial morphology was investigated using Mitotracker Deep-Red FM stain. Our results indicated that AESN markedly inhibited cell viability of MCF-7 breast cancer cells through apoptosis induction and cell cycle arrest mediated by activation of caspase-3 and production of reactive oxygen species. Furthermore, mitochondrial fission was observed in MCF-7 breast cancer cells treated with AESN. In addition to elevation of E-cadherin, downregulations of ZEB1, N-cadherin, and vimentin were found in AESN-treated MCF-7 breast cancer cells. These results suggested that AESN could inhibit EMT of MCF-7 breast cancer cells mediated by attenuation of mitochondrial function. AESN could be potentially beneficial in treating breast cancer cells, and may be of interest for future studies in developing integrative cancer therapy against proliferation, metastasis, and migration of breast cancer cells.

  3. Synthesis, structure analysis, anti-bacterial and in vitro anti-cancer activity of new Schiff base and its copper complex derived from sulfamethoxazole

    I Rama; R Selvameena

    2015-04-01

    A new bidentate Schiff base ligand (HL1), containing O,N donors was prepared by the reaction of sulfamethoxazole with 5-nitrosalicylaldehyde and characterized by elemental analysis, FT-IR, 1H and 13C NMR. The copper complex of this ligand was synthesised by treating DMF-ethanolic mixture solution of the ligand of two equivalents with one equivalent of copper acetate. The complex was characterized on the basis of UV, FT-IR, molar conductance, EPR, magnetic moment and single crystal X-ray diffraction. Interestingly, the crystal structure of the octahedral complex showed two solvent molecules (DMF) as ligands at their axial positions. The molar conductance data revealed that the complex is a non-electrolyte. The Schiff base and its copper complex have been investigated as anti-bacterial and anti-fungal agents against various microorganisms. The in vitro cytotoxicity tests of the ligand and its copper complex were carried out in two different human tumour cell lines, HCT-116 and MDA – MB - 231. The cytotoxicity studies showed that the complex exhibited higher activity than cisplatin and carboplatin towards MDA – MB – 231.

  4. Combined active and passive immunization enhances the efficacy of immunotherapy against nicotine in rats.

    Roiko, Samuel A; Harris, Andrew C; Keyler, Daniel E; Lesage, Mark G; Zhang, Yan; Pentel, Paul R

    2008-06-01

    Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this. PMID:18305013

  5. The in vitro and in vivo anti-cancer activities of a standardized quassinoids composition from Eurycoma longifolia on LNCaP human prostate cancer cells.

    Kind Leng Tong

    composition from E. longifolia promotes anti-prostate cancer activities in LNCaP human prostate cancer cells.

  6. Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy

    Simovic B

    2015-10-01

    Full Text Available Boris Simovic, Scott R Walsh, Yonghong Wan Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada Abstract: Immunotherapy and oncolytic virotherapy have both shown anticancer efficacy in the clinic as monotherapies but the greatest promise lies in therapies that combine these approaches. Vesicular stomatitis virus is a prominent oncolytic virus with several features that promise synergy between oncolytic virotherapy and immunotherapy. This review will address the cytotoxicity of vesicular stomatitis virus in transformed cells and what this means for antitumor immunity and the virus' immunogenicity, as well as how it facilitates the breaking of tolerance within the tumor, and finally, we will outline how these features can be incorporated into the rational design of new treatment strategies in combination with immunotherapy. Keywords: virotherapy, rhabdovirus, anti-tumor immunity, t cell, natural killer cell, therapeutic vaccine

  7. ANTI - CANCER DRUGS FROM TRADITIONAL PLANTS OF SITAPUR DISTRICT (UTTAR PRADESH)

    Siddiqui, M. Badruzzaman

    2003-01-01

    The paper deals with some important medicinal plants growing in the Sitapur district of Vttar Pradesh province used as an anti cancer activities. 10 spaceies are reported along with doses and mode of administration. Neither the putative plant remedies evaluated nor any chemical principles identified.

  8. Low-Dose Cyclophosphamide Synergizes with Dendritic Cell-Based Immunotherapy in Antitumor Activity

    Joris D. Veltman

    2010-01-01

    Full Text Available Clinical immunotherapy trials like dendritic cell-based vaccinations are hampered by the tumor's offensive repertoire that suppresses the incoming effector cells. Regulatory T cells are instrumental in suppressing the function of cytotoxic T cells. We studied the effect of low-dose cyclophosphamide on the suppressive function of regulatory T cells and investigated if the success rate of dendritic cell immunotherapy could be improved. For this, mesothelioma tumor-bearing mice were treated with dendritic cell-based immunotherapy alone or in combination with low-dose of cyclophosphamide. Proportions of regulatory T cells and the cytotoxic T cell functions at different stages of disease were analyzed. We found that low-dose cyclophosphamide induced beneficial immunomodulatory effects by preventing the induction of Tregs, and as a consequence, cytotoxic T cell function was no longer affected. Addition of cyclophosphamide improved immunotherapy leading to an increased median and overall survival. Future studies are needed to address the usefulness of this combination treatment for mesothelioma patients.

  9. Screening for Anti-Cancer Compounds in Marine Organisms in Oman

    Sergey Dobretsov

    2016-05-01

    Full Text Available Objectives: Marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the Arabian Gulf and the Gulf of Oman. This study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the Gulf of Oman. Methods: This study was carried out between January 2012 and December 2014 at the Sultan Qaboos University, Muscat, Oman. Fungi, bacteria, sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers were collected from seawater at Marina Bandar Al-Rowdha and Bandar Al-Khayran in Oman. Bacteria and fungi were isolated using a marine broth and organisms were extracted with methanol and ethyl acetate. Compounds were identified from spectroscopic data. The anti-cancer activity of the compounds and extracts was tested in a Michigan Cancer Foundation (MCF-7 cell line breast adenocarcinoma model. Results: Eight pure compounds and 32 extracts were investigated. Of these, 22.5% showed strong or medium anti-cancer activity, with malformin A, kuanoniamine D, hymenialdisine and gallic acid showing the greatest activity, as well as the soft coral Sarcophyton sp. extract. Treatment of MCF-7 cells at different concentrations of Sarcophyton sp. extracts indicated the induction of concentration-dependent cell death. Ultrastructural analysis highlighted the presence of nuclear fragmentation, membrane protrusion, blebbing and chromatic segregation at the nuclear membrane, which are typical characteristics of cell death by apoptosis induction. Conclusion: Some Omani marine organisms showed high anti-cancer potential. The efficacy, specificity and molecular mechanisms of anti-cancer compounds from Omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies.

  10. Sarcoma Immunotherapy

    Gouw, Launce G., E-mail: launce.gouw@hsc.utah.edu [Departments of Oncology, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Jones, Kevin B. [Departments of Orthopaedic Surgery, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Sharma, Sunil [Departments of Oncology, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Randall, R. Lor [Departments of Orthopaedic Surgery, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States)

    2011-11-10

    Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.

  11. Sarcoma Immunotherapy

    Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis

  12. Mouse Models of Tumor Immunotherapy.

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients. PMID:26922998

  13. Cancer Immunotherapy of Targeting Angiogenesis

    JianmeiHou; LingTian; YuquanWei

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  14. Integrated cancer therapy combined radiotherapy and immunotherapy. The challenge of using Gc protein-derived macrophage activating factor (GcMAF) as a key molecule

    Radiation oncologists know the conflict between radiotherapy and immunotherapy, but now challenged trails of the integrative cancer therapies combined radiation therapy and various immunoreaction/immune therapies begin. We therefore review the recent results of basic research and clinical trial of the integrated cancer therapies which combined radiotherapy and various immune therapies/immunoreaction, and the challenged studies of combined use of radiotherapy and our developed cancer immunotherapy using serum GcMAF which is human serum containing Gc protein-derived macrophage activating factor (GcMAF). (author)

  15. A Journey Under the Sea: The Quest for Marine Anti-Cancer Alkaloids

    Nadine Darwiche

    2011-11-01

    Full Text Available The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action.

  16. A journey under the sea: the quest for marine anti-cancer alkaloids.

    Tohme, Rita; Darwiche, Nadine; Gali-Muhtasib, Hala

    2011-01-01

    The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action. PMID:22113577

  17. Fucoxanthin: A Marine Carotenoid Exerting Anti-Cancer Effects by Affecting Multiple Mechanisms

    Sangeetha Ravi Kumar; Masashi Hosokawa; Kazuo Miyashita

    2013-01-01

    Fucoxanthin is a marine carotenoid exhibiting several health benefits. The anti-cancer effect of fucoxanthin and its deacetylated metabolite, fucoxanthinol, is well documented. In view of its potent anti-carcinogenic activity, the need to understand the underlying mechanisms has gained prominence. Towards achieving this goal, several researchers have carried out studies in various cell lines and in vivo and have deciphered that fucoxanthin exerts its anti-proliferative and cancer preventing ...

  18. In vitro characterization of the human biotransformation of marine derived anti-cancer drugs

    Brandon, E.F.A. (Esther Fleur Annette)

    2004-01-01

    Cancer is the second cause of death in The Netherlands. Although the treatment options over the past few decades have substantially improved, the cure rate for patients with advanced cancer remains low. In addition, hopefully new therapies will induce less severe side effects compared to the present therapies. Overall, new anti cancer drugs are still very much needed to improve treatment outcome of patients. Many active cytotoxic agents originate from natural resources, mainly plants (e.g. pa...

  19. Screening for Anti-Cancer Compounds in Marine Organisms in Oman

    Sergey Dobretsov; Yahya Tamimi; Al-Kindi, Mohamed A.; Ikram Burney

    2016-01-01

    Objectives: Marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the Arabian Gulf and the Gulf of Oman. This study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the Gulf of Oman. Methods: This study was carried out between January 2012 and December ...

  20. Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds

    Baharum, Zainal; Akim, Abdah Md; Hin, Taufiq Yap Yun; Hamid, Roslida Abdul; Kasran, Rosmin

    2016-01-01

    Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert...

  1. Moringa oleifera as an Anti-Cancer Agent against Breast and Colorectal Cancer Cell Lines

    Al-Asmari, Abdulrahman Khazim; Albalawi, Sulaiman Mansour; Athar, Md Tanwir; Khan, Abdul Quaiyoom; Al-Shahrani, Hamoud; Islam, Mozaffarul

    2015-01-01

    In this study we investigated the anti-cancer effect of Moringa oleifera leaves, bark and seed extracts. When tested against MDA-MB-231 and HCT-8 cancer cell lines, the extracts of leaves and bark showed remarkable anti-cancer properties while surprisingly, seed extracts exhibited hardly any such properties. Cell survival was significantly low in both cells lines when treated with leaves and bark extracts. Furthermore, a striking reduction (about 70–90%) in colony formation as well as cell motility was observed upon treatment with leaves and bark. Additionally, apoptosis assay performed on these treated breast and colorectal cancer lines showed a remarkable increase in the number of apoptotic cells; with a 7 fold increase in MD-MB-231 to an increase of several fold in colorectal cancer cell lines. However, no significant apoptotic cells were detected upon seeds extract treatment. Moreover, the cell cycle distribution showed a G2/M enrichment (about 2–3 fold) indicating that these extracts effectively arrest the cell progression at the G2/M phase. The GC-MS analyses of these extracts revealed numerous known anti-cancer compounds, namely eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester, all of which possess long chain hydrocarbons, sugar moiety and an aromatic ring. This suggests that the anti-cancer properties of Moringa oleifera could be attributed to the bioactive compounds present in the extracts from this plant. This is a novel study because no report has yet been cited on the effectiveness of Moringa extracts obtained in the locally grown environment as an anti-cancer agent against breast and colorectal cancers. Our study is the first of its kind to evaluate the anti-malignant properties of Moringa not only in leaves but also in bark. These findings suggest that both the leaf and bark extracts of Moringa collected from the Saudi Arabian region possess anti-cancer activity that can be used to develop new drugs for treatment of

  2. Mechanistic study of the anti-cancer effect of Gynostemma pentaphyllum saponins in the Apc(Min/+) mouse model.

    Tai, William Chi-Shing; Wong, Wing-Yan; Lee, Magnolia Muk-Lan; Chan, Brandon Dow; Lu, Cheng; Hsiao, Wen-Luan Wendy

    2016-05-01

    Gynostemma pentaphyllum saponins (GpS) have been shown to have anti-cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc(Min) (/+) colorectal cancer (CRC) mouse model to investigate the anti-cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc(Min) (/+) mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf-1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin-1 (Prdx1) and peroxiredoxin-2 (Prdx2), and the downregulation of Raf-1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti-cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5-fluorouracil (5-FU) and found that GpS could enhance the anti-cancer efficacy of 5-FU, further suppressing the number of polyps in Apc(Min/+) mice. Our findings highlight the potential of GpS as an anti-cancer agent, the potential mechanisms of its anti-cancer activities, and its effect as an adjuvant of 5-FU in the chemotherapy of CRC. PMID:26970558

  3. Brain Cancer Immunotherapy (Review

    Yashin К.S.

    2014-12-01

    Full Text Available The review analyzes Russian and foreign reports concerned with a rapidly developing brain cancer treatment technique — immunotherapy. There has been presented a current view on the basic concept of antitumor immunity, on the problem of immune system interaction with a tumor in general and under the conditions of an immunologically privileged nervous system, shown the theoretical background of efficiency of immunotherapy used against brain cancer (the capability of tumor antigens and activated lymphocytes to penetrate the blood-brain barrier. There has been demonstrated the role of a transforming growth factor β, interleukin 10, cyclooxygenase-2, prostaglandin Е2, protein MCP-1, interactions Fas-receptor/Fas-ligand, antigen-4 cytotoxic Т-lymphocytes in tumor immunoresistance development. The review presents a current classification of the types of active and passive immunotherapy, each of the types being considered separately specifying the characteristics, the results of preclinical and clinical trials of each type efficiency, and possible side effects. Special attention has been paid to a new concept of a key role of tumor stem cells in the pathogenesis of cerebral gliomas and the target action on these cells.

  4. Delivering anti-cancer drugs with endosomal pH-sensitive anti-cancer liposomes.

    Moku, Gopikrishna; Gulla, Suresh Kumar; Nimmu, Narendra Varma; Khalid, Sara; Chaudhuri, Arabinda

    2016-04-22

    Numerous prior studies have been reported on the use of pH-sensitive drug carriers such as micelles, liposomes, peptides, polymers, nanoparticles, etc. that are sensitive to the acidic (pH = ∼6.5) microenvironments of tumor tissues. Such systems have been primarily used in the past as effective drug/gene/microRNA carriers for releasing their anti-cancer payloads selectively to tumor cells/tissues. Herein, we report on the development of new liposomal drug carriers prepared from glutamic acid backbone-based cationic amphiphiles containing both endosomal pH-sensitive histidine as well as cellular uptake & solubility enhancing guanidine moieties in their polar head-group regions. The most efficient one among the four presently described endosomal pH-sensitive liposomal drug carriers not only effectively delivers potent anti-cancer drugs (curcumin & paclitaxel) to mouse tumor, but also significantly contributes to inhibiting mouse tumor growth. The findings in the in vitro mechanistic studies are consistent with apoptosis of tumor cells being mediated through increased cell cycle arrest in the G2/M phase. Findings in the FRET assay and in vitro drug release studies conducted with the liposomes of the most efficient pH-sensitive lipid demonstrated its pH dependent fusogenic and controlled curcumin release properties. Importantly, the presently described liposomal formulation of curcumin & paclitaxel enhanced overall survivability of tumor bearing mice. To the best of our knowledge, the presently described system (curcumin, paclitaxel and liposomal carrier itself) is the first of its kind pH-sensitive liposomal formulation of potent chemotherapeutics in which the liposomal drug itself exhibits significant mouse tumor growth inhibition properties. PMID:26806172

  5. Anti-cancer natural products isolated from chinese medicinal herbs

    Wu Guosheng

    2011-07-01

    Full Text Available Abstract In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin, alkaloids (berberine, terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid, quinones (shikonin and emodin and saponins (ginsenoside Rg3, which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.

  6. Hydrofocusing Bioreactor Produces Anti-Cancer Alkaloids

    Gonda, Steve R.; Valluri, Jagan V.

    2011-01-01

    microgravitation of an HFB do not need to maintain the same surface forces as in normal Earth gravitation, they can divert more energy sources to growth and differentiation and, perhaps, to biosynthesis of greater quantities of desired medicinal compounds. Because one can adjust the HFB to vary effective gravitation, one can also test the effects of intermediate levels of gravitation on biosynthesis of various products. The potential utility of this methodology for producing drugs was demonstrated in experiments in which sandalwood and Madagascar periwinkle cells were grown in an HFB. The conditions in the HFB were chosen to induce the cells to form into aggregate cultures that produced anti-cancer indole alkaloids in amounts greater than do comparable numbers of cells of the same species cultured according to previously known methodologies. The observations made in these experiments were interpreted as suggesting that the aggregation of the cells might be responsible for the enhancement of production of alkaloids.

  7. Classification of mitocans, anti-cancer drugs acting on mitochondria

    Neužil, Jiří; Dong, L. F.; Rohlena, Jakub; Truksa, Jaroslav; Ralph, S. J.

    2013-01-01

    Roč. 13, č. 3 (2013), s. 199-208. ISSN 1567-7249 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitocans * Anti- cancer therapeutics * Classification Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.524, year: 2013

  8. Classification of mitocans, anti-cancer drugs acting on mitochondria

    Neužil, Jiří; Dong, L. F.; Rohlena, Jakub; Truksa, Jaroslav; Ralph, S. J.

    2013-01-01

    Roč. 13, č. 3 (2013), s. 199-208. ISSN 1567-7249 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitocans * Anti-cancer therapeutics * Classification Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.524, year: 2013

  9. Zinc-phosphate nanoparticles with reversibly attached TNF-α analogs: an interesting concept for potential use in active immunotherapy

    The authors’ intention was to prepare nanometer-sized zinc-phosphate nanoparticles that would be capable of binding histidine-rich TNF-α analogs onto their surface via a coordinative bond. Zinc-phosphate nanoparticles with a size of around 60 nm were prepared by a wet precipitation method and characterized using SEM, EDX, XRD, and DLS. First, BSA was bound as a testing protein, afterward two TNF-α analogs with decreased activity were bound to the described nanoparticles. The efficiency of binding and the existence of coordinative bond were confirmed with SDS-PAGE analysis. During binding, particle storage, and release experiments, the prepared TNF-α analogs retained their biological activity—hence the epitopes necessary for formation of antibodies stayed intact. The particle size did not change within a period of 2 weeks. No significant agglomeration was observed, the particles could be quickly dispersed in ultrasound. The present nanoparticles and the general approach of coordinative binding are widely applicable for natural and engineered histidine-rich proteins. The nanoparticles bearing appropriate TNF-α analogs could also be potentially used for active immunotherapy to tackle the chronic inflammatory diseases associated with pathogenically elevated levels of TNF-α.

  10. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work. PMID:27561803

  11. 3-PHENYLQUINOLINYLCHALCONE DERIVATIVES: PHARMACOPHORE MODELLING, 3D-QSAR ANALYSIS AND DOCKING STUDIES AS ANTI-CANCER AGENTS

    2014-01-01

    Certain 3-Phenylquinolinylchalcone derivatives were evaluated for their anti-proliferative activities and found to exhibit anti-cancer and anti-inflammatory activities. 3D-QSAR and molecular docking approaches were performed on 3-Phenylquinolinylchalcone derivatives to understand their structural requisites and binding mode of the best fitted ligand for cancer inhibitory activity. Among them, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-one (6a) was the most active compound ag...

  12. DNA binding and anti-cancer activity of redox-active heteroleptic piano-stool Ru(II), Rh(III), and Ir(III) complexes containing 4-(2-methoxypyridyl)phenyldipyrromethene.

    Gupta, Rakesh Kumar; Pandey, Rampal; Sharma, Gunjan; Prasad, Ritika; Koch, Biplob; Srikrishna, Saripella; Li, Pei-Zhou; Xu, Qiang; Pandey, Daya Shankar

    2013-04-01

    The synthesis of four novel heteroleptic dipyrrinato complexes [(η(6)-arene)RuCl(2-pcdpm)] (η(6)-arene = C6H6, 1; C10H14, 2) and [(η(5)-C5Me5)MCl(2-pcdpm)] (M = Rh, 3; Ir, 4) containing a new chelating ligand 4-(2-methoxypyridyl)-phenyldipyrromethene (2-pcdpm) have been described. The complexes 1-4 have been fully characterized by various physicochemical techniques, namely, elemental analyses, spectral (ESI-MS, IR, (1)H, (13)C NMR, UV/vis) and electrochemical studies (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)). Structures of 3 and 4 have been determined crystallographically. In vitro antiproliferative and cytotoxic activity of these complexes has been evaluated by trypan blue exclusion assay, cell morphology, apoptosis, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA fragmentation assay in Dalton lymphoma (DL) cell lines. Interaction of 1-4 with calf thymus DNA (CT DNA) has also been supported by absorption titration and electrochemical studies. Our results suggest that in vitro antitumor activity of 1-4 lies in the order 2 > 1 > 4 > 3. PMID:23477351

  13. Design, synthesis, and mechanistic studies of Sansalvamide A derivatives as anti-cancer agents

    Alexander, Leslie Diane

    2012-01-01

    Sansalvamide A (SanA) is a cyclic depsipeptide that was isolated from a marine fungus and demonstrates mid- micromolar anti-cancer activity in the NCI 60-cell line panel. Our laboratory has synthesized over 100 peptide derivatives of this molecule, 5 of which were contributed by the author of this dissertation. The design and solution-phase synthesis of these derivatives is described in Chapter 2. The author was also responsible for attaching PEG-biotin and fluorescein tags to lead SanA deriv...

  14. Telomere and telomerase as targets for anti-cancer and regeneration therapies

    Yi-hsin HSU; Jing-jer LIN

    2005-01-01

    Telomerase is a ribonucleoprotein that directs the synthesis of telomeric sequence.It is detected in majority of malignant tumors, but not in most normal somatic cells.Because telomerase plays a critical role in cell immortality and tumor formation, it has been one of the targets for anti-cancer and regeneration drug development. In this review, we will discuss therapeutic approaches based mainly on small molecules that have been developed to inhibit telomerase activity, modulate telomerase expression, and telomerase directed gene therapy.

  15. The immunotherapy of Alzheimer's disease

    Weksler Marc E

    2004-11-01

    Full Text Available Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.

  16. Multivariate statistical analysis for anti-cancer drug treatment evaluation

    Hrabáková, Rita; Martinková, Jiřina; Skalníková, Helena; Novák, Petr; Radová, L.; Džubák, P.; Kollareddy, M. R.; Hajduch, M.; Gadher, S. J.; Kovářová, Hana

    Budapešť : Hungarian Chemical Society, 2009, s. 119-119. ISBN 978-963-9319-99-8. [3rd Central and Eastern European Proteomics Conference. Budapešť (HU), 06.10.2009-09.10.2009] R&D Projects: GA MŠk LC07017 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z50450515 Keywords : drug resistance * anti-cancer therapy * proteomics Subject RIV: CE - Biochemistry

  17. Molecular Biological Study of Anti-cancer Effects of Bee Venom Aqua-acupuncture

    Park Chan-Yol

    2000-07-01

    Full Text Available To study anti-cancer effect and molecular biological mechanism of bee venom for aqua-acupuncture, the effects of bee venom on cell viability and apoptosis were analyzed using MTT assay, tryphan blue assay, [3H]thymidine release assay, flow cytometric analysis, and activity of caspase-3 protease activity assay. To explore whether anti-cancer effects of bee venom are associated with the transcriptional control of gene expression, quantitative RT-PCR analysis of apoptosis-related genes was performed. The obtained results are summarized as follows: 1. The MTT assay demonstrated that cell viability was decreased by bee venom in a dose-dependant manner. 2. Significant induction of apoptosis was identified using tryphan blue assay, [3H]thymidine release assay, and flow cytometric analysis of sub G1 fraction. 3. In analysis of caspase-3 protease activity, the activity had increased significantly, in a dose-dependant manner. 4. Quantitative RT-PCR analysis of the apoptosis-related genes showed that Bcl-2 and Bcl-XL were down-regulated whereas Bax was up-regulated by bee venom treatment.

  18. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

    2008-07-01

    Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years. PMID:18633461

  19. In Vivo Anti-Cancer Mechanism of Low-Molecular-Weight Fucosylated Chondroitin Sulfate (LFCS) from Sea Cucumber Cucumaria frondosa.

    Liu, Xiaoxiao; Liu, Yong; Hao, Jiejie; Zhao, Xiaoliang; Lang, Yinzhi; Fan, Fei; Cai, Chao; Li, Guoyun; Zhang, Lijuan; Yu, Guangli

    2016-01-01

    The low-molecular-weight fucosylated chondroitin sulfate (LFCS) was prepared from native fucosylated chondroitin sulfate (FCS), which was extracted and isolated from sea cucumber Cucumaria frondosa, and the anti-cancer mechanism of LFCS on mouse Lewis lung carcinoma (LLC) was investigated. The results showed that LFCS remarkably inhibited LLC growth and metastasis in a dose-dependent manner. LFCS induced cell cycle arrest by increasing p53/p21 expression and apoptosis through activation of caspase-3 activity in LLC cells. Meanwhile, LFCS suppressed the expression of vascular endothelial growth factor (VEGF), increased the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and downregulated the matrix metalloproteinases (MMPs) level. Furthermore, LFCS significantly suppressed the activation of ERK1/2/p38 MAPK/NF-κB pathway, which played a prime role in expression of MMPs. All of these data indicate LFCS may be used as anti-cancer drug candidates and deserve further study. PMID:27187337

  20. Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide.

    Deng, Xin; Qiu, Qianqian; Ma, Ke; Huang, Wenlong; Qian, Hai

    2015-11-01

    Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells. PMID:26058357

  1. In Vivo Anti-Cancer Mechanism of Low-Molecular-Weight Fucosylated Chondroitin Sulfate (LFCS from Sea Cucumber Cucumaria frondosa

    Xiaoxiao Liu

    2016-05-01

    Full Text Available The low-molecular-weight fucosylated chondroitin sulfate (LFCS was prepared from native fucosylated chondroitin sulfate (FCS, which was extracted and isolated from sea cucumber Cucumaria frondosa, and the anti-cancer mechanism of LFCS on mouse Lewis lung carcinoma (LLC was investigated. The results showed that LFCS remarkably inhibited LLC growth and metastasis in a dose-dependent manner. LFCS induced cell cycle arrest by increasing p53/p21 expression and apoptosis through activation of caspase-3 activity in LLC cells. Meanwhile, LFCS suppressed the expression of vascular endothelial growth factor (VEGF, increased the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1 and downregulated the matrix metalloproteinases (MMPs level. Furthermore, LFCS significantly suppressed the activation of ERK1/2/p38 MAPK/NF-κB pathway, which played a prime role in expression of MMPs. All of these data indicate LFCS may be used as anti-cancer drug candidates and deserve further study.

  2. Aloe-emodin loaded solid lipid nanoparticles: formulation design and in vitro anti-cancer study.

    Chen, Ruie; Wang, Shengpeng; Zhang, Jinming; Chen, Meiwan; Wang, Yitao

    2015-01-01

    Aloe-emodin (AE) is a promising anti-tumor candidate for its significant activity against various tumors such as lung cancer, hepatic cancer, breast cancer and so on. Nevertheless, AE is clinically limited due to its poor water solubility and low bioavailability. This study was designed to prepare AE-loaded solid lipid nanoparticles (AE-SLNs) in an attempt to improve the anti-cancer efficacy of AE. The AE-SLNs were prepared with optimized prescription using high pressure homogenization (HPH) technique. Ultimately, the AE-SLNs showed stable particle size at 88.9 ± 5.2 nm, ideal drug entrapment efficiency (EE) of 97.71 ± 0.5% and good stability with regard to zeta-potential as high as -42.8 mV. The in vitro release profiles revealed that AE achieved sustained release by loading into SLNs. Moreover, AE-SLNs showed significantly higher in vitro cytotoxicity against human breast cancer MCF-7 cells and human hepatoma HepG2 cells as compared to the AE solution, while they showed no significant toxicity on human mammary epithelial MCF-10A cells. Hoechst 33342 staining and Annexin V/PI double staining indicated that AE-SLNs induced higher apoptotic rates in MCF-7 cells. Further study elucidated that the improved anti-cancer efficacy may be attributed to the increased cellular uptake of AE. Based on these findings, we believe that the development of AE-SLNs is an effective way for improving the anti-cancer efficacy of AE. PMID:24512431

  3. Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug.

    Jing Wang

    Full Text Available Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C's effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.

  4. Breast Cancer Immunotherapy

    JuhuaZhou; YinZhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy, radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future. Cellular & Molecular Immunology.

  5. Trends in Cancer Immunotherapy

    Murphy, Joseph F.

    2010-01-01

    Modulation of the immune system for therapeutic ends has a long history, stretching back to Edward Jenner’s use of cowpox to induce immunity to smallpox in 1796. Since then, immunotherapy, in the form of prophylactic and therapeutic vaccines, has enabled doctors to treat and prevent a variety of infectious diseases, including cholera, poliomyelitis, diphtheria, measles and mumps. Immunotherapy is now increasingly being applied to oncology. Cancer immunotherapy attempts to harness the power an...

  6. Breast Cancer Immunotherapy

    Juhua Zhou; Yin Zhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy,radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future.

  7. Immunotherapy for tuberculosis: future prospects

    Abate G

    2016-04-01

    Full Text Available Getahun Abate,1 Daniel F Hoft1,2 1Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, 2Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, USA Abstract: Tuberculosis (TB is still a major global health problem. A third of the world's population is infected with Mycobacterium tuberculosis. Only ~10% of infected individuals develop TB but there are 9 million TB cases with 1.5 million deaths annually. The standard prophylactic treatment regimens for latent TB infection take 3–9 months, and new cases of TB require at least 6 months of treatment with multiple drugs. The management of latent TB infection and TB has become more challenging because of the spread of multidrug-resistant and extremely drug-resistant TB. Intensified efforts to find new TB drugs and immunotherapies are needed. Immunotherapies could modulate the immune system in patients with latent TB infection or active disease, enabling better control of M. tuberculosis replication. This review describes several types of potential immunotherapies with a focus on those which have been tested in humans. Keywords: tuberculosis, HDT, immunotherapy, treatment

  8. Classification of current anticancer immunotherapies

    Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

    2014-01-01

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  9. Anti-Cancer Effects of Green Tea by Either Anti- or Pro- Oxidative Mechanisms.

    Hayakawa, Sumio; Saito, Kieko; Miyoshi, Noriyuki; Ohishi, Tomokazu; Oishi, Yumiko; Miyoshi, Mamoru; Nakamura, Yoriyuki

    2016-01-01

    Tea derived from the leaves and buds of Camellia sinensis (Theaceae) is consumed worldwide. Green tea contains various components with specific health-promoting effects, and is believed to exert protective effects against diseases including cancer, diabetes and hepatitis, as well as obesity. Of the various tea components, the polyphenol catechins have been the subject of extensive investigation and among the catechins, (-)-epigallocatechin gallate has the strongest bioactivity in most cases. Our research group has postulated that hepatocyte nuclear factor-4α, sterol regulatory element-binding proteins, and tumor necrosis factor-α are targets of green tea constituents including (-)-epigallocatechin gallate for their anti-diabetes, anti-obesity, and anti-hepatitis effects, respectively. Published papers were reviewed to determine whether the observed changes in these factors can be correlated with anti-cancer effects of green tea. Two major action mechanisms of (-)-epigallocatechin gallate have been proposed; one associated with its anti-oxidative properties and the other with its pro-oxidative activity. When reactive oxygen species are assumed to be involved, our findings that (-)-epigallocatechin gallate down- regulated hepatocyte nuclear factor-4α, sterol regulatory element-binding proteins, and tumor necrosis factor-α may explain the anti-cancer effect of green tea as well. However, further studies are required to elucidate which determinant directs (-)-epigallocatechin gallate action as an anti-oxidant or a pro-oxidant for favorable activity. PMID:27221834

  10. Liquid Chromatography - Triple Quadrupole Mass Spectrometry : The gold standard for quantitative bioanalysis of anti-cancer agents

    Vainchtein, L.D.

    2008-01-01

    To understand the pharmacologic mechanisms of action, efficacy and toxicity of any anti-cancer drug it is important to know how the compound is transformed in the body: either into active metabolites or inactive and toxic (degradation) products. This information may lead to the success or failure of a drug in arresting cancer cell growth, and facilitates the design of more effective drugs. To quantify the drug and to follow its absorption, distribution, metabolism, and elimination (ADME) in b...

  11. In Vivo Anti-Cancer Mechanism of Low-Molecular-Weight Fucosylated Chondroitin Sulfate (LFCS) from Sea Cucumber Cucumaria frondosa

    Xiaoxiao Liu; Yong Liu; Jiejie Hao; Xiaoliang Zhao; Yinzhi Lang; Fei Fan; Chao Cai; Guoyun Li; Lijuan Zhang; Guangli Yu

    2016-01-01

    The low-molecular-weight fucosylated chondroitin sulfate (LFCS) was prepared from native fucosylated chondroitin sulfate (FCS), which was extracted and isolated from sea cucumber Cucumaria frondosa, and the anti-cancer mechanism of LFCS on mouse Lewis lung carcinoma (LLC) was investigated. The results showed that LFCS remarkably inhibited LLC growth and metastasis in a dose-dependent manner. LFCS induced cell cycle arrest by increasing p53/p21 expression and apoptosis through activation of ca...

  12. Recent progress in allergen immunotherapy.

    Nouri-Aria, Kayhan T

    2008-03-01

    The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by peripheral T cells. Recent researches into the cellular and molecular basis of allergic reactions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to further improve the control of allergic responses in the future. Novel approaches to immunotherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both Th1 and Th2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory sequences derived from bacteria CpG or monophosphoryl lipid A that potentiate Th1 responses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the

  13. IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation.

    Koehl, Ulrike; Sörensen, Jan; Esser, Ruth; Zimmermann, Stefanie; Grüttner, Hans Peter; Tonn, Torsten; Seidl, Christian; Seifried, Erhard; Klingebiel, Thomas; Schwabe, Dirk

    2004-01-01

    Natural killer (NK) cells are thought to be of benefit in HLA-mismatched hematopoietic transplantation (H-SCT). Therefore, we developed a protocol for clinical-use expansion of highly enriched and IL-2-stimulated NK cells. Purification of unstimulated leukaphereses by a two-step T cell depletion with a final CD56 enrichment procedure leads to a mean purity of 95% CD56(+)CD3- NK cells with a four- to five-log depletion of T cells. So far, three pediatric patients with multiply relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were treated with repeated transfusions post-H-SCT. Directed killer immunoglobulin-like receptor (KIR) mismatches were demonstrated in all three cases. Although all patients showed blast persistence at the time of transplant, they reached complete remission and complete donor chimerism within 1 month post-H-SCT. NK cell therapy was tolerated well without graft-versus-host disease (GvHD) induction or other adverse events. The AML patient died of early relapse on day +80, while the ALL patients died of thrombotic-thrombocytopenic purpura and atypical viral pneumonia on days +45 and +152, respectively. This initial trial showed the feasibility of good manufacturing practice (GMP)-compliant NK cell isolation and expansion for clinical applications. We now launch a clinical phase I trial with activated NK cells post-H-SCT. PMID:15528141

  14. Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model.

    Mayzlish-Gati, Einav; Laufer, Dana; Grivas, Christopher F; Shaknof, Julia; Sananes, Amiram; Bier, Ariel; Ben-Harosh, Shani; Belausov, Eduard; Johnson, Michael D; Artuso, Emma; Levi, Oshrat; Genin, Ola; Prandi, Cristina; Khalaila, Isam; Pines, Mark; Yarden, Ronit I; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined. PMID:26192476

  15. Immunotherapy for bladder cancer

    Fuge O

    2015-05-01

    Full Text Available Oliver Fuge,1 Nikhil Vasdev,1 Paula Allchorne,2 James SA Green2 1Department of Urology, Lister Hospital, Stevenage, UK; 2Department of Urology, Bartshealth NHS Trust, Whipps Cross Rd, London, UK Abstract: It is nearly 40 years since Bacillus Calmette–Guérin (BCG was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest

  16. Triterpenoids of Marine Origin as Anti-Cancer Agents

    Yong-Xin Li

    2013-07-01

    Full Text Available Triterpenoids are the most abundant secondary metabolites present in marine organisms, such as marine sponges, sea cucumbers, marine algae and marine-derived fungi. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells, as well as anticancer efficacy in preclinical animal models. In this review efforts have been taken to review the structural features and the potential use of triterpenoids of marine origin to be used in the pharmaceutical industry as potential anti-cancer drug leads.

  17. Selective anti-cancer agents as anti-aging drugs

    Blagosklonny, Mikhail V.

    2013-01-01

    Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFκB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are inv...

  18. Adoptive immunotherapy of human pancreatic cancer with lymphokine-activated killer cells and interleukin-2 in a nude mouse model

    A pancreatic cancer cell line was grown in orthotopic and heterotopic positions in young Swiss/NIH nude mice, which were tested with adoptive immunotherapy. Mice were injected with 1 x 10(7) human cancer cells in the subcutaneous tissue and duodenal lobe of the pancreas. The mice were randomly divided into four groups: group IA (LAK + IL-2) (N = 25) received 2 X 10(7) human lymphokine-activated killer (LAK) cells from normal donors by tail vein injection followed by 10,000 units of human recombinant interleukin-2 (IL-2) given intraperitoneally every 12 hours for 28 days; group IB (IL-2) (N = 27) was given the same dose of IL-2 alone; group IC (RPMI-1640) (N = 18) received a placebo consisting of 1 ml of RPMI-1640 intraperitoneally every 12 hours; and group ID (LAK) (N = 14) received 2 X 10(7) LAK cells but no IL-2. Toxicity was significantly higher in group IB, with a mortality rate of 45.5% (10/22 animals) versus a 0% mortality (0/25) in group IA. None of the group IA or IB animals died of pancreatic cancer during the experiment. The animals that did not receive IL-2 died before 28 days in 14.2% of group IC and in 16.7% of group ID. The area under the growth curve of subcutaneous tumors during the course of treatment and the pancreatic tumor weight at the end of treatment were compared in each group. Subcutaneous tumors had a reduced rate of growth in group IA animals compared to all the other treatments. Pancreatic tumor growth was slowed in group IA. The animals treated with IL-2 alone (group IB) showed some slowing of tumor growth that was intermediate between group IA, group IC, and group ID. A similar experiment was done with irradiated (375 rad) mice. Nine nude mice with tumors were treated with LAK + IL-2 (group IIA), eight received IL-2 alone (group IIB), and seven received placebo (group IIC)

  19. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment. PMID:27059255

  20. Heat shock proteins and immunotherapy

    XinZHAO; XueMeiXU; GuoxingSONG

    2005-01-01

    Being one of the most abundant intracellular proteins,heat shock proteins(HSPs) have many housekeeping functions which are crucial for the survival of organisms.In addition,some HSPs are new immunoactive molecules which play important roles in both adaptive and innate immunity.They could activate CD8+ and CD4+ lymphocytes,induce innate immune response including natural killer(NK) cell activation and cytokine secretion,and induce maturation of dendritic cells(DCs).These characteristics have been used for immunotherapy of various types of cancers and infectious disenses.This review focuses on the main HSP families——HSP70 and 90 families.The mechanism of HSPs’ function in eliciting immune response are elucidated and various forms of HSPs used in immunotherapy are discussed in details.At the end of this review,authors summarize clinical trials related to HSPs and evaluate their clinical efficacy.

  1. Immunotherapy for bladder cancer.

    Fuge, Oliver; Vasdev, Nikhil; Allchorne, Paula; Green, James Sa

    2015-01-01

    It is nearly 40 years since Bacillus Calmette-Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear. PMID:26000263

  2. Activities of AREVA Med. Extraction and purification of the 212Pb isotope from Thorium for radio-immunotherapy

    After having recalled the definition of radio-immunotherapy (RIT) and the benefits of alpha RIT for the treatment of some cancers, this document explains the choice of the 212-Pb isotope instead of the 212-Bi isotope (the first one has a longer half-life than the second). The Pb isotope in fact progressively transforms itself into the Bi isotope. The production process is evoked with its important steps. A second part reports the first clinic tests performed in the Alabama Centre for the treatment of different cancer (breast, colon, ovarian, pancreas, stomach). Processes and doses are discussed

  3. Anti-ulcer, anti-protozoan and anti-cancer activities of irradiated κ-carrageenan: some biological effects of irradiated food grade-carrageenan on various gastrointestinal disorders

    κ carrageenan and its radiolytic products are both shown to strongly inhibit pepsin activity based on our in vitro peptic ulcer model. Generated Lineweaver-Burke (LB) plots resemble the trend for competitive inhibition except that the changes in the slopes are too large rendering Km to approach a negative value. Our observations corroborate with the published dual behavior of carrageenan in inhibiting peptic ulcers, that is, by exerting simultaneously both enzyme (E) competitive inhibition and substrate (S) occlusion. Irradiated-carrageenan does not display anti-protozoan activity against Tetrahymena and pathogenic Entamoeba histolytica, and anti-tumor potential based on Artemia salina (brine shrimp) nauplus tests and the MTT assay with human MCF7 breast carcinoma cell line. (Author)

  4. Structure Identification and Anti-Cancer Pharmacological Prediction of Triterpenes from Ganoderma lucidum.

    Shao, Yanyan; Qiao, Liansheng; Wu, Lingfang; Sun, Xuefei; Zhu, Dan; Yang, Guanghui; Zhang, Xiaoxue; Mao, Xin; Chen, Wenjing; Liang, Wenyi; Zhang, Yanling; Zhang, Lanzhen

    2016-01-01

    Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, which is a popularly used traditional Chinese medicine for complementary cancer therapy. In the present study, systematic isolation, and in silico pharmacological prediction are implemented to discover potential anti-cancer active GTs from G. lucidum. Nineteen GTs, three steroids, one cerebroside, and one thymidine were isolated from G. lucidum. Six GTs were first isolated from the fruiting bodies of G. lucidum, including 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester (1), 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (2), 3β,7β,15α,28-tetrahydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (3), ganotropic acid (4), 26-nor-11,23-dioxo-5α-lanost-8-en-3β,7β,15α,25-tetrol (5) and (3β,7α)-dihydroxy-lanosta-8,24-dien- 11-one (6). (4E,8E)-N-d-2'-hydroxypalmitoyl-l-O-β-d-glucopyranosyl-9-methyl-4,8-spingodienine (7), and stigmasta-7,22-dien-3β,5α,6α-triol (8) were first reported from the genus Ganodema. By using reverse pharmacophoric profiling of the six GTs, thirty potential anti-cancer therapeutic targets were identified and utilized to construct their ingredient-target interaction network. Then nineteen high frequency targets of GTs were selected from thirty potential targets to construct a protein interaction network (PIN). In order to cluster the pharmacological activity of GTs, twelve function modules were identified by molecular complex detection (MCODE) and gene ontology (GO) enrichment analysis. The results indicated that anti-cancer effect of GTs might be related to histone acetylation and interphase of mitotic cell cycle by regulating general control non-derepressible 5 (GCN5) and cyclin-dependent kinase-2 (CDK2), respectively. This research mode of extraction, isolation, pharmacological prediction, and PIN analysis might be beneficial to rapidly predict and discover pharmacological activities of novel compounds

  5. An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.

    Young-Ki Bae

    Full Text Available The epidermal growth factor receptor (EGFR is a well-established target for cancer treatment. EGFR tyrosine kinase (TK inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK, a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R], or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R] in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor and U0126 (a MEK inhibitor were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.

  6. Cancer immunotherapy in children

    More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient

  7. Immunotherapy for Cervical Cancer

    In an early phase NCI clinical trial, two patients with metastatic cervical cancer had a complete disappearance of their tumors after receiving treatment with a form of immunotherapy called adoptive cell transfer.

  8. Development of cancer immunotherapy

    To increase the curative rate of cancer patients, we developed ideal biological response modifier from medicinal plants: Ginsan, KC68IId-8, KC-8Ala, KG-30. Ginsan activated natural killer cell activity of spleen cells more than 5.4 times than lentinan, 1.4 times than picibanil. Radioprotective activity of Ginsan is stronger than WR2721, glucan, and selenium. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of A20 tumor cells was also augmented by transfection with B7.1 gene. The immunosuppression of gamma-irradiation was due to the reduction of Th1 sytokine gene expression through STAT pathway. These research will devote to develop new cancer immunotherapy and to reduce side effect of cancer radiotherapy and chemotherapy

  9. Development of cancer immunotherapy

    Yun, Yeon Sook; Chung, H. Y.; Yi, S. Y.; Kim, K. W.; Kim, B. K.; Chung, I. S.; Park, J. Y

    1999-04-01

    To increase the curative rate of cancer patients, we developed ideal biological response modifier from medicinal plants: Ginsan, KC68IId-8, KC-8Ala, KG-30. Ginsan activated natural killer cell activity of spleen cells more than 5.4 times than lentinan, 1.4 times than picibanil. Radioprotective activity of Ginsan is stronger than WR2721, glucan, and selenium. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of A20 tumor cells was also augmented by transfection with B7.1 gene. The immunosuppression of gamma-irradiation was due to the reduction of Th1 sytokine gene expression through STAT pathway. These research will devote to develop new cancer immunotherapy and to reduce side effect of cancer radiotherapy and chemotherapy.

  10. Cancer Immunotherapy: A Review

    Anna Meiliana

    2016-04-01

    Full Text Available BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy. CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. The use of antibodies to block pathways inhibiting the endogenous immune response to cancer, known as checkpoint blockade therapy, has stirred up a great deal of excitement among scientists, physicians, and patients alike. Clinical trials evaluating the safety and efficacy of antibodies that block the T cell inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 and programmed cell death 1 (PD-1 have reported success in treating subsets of patients. Adoptive cell transfer (ACT is a highly personalized cancer therapy that involve administration to the cancer-bearing host of immune cells with direct anticancer activity. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. SUMMARY: For cancer treatment, 2011 marked the beginning of a new era. The underlying basis of cancer immunotherapy is to activate a patient’s own T cells so that they can kill their tumors. Reports of amazing recoveries abound, where patients remain cancer-free many years after receiving the therapy. The idea of harnessing immune cells to fight cancer is

  11. Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2.

    Xu, Yi; Yang, Xiaoyu; Zhao, Pinjing; Yang, Zhongyu; Yan, Changhui; Guo, Bin; Qian, Steven Y

    2016-07-01

    Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived byproduct (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5-1.0μM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational

  12. 一种黄酮衍生物的合成及其体外抗癌活性%Synthesis of a flavone derivative and evaluation of its in vitro anti-cancer activity

    范攀越; 王江; 黄远; 张幸博

    2013-01-01

    以柚皮素为原料,通过对其结构进行修饰,合成了黄酮衍生物5-羟基-2-(4羟基苯基)-7-(2-吗啉基乙氧基)-4H-苯骈吡喃-4-酮;利用核磁共振、元素分析及质谱确认了产物的结构,利用MTT法测定了其对人肝癌细胞(HepG2)、7721以及QSG7701正常肝细胞株的抑制率.结果表明,同槲皮素相对照,合成的黄酮衍生物对肝癌细胞具有良好的抑制活性.%A flavone derivative, 5-hydroxyl-2-(4-hydroxyphenyl)-7-(2-morpholinoethoxy)-4H-chroxmen-4-one, was synthesized with naringenin as the raw material. The structure of as-synthesized product was characterized by nuclear magnetic resonance spectroscopy, elemental analysis and mass spectrometry. Moreover, the inhibition ratio of the synthesized product for human liver cells (HepG2) and SMMO7721 human hepatoma cell line as well as normal human fetal liver (QSG-7701) was tested with MTT method. Results show that as-synthesized compound has good inhibitory activity against the cells of liver canner.

  13. The future of sublingual immunotherapy.

    Marcucci, F; Duse, M; Frati, F; Incorvaia, C; Marseglia, G L; La Rosa, M

    2009-01-01

    Sublingual immunotherapy (SLIT) is currently the most prescribed form of allergen immunotherapy in many European countries. Its use has been accepted in the international consensus publications, and recently also the scepticism of USA scientists is attenuated. Still, this treatment may be improved, and the possible developments consist of modification of the materials, use of adjuvants and use of recombinant allergens. Moreover, new applications of SLIT, such as food allergy, seem promising. Concerning materials, the future form of SLIT is likely to be represented by tablets, which were already tested for efficacy and safety with grass pollen extracts, and are likely to increase the convenience for the patient by the use of no-updosing schedule. Adjuvants fitting with the characteristics of SLIT seem to be CpG oligodeoxynucleotides (CpG), able to interact with the Toll-like receptor 9 (TLR9) whose activation induces a Th1-like pattern of cytokine release, combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3-Dex), and Lactobacillus plantarum. The approach with recombinant allergens, named component-resolved diagnosis, offers the possibility to tailor immunotherapy, which was found to be effective in two randomized trials of subcutaneous SIT (16-17), while studies with SLIT are not yet available. Regarding food allergy, an important controlled study demonstrated that SLIT with hazelnut is able to increase patients tolerance over possible reactions from inadvertent assumption of the culprit food, and warrants for further trials with other foods. PMID:19944008

  14. Ginseng Extract Enhances Anti-cancer Effect of Cytarabine on Human Acute Leukemia Cells

    Yiju Hou

    2015-02-01

    Full Text Available Ginseng as a traditional medicine is well known to exhibit various pharmacological effects. Ginsenoside Rg3 is the active ingredient extracted from ginseng. The pharmacological modulatory effects of Rg3 on multidrug resistant cancer cells are reported in the present study. Cytarabine is a chemotherapeutic agent for the treatment of acute leukemia. However, this compound has serious side effects at high doses, for example hematopoiesis depression. In this study, using hl60 human leukemia cells, we investigated the possible synergistic anti-cancer effects between ginseng extract Rg3 and cytarabine on acute myeloid leukemia cells. Results of this study demonstrate that Rg3 can enhance the anti-proliferation effect of cytarabine on hl60 cells and may decrease the dosage of cytarabine needed for acute myeloid leukemia treatment.

  15. Potential of radioiodinated anti cancer compounds of natural origin for cancer therapy

    Plumbagin and Quercetin are naturally occurring compounds which exhibit anti-cancerous activity. To evaluate the effect of radioiodination on cytotoxicity, both Plumbagin and Quercetin were radioiodinated with 125I. 125I-Plumbagin and 125I-Quercetin could be prepared in moderate yields and good radiochemical purity and were characterized using reverse phase HPLC. In Swiss mice bearing fibrosarcoma, 125I-Plumbagin showed a tumor uptake of ∼2.5%ID/g at 3 h p.i. and ∼0.5%ID/g at 24 h p.i on i.v. injection. When injected intratumorally, greater tumor uptake and retention was observed (∼20%ID/g at 3 h p.i. and ∼14%ID/g at 24 h p.i. respectively). (author)

  16. Association Between hTERT rs2736100 Polymorphism and Sensitivity to Anti-cancer Agents

    Julie eKim

    2013-08-01

    Full Text Available Background: The rs2736100 single nucleotide polymorphism (SNP is located in the intron 2 of human telomerase reverse transcriptase (hTERT gene. Recent genome-wide association studies (GWAS have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel. Methods and Materials: The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length of each cell line was quantified using real-time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor and RHPS4/BRACO19 (G-quadruplex stabilizer as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested.Results: The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r=-0.35, p=0.009 but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p=0.003. The highest correlation was observed between the SNP and paclitaxel (r=-0.36, p=0.005. The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p=0.004.Conclusion: Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated

  17. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

    Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU. Our

  18. Pathological Mobilization and Activities of Dendritic Cells in Tumor-Bearing Hosts: Challenges and Opportunities for Immunotherapy of Cancer

    Tesone, Amelia J.; Svoronos, Nikolaos; Allegrezza, Michael J.; Conejo-Garcia, Jose R.

    2013-01-01

    A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor’s ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach. PMID:24339824

  19. Designing anti-cancer drugs and directing anti-cancer therapy

    Velasquez, Elinor; Soto-Andrade, Jorge; Bongalon, Ben

    2014-01-01

    A prototype for a web application was designed and implemented as a guide to be used by clinicians when designing the best drug therapy for a specific cancer patient, given biological data derived from the patients tumor tissue biopsy. A representation of the patients metabolic pathways is displayed as a graph in the application, with nodes as substrates and products and edges as enzymes. The top metabolically active sub- paths in the pathway, ranked using an algorithm based on both the patie...

  20. A microfluidic approach towards hybridoma generation for cancer immunotherapy.

    Lu, Yen-Ta; Pendharkar, Gaurav Prashant; Lu, Chung-Huan; Chang, Chia-Ming; Liu, Cheng-Hsien

    2015-11-17

    Dendritic cells/tumor fusions have shown to elicit anti-cancer immunity in different cancer types. However, the application of these vaccines for human cancer immunotherapy are limited by the instable quality and insufficient quanity of fusion cells. We present a cell electrofusion chip fabricated using soft lithography technique, which combines the rapid and precise cell pairing microstructures and the high yield electrofusion micro-electrodes to improve the cell fusion. The design uses hydrodynamic trapping in combination with positive dielectrophoretic force (pDEP) to achieve cell fusion. The chip consists of total 960 pairs of trapping channels, which are capable of pairing and fusing both homogeneous and heterogeneous types of cells. The fused cells can be easily taken out of the chip that makes this device a distinguishable from other designs. We observe pairing efficiency of 68% with fusion efficiency of 64%. PMID:26462149

  1. Strategic development on generic anti-cancer drugs Bevacizumab and Erlotinib Hydrochloride for Harbin Pharmaceutical Group

    Cheung Fat Ping

    2011-01-01

    @@ With improved economy, changing life styles, aging population and health care reform, China had a very potential anti-cancer drug market.The patents of popular anti-cancer drugs Avastin and Tarceva would expire in few years.Generic versions of Avastin and Tarceva were Bevacizumab and Erlotinib Hydrochloride respectively.Harbin Pharmaceutical Group was proposed to develop strategically both generic medicines to enter the high-end anti-cancer drug market for targeted cancer therapies.The vital to success of developing the generic drugs were discussed.

  2. Quinones derived from plant secondary metabolites as anti-cancer agents.

    Lu, Jin-Jian; Bao, Jiao-Lin; Wu, Guo-Sheng; Xu, Wen-Shan; Huang, Ming-Qing; Chen, Xiu-Ping; Wang, Yi-Tao

    2013-03-01

    Quinones are plant-derived secondary metabolites that present some anti-proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones. PMID:22931417

  3. Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

    Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

    2015-01-01

    The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID:26626257

  4. Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic.

    Breitbach, Caroline J; Parato, Kelley; Burke, James; Hwang, Tae-Ho; Bell, John C; Kirn, David H

    2015-08-01

    Oncolytic immunotherapies (OI) selectively infect, amplify within and destroy cancer cells, thereby representing a novel class of anti-cancer therapy. In addition to this primary mechanism-of-action (MOA), OI based on vaccinia have been shown to selectively target tumor-associated vasculature, triggering an acute reduction in tumor perfusion. This review focuses on a third complementary MOA for this product class: the induction of active immunotherapy. While the active immunotherapy approach has been validated by recent product approvals, the field is still faced with significant challenges. Tumors have evolved diverse mechanisms to hide from immune-mediated destruction. Here we hypothesize that oncolytic immunotherapy replication within tumors may tip the immune balance to allow for the effective induction and execution of adaptive anti-tumor immunity, resulting in long-term tumor control following OI clearance. This immune activation against the cancer can be augmented through OI 'arming' for the expression of immunostimulatory transgene products from the virus genome. With the first vaccinia OI (Pexa-Vec, thymidine kinase-inactivated vaccinia expressing Granulocyte-colony stimulating factor [GM-CSF]) now in advanced-stage clinical trials, it has become more important than ever to understand the complimentary MOA that contributes to tumor destruction and control in patients. PMID:25900822

  5. Anti-CD40-mediated cancer immunotherapy

    Hassan, Sufia Butt; Sørensen, Jesper Freddie; Olsen, Barbara Nicola;

    2014-01-01

    activation and thus enhancement of immune responses. Treatment with anti-CD40 monoclonal antibodies has been exploited in several cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use. Here, Dacetuzumab and Lucatumumab are in the most advanced stage...... with other cancer immunotherapies, in particular interleukin (IL)-2. An in-depth analysis of this immunotherapy is provided elsewhere. In the present review, we provide an update of the most recent clinical trials with anti-CD40 antibodies. We present and discuss recent and ongoing clinical trials...... in this field, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab....

  6. Immunotherapy of childhood Sarcomas

    Stephen S Roberts

    2015-08-01

    Full Text Available Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing’s family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and Liposomal-muramyl  tripeptide phosphatidyl-ethanolamine (L-MTP have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody based and cell based therapies into an overall treatment strategy of sarcoma will be discussed.

  7. Immunotherapy of Childhood Sarcomas.

    Roberts, Stephen S; Chou, Alexander J; Cheung, Nai-Kong V

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed. PMID:26301204

  8. 3-PHENYLQUINOLINYLCHALCONE DERIVATIVES: PHARMACOPHORE MODELLING, 3D-QSAR ANALYSIS AND DOCKING STUDIES AS ANTI-CANCER AGENTS

    Manoj Kumar Mahto

    2014-02-01

    Full Text Available Certain 3-Phenylquinolinylchalcone derivatives were evaluated for their anti-proliferative activities and found to exhibit anti-cancer and anti-inflammatory activities. 3D-QSAR and molecular docking approaches were performed on 3-Phenylquinolinylchalcone derivatives to understand their structural requisites and binding mode of the best fitted ligand for cancer inhibitory activity. Among them, (E-3-(3-(4-methoxyphenylquinolin-2-yl-1-phenylprop-2-en-1-one (6a was the most active compound against the growth of  H460, MCF-7, MDA-MB-231 and SKBR-3 cancer cell line respectively. Four featured hypothesis  AHRR.521 of  H460 was considered to be the best hypothesis which yielded a statistically significant 3D-QSAR model built with PLS values 3, Regression coefficient (R2 = 0.8986, Cross validation coefficient (Q2 = 0.9542, Root Mean Square Deviation (RMSD = 0.0067, Pearson-R = 1. Interestingly, the result of docking was found to correlate with the pharmacophore study where this compound was active against all six oncoproteins p53, Raf Kinase, Aurora-A-Kinase, CDK-2, Resveratrol and HSP90. The results provide detailed insights of 6a compound which can afford guidance for rational drug design of novel potent anti-cancer agents

  9. Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics

  10. Glycan changes: cancer metastasis and anti-cancer vaccines

    Min Li; Lujun Song; Xinyu Qin

    2010-12-01

    Complex carbohydrates, which are major components of the cell membrane, perform important functions in cell–cell and cell–extracellular matrix interactions, as well as in signal transduction. They comprise three kinds of biomolecules: glycoproteins, proteoglycans and glycosphingolipids. Recent studies have also shown that glycan changes in malignant cells take a variety of forms and mediate key pathophysiological events during the various stages of tumour progression. Glycosylation changes are universal hallmarks of malignant transformation and tumour progression in human cancer, which take place on the whole cells or some specific molecules. Accordingly, those changes make them prominent candidates for cancer biomarkers in the meantime. This review mainly focuses on the correlation between glycosylation and the metastasis potential of tumour cells from comprehensive aspects to further address the vital roles of glycans in oncogenesising. Moreover, utilizing these glycosylation changes to ward off tumour metastasis by means of anti-adhesion approach or devising anti-cancer vaccine is one of promising targets of future study.

  11. Human synthetic lethal inference as potential anti-cancer target gene detection

    Solé Ricard V; Munteanu Andreea; Conde-Pueyo Nuria; Rodríguez-Caso Carlos

    2009-01-01

    Abstract Background Two genes are called synthetic lethal (SL) if mutation of either alone is not lethal, but mutation of both leads to death or a significant decrease in organism's fitness. The detection of SL gene pairs constitutes a promising alternative for anti-cancer therapy. As cancer cells exhibit a large number of mutations, the identification of these mutated genes' SL partners may provide specific anti-cancer drug candidates, with minor perturbations to the healthy cells. Since exi...

  12. Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

    Thomas Hart; Shihab Dider; Weiwei Han; Hua Xu; Zhongming Zhao; Lei Xie

    2016-01-01

    Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification ...

  13. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti...

  14. Mechanisms of immunotherapy to aeroallergens.

    Shamji, M H; Durham, S R

    2011-09-01

    Allergen immunotherapy is allergen-specific, allergen dose- and time-dependent and is associated with long-term clinical and immunological tolerance that persists for years after discontinuation. Successful immunotherapy is accompanied by the suppression of numbers of T-helper 2 (Th2) effector cells, eosinophils, basophils, c-kit+mast cells and neutrophils infiltration in target organs, induction of IL-10 and/or TGF-β+Treg cells and increases in 'protective' non-inflammatory blocking antibodies, particularly IgG4 and IgA2 subclasses with inhibitory activity. These events are accompanied by a reduction and/or a redirection of underlying antigen-specific Th2-type T cell-driven hypersensitivity to the allergen(s) used for therapy. This suppression occurs within weeks or months as a consequence of the appearance of a population of regulatory T cells that exert their effects by mechanisms involving cell-cell contact, but also by the release of cytokines such as IL-10 (increases IgG4) and TGF-β (increases specific IgA). The more delayed-in-time appearance of antigen-specific T-helper 1 responses and alternative mechanisms such as Th2 cell anergy and/or apoptosis may also be involved. The mechanisms of sublingual immunotherapy are similar to those following a subcutaneous administration of allergen, whereas it is likely that additional events following antigen presentation in the sublingual mucosa and regional lymph nodes are involved. These insights have resulted in novel approaches and portend future biomarkers that may be surrogate or predictive of the clinical response to treatment. PMID:21762223

  15. Listeria monocytogenes as a vector for anti-cancer therapies.

    Tangney, Mark

    2012-01-31

    The intracellular pathogen Listeria monocytogenes represents a promising therapeutic vector for the delivery of DNA, RNA or protein to cancer cells or to prime immune responses against tumour-specific antigens. A number of biological properties make L. monocytogenes a promising platform for development as a vector for either gene therapy or as an anti-cancer vaccine vector. L. monocytogenes is particularly efficient in mediating internalization into host cells. Once inside cells, the bacterium produces specific virulence factors which lyse the vaculolar membrane and allow escape into the cytoplasm. Once in the cytosol, L. monocytogenes is capable of actin-based motility and cell-to-cell spread without an extracellular phase. The cytoplasmic location of L. monocytogenes is significant as this potentiates entry of antigens into the MHC Class I antigen processing pathway leading to priming of specific CD8(+) T cell responses. The cytoplasmic location is also beneficial for the delivery of DNA (bactofection) by L. monocytogenes whilst cell-to-cell spread may facilitate access of the vector to cells throughout the tumour. Several preclinical studies have demonstrated the ability of L. monocytogenes for intracellular gene or protein delivery in vitro and in vivo, and this vector has also displayed safety and efficacy in clinical trial. Here, we review the features of the L. monocytogenes host-pathogen interaction that make this bacterium such an attractive candidate with which to induce appropriate therapeutic responses. We focus primarily upon work that has led to attenuation of the pathogen, demonstrated DNA, RNA or protein delivery to tumour cells as well as research that shows the efficacy of L. monocytogenes as a vector for tumour-specific vaccine delivery.

  16. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    Obara, Akio; Fujita, Yoshihito; Abudukadier, Abulizi; Fukushima, Toru; Oguri, Yasuo; Ogura, Masahito; Harashima, Shin-ichi; Hosokawa, Masaya; Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp

    2015-05-15

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.

  17. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action

  18. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa

    Hammad Shafiq

    2015-12-01

    Full Text Available Nigella sativa is the miraculous plant having a lot of nutritional and medicinal benefits, and attracts large number of nutrition and pharmacological researchers. N. sativa seed composition shows that it is the blessing of nature and it contains and many bioactive compounds like thymoquinone, α-hederin, alkaloids, flavonoids, antioxidants, fatty acids many other compounds that have positive effects on curing of different diseases. Several medicinal properties of N. sativa like its anti-cancer, anti-inflammatory, anti-diabetic, antioxidant activities and many others are well acknowledged. However, this article focuses on activity of N. sativa against cardiovascular diseases and cancer. For gathering required data the authors went through vast number of articles using search engines like Science direct, ELSEVIER, Pub Med, Willey on Line Library and Google scholar and the findings were classified on the basis of relevance of the topic and were reviewed in the article. N. sativa is rich source of different biologically active compounds and is found effective in controlling number of cardiovascular diseases and various cancers both in vivo and in vitro studies.

  19. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  20. Cancer immunotherapy with surgery

    Orita,Kunzo

    1977-08-01

    Full Text Available With the recent advances in the immunological surveillance system, an understanding of the role of host immunity has become essential to the management of carcinogenesis, tumor proliferation, recurrence and metastasis. Although it is important to continue chemical and surgical treatment of cancer, support of the anti-tumor immune system of the host should also be considered. Long term remission has been reported in leukemia by treating with BCG after chemotherapy whereas surgical treatment is usually more effective in preventing cancer recurrence in digestive organ cancer. The first step is extirpating the tumor as thoroughly as possible and the second step is chemo-immunotherapy. Cancer immunity, however weak, constitutes the basis for other treatments in selectively attacking cancer cells remaining after surgery, chemotherapy or irradiation. Immunotherapy should thus not replace chemotherapy or radiotherapy, but these methods should be employed in combination to attain more favorable results.

  1. Sublingual allergen immunotherapy

    Calderón, M A; Simons, F E R; Malling, Hans-Jørgen;

    2012-01-01

    To cite this article: Calderón MA, Simons FER, Malling H-J, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302-311. ABSTRACT: Allergen immunotherapy reorients inappropriate immune responses in......-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast...... cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical...

  2. Immunotherapy of Melanoma.

    Snyder, Alexandra; Zamarin, Dmitriy; Wolchok, Jedd D

    2015-01-01

    The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma. PMID:26376963

  3. Bladder cancer immunotherapy.

    Lamm, D L; Thor, D E; Stogdill, V D; Radwin, H M

    1982-11-01

    A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional cell carcinoma of the bladder. In addition, 9 patients at high risk for tumor recurrence were treated with bacillus Calmette-Guerin produced a self-limited cystitis and 1 complication (hydronephrosis) of immunotherapy was observed. Of the 57 randomized patients 54 were followed for 3 to 30 months. Tumor recurrence was documented in 13 of 26 controls (50 per cent) and only 6 of 28 patients (21 per cent) treated with bacillus Calmette-Guerin (p equals 0.027, chi-square). The interval free of disease was prolonged significantly with bacillus Calmette-Guerin treatment (p equals 0.014, generalized Wilcoxon test). Importantly, a simple purified protein derivative skin test distinguished those patients who responded to bacillus Calmette-Guerin immunotherapy from those who did not. Only 1 of 17 treated patients (6 per cent) whose purified protein derivative test converted from negative to positive had tumor recurrence compared to 5 recurrences (38 per cent) among the 13 patients whose test remained negative or had been positive before treatment (p equals 0.022, chi-square). Bacillus Calmette-Guerin was given to 10 patients with stage B transitional cell carcinoma who were not candidates for cystectomy and 7 are free of disease. Of 5 patients with carcinoma in situ 3 remain free of tumor after bacillus Calmette-Guerin treatment and 5 of 6 who had multiple recurrences after intravesical chemotherapy responded favorably to bacillus Calmette-Guerin immunotherapy. PMID:6757467

  4. Change in peripheral blood lymphocyte count in dogs following adoptive immunotherapy using lymphokine-activated T killer cells combined with palliative tumor resection.

    Mie, Keiichiro; Shimada, Terumasa; Akiyoshi, Hideo; Hayashi, Akiyoshi; Ohashi, Fumihito

    2016-09-01

    We evaluated changes in peripheral blood lymphocyte (PBL) count in dogs following adoptive immunotherapy using lymphokine-activated T killer cells (T-LAK) in combination with surgery. Fifteen tumor-bearing dogs treated with T-LAK therapy combined with palliative resection of tumors were enrolled in the present study. T-LAK were generated from autologous peripheral blood mononuclear cells (PBMC) by culture with recombinant human interleukin -2 (rhIL-2) and solid phase anti-canine cluster of differentiation (CD)3 antibody. T-LAK were administrated intravenously at 2-4-week intervals. After the first administration of T-LAK, counts of PBL and T lymphocyte subsets (CD3(+), CD4(+) and CD8(+) cells) increased and the CD4/CD8 ratio decreased, with significant increases in CD8(+) cells (P<0.05). In 8 tumor-bearing dogs that were administered sequential T-LAK, available data on changes in PBL and T lymphocyte phenotypes until the fifth administration were also analyzed. In tumor-bearing dogs administered 5 rounds of T-LAK, CD8(+) cell counts were maintained high until the fifth administration of T-LAK. Moreover, the CD4/CD8 ratio remained low until the fifth administration of T-LAK. These results indicate that T-LAK therapy combined with surgery may increase peripheral blood T lymphocytes, particularly CD8(+) cells, in tumor-bearing dogs. PMID:27436446

  5. Mesua beccariana (Clusiaceae, A Source of Potential Anti-cancer Lead Compounds in Drug Discovery

    Soek Sin Teh

    2012-09-01

    Full Text Available An investigation on biologically active secondary metabolites from the stem bark of Mesua beccariana was carried out. A new cyclodione, mesuadione (1, along with several known constituents which are beccamarin (2, 2,5-dihydroxy-1,3,4-trimethoxy anthraquinone (3, 4-methoxy-1,3,5-trihydroxyanthraquinone (4, betulinic acid (5 and stigmasterol (6 were obtained from this ongoing research. Structures of these compounds were elucidated by extensive spectroscopic methods, including 1D and 2D-NMR, GC-MS, IR and UV techniques. Preliminary tests of the in vitro cytotoxic activities of all the isolated metabolites against a panel of human cancer cell lines Raji (lymphoma, SNU-1 (gastric carcinoma, K562 (erythroleukemia cells, LS-174T (colorectal adenocarcinoma, HeLa (cervical cells, SK-MEL-28 (malignant melanoma cells, NCI-H23 (lung adenocarcinoma, IMR-32 (neuroblastoma and Hep-G2 (hepatocellular liver carcinoma were carried out using an MTT assay. Mesuadione (1, beccamarin (2, betulinic acid (5 and stigmasterol (6 displayed strong inhibition of Raji cell proliferation, while the proliferation rate of SK-MEL-28 and HeLa were strongly inhibited by stigmasterol (6 and beccamarin (2, indicating these secondary metabolites could be anti-cancer lead compounds in drug discovery.

  6. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation.

    Zhong, Bo; Cai, Xiaohan; Chennamaneni, Snigdha; Yi, Xin; Liu, Lili; Pink, John J; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

    2012-01-01

    Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC(50)s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC(50)s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5  mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

  7. Allergen-specific immunotherapy

    Moote William

    2011-11-01

    Full Text Available Abstract Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries the risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergy. Furthermore, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and the administration, safety and efficacy of allergen-specific immunotherapy.

  8. Anti-cancer effect of rubropunctatin against human gastric carcinoma cells BGC-823.

    Zheng, Yunquan; Xin, Yanwen; Shi, Xianai; Guo, Yanghao

    2010-11-01

    The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR) and its cytotoxic activities against human gastric adenocarcinoma BGC-823 cells were studied both in vitro and in vivo. Rubropunctatin inhibited the proliferation of BGC-823 cells with an inhibitory concentration (IC₅₀) of 12.57 μM, while it exhibited no significant toxicity to normal gastric epithelial cell GES-1 at the same concentration. Treatment of BGC-823 cells with rubropunctatin resulted in a dose- and time-dependent apoptosis, as validated by the increase in the percentage of cells in sub-G1 phase and phosphotidylserine externalization. The in vivo experimental data demonstrated that rubropunctatin could offer similar therapeutic benefits in comparison with the same dose of taxol. After five times of intravenous injection, tumor weight in BGC-823-bearing nude mice reduced 23.5% at the dose of 8 mg/kg and 37.7% at the dose of 32 mg/kg, respectively. The expressions of 30 genes related to induction of apoptosis were found up-regulated significantly. The two most expressed genes were tumor necrosis factor (TNF) and DNA-damage inducible transcript 3. TNF was considered as a major mediator of apoptosis induced by rubropunctatin. This is the first report describing the anti-proliferative effect of rubropunctatin and its apoptosis mechanism on BGC-823 cells. Rubropunctatin has potential to be developed as a new natural anti-cancer agent. PMID:20730532

  9. Fucoxanthin: A Marine Carotenoid Exerting Anti-Cancer Effects by Affecting Multiple Mechanisms

    Sangeetha Ravi Kumar

    2013-12-01

    Full Text Available Fucoxanthin is a marine carotenoid exhibiting several health benefits. The anti-cancer effect of fucoxanthin and its deacetylated metabolite, fucoxanthinol, is well documented. In view of its potent anti-carcinogenic activity, the need to understand the underlying mechanisms has gained prominence. Towards achieving this goal, several researchers have carried out studies in various cell lines and in vivo and have deciphered that fucoxanthin exerts its anti-proliferative and cancer preventing influence via different molecules and pathways including the Bcl-2 proteins, MAPK, NFκB, Caspases, GADD45, and several other molecules that are involved in either cell cycle arrest, apoptosis, or metastasis. Thus, in addition to decreasing the frequency of occurrence and growth of tumours, fucoxanthin has a cytotoxic effect on cancer cells. Some studies show that this effect is selective, i.e., fucoxanthin has the capability to target cancer cells only, leaving normal physiological cells unaffected/less affected. Hence, fucoxanthin and its metabolites show great promise as chemotherapeutic agents in cancer.

  10. Photochemical properties of a new kind of anti-cancer drug: N-glycoside compound

    ZHAO Ping; WANG Mei; ZHANG ShuPing; SHAO SiChang; SUN XiaoYu; YAO SiDe; WANG ShiLong

    2008-01-01

    Due to the nontoxicity and efficient anti-cancer activity, more and more attention has been paid to N-glycoside compounds. Laser photolysis of N-(α-D-glucopyranoside) salicyloyl hydrazine (NGSH) has been performed for the first time. The research results show that NGSH has high photosensitivity and is vulnerable to be photo-ionized via a monophotonic process with a quantum yield of 0.02, generating NGSH+ and hydrated electrons. Under the aerobic condition of cells, the hydrated electrons are very easy to combine with oxygen to generate 1O2 and O2-, both of which are powerful oxidants that can kill the cancer cells. In addition, NGSH+ can be changed into neutral radicals by deprotonation with a pKa value of 4.02 and its decay constant was determined to be 2.55×109dm3·mol-1·s-1. NGSH also can be oxidized by SO4- with a rate constant of 1.76×109 dm3·mol-1·s-1, which further confirms the results of photoionization. All of these results suggest that this new N-glycoside compound might be useful for cancer treatment.

  11. Pectenotoxin-2 from Marine Sponges: A Potential Anti-Cancer Agent—A Review

    Wun-Jae Kim

    2011-11-01

    Full Text Available Pectenotoxin-2 (PTX-2, which was first identified as a cytotoxic entity in marine sponges, has been reported to display significant cytotoxicity to human cancer cells where it inhibits mitotic separation and cytokinesis through the depolymerization of actin filaments. In the late stage of endoreduplication, the effects of PTX-2 on different cancer cells involves: (i down-regulation of anti-apoptotic Bcl-2 members and IAP family proteins; (ii up-regulation of pro-apoptotic Bax protein and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL-receptor 1/receptor 2 (DR4/DR5; and (iii mitochondrial dysfunction. In addition, PTX-2 induces apoptotic effects through suppression of the nuclear factor κB (NF-κB signaling pathway in several cancer cells. Analysis of cell cycle regulatory proteins showed that PTX-2 increases phosphorylation of Cdc25c and decreases protein levels of Cdc2 and cyclin B1. Cyclin-dependent kinase (Cdk inhibitor p21 and Cdk2, which are associated with the induction of endoreduplication, were upregulated. Furthermore, it was found that PTX-2 suppressed telomerase activity through the transcriptional and post-translational suppression of hTERT. The purpose of this review was to provide an update regarding the anti-cancer mechanism of PTX-2, with a special focus on its effects on different cellular signaling cascades.

  12. Photochemical properties of a new kind of anti-cancer drug: N-glycoside compound

    2008-01-01

    Due to the nontoxicity and efficient anti-cancer activity, more and more attention has been paid to N-glycoside compounds. Laser photolysis of N-(α-D-glucopyranoside) salicyloyl hydrazine (NGSH) has been performed for the first time. The research results show that NGSH has high photosensitivity and is vulnerable to be photo-ionized via a monophotonic process with a quantum yield of 0.02, generating NGSH+· and hydrated electrons. Under the aerobic condition of cells, the hydrated electrons are very easy to combine with oxygen to generate 1O2 and O2-, both of which are powerful oxidants that can kill the cancer cells. In addition, NGSH+· can be changed into neutral radicals by deprotonation with a pKa value of 4.02 and its decay constant was determined to be 2.55×109dm3·mol-1·s-1. NGSH also can be oxidized by SO4-. with a rate constant of 1.76×109 dm3·mol-1.s-1, which further confirms the results of photoionization. All of these results suggest that this new N-glycoside compound might be useful for cancer treatment.

  13. The Study on Acute and Subacute Toxicity and Sarcoma-180 Anti-cancer Effects of Vermilionum

    Ki-Rok Kwon

    2003-12-01

    Full Text Available Background & Methods : In order to measure the acute and subacute toxicity of Vermilionum and it's anti-cancer effects, Sarcoma-180 abdominal cancer cells were injected intravenously. The following results were obtained after measuring the survival rate, toxicity of the NK cells, and IL-2 productivity. Results : 1. It was impossible to measure LD50 value in the acute toxicity test and no toxic effects were witnessed in the clinical observation. 2. No significant differences were shown in the weight changes between the experiment groups and the control group in the acute toxicity test. 3. No peculiar toxic effects were shown in the subacute toxicity test and the weight changes were insignificant between the experiment groups and the control group. 4. In measuring the survival rate after inducing abdominal cancer by Sarcoma-180, the experiment groups showed increased of 9,52% compared to the control group. 5. In measuring the activity of NK cells, no significant changes were shown between the experiment groups and the control group. 6. In measuring the productivity of IL-2, significant reduction was shown in the experiment groups compared to the normal group, but no significance was witnessed compared to the control group.

  14. The anti-cancer property of proteins extracted from Gynura procumbens (Lour. Merr.

    Chaw-Sen Hew

    Full Text Available Gynura procumbens (Lour. Merr. belongs to the Asteraceae Family. The plant is a well-known traditional herb in South East Asia and it is widely used to treat inflammation, kidney discomfort, high cholesterol level, diabetic, cancer and high blood pressure. Our earlier study showed the presence of valuable plant defense proteins, such as peroxidase, thaumatin-like proteins and miraculin in the leaf of G. procumbens. However, the effects of these defense proteins on cancers have never been determined previously. In the present study, we investigated the bioactivity of gel filtration fractionated proteins of G. procumbens leaf extract. The active protein fraction, SN-F11/12, was found to inhibit the growth of a breast cancer cell line, MDA-MB-231, at an EC50 value of 3.8 µg/mL. The mRNA expressions of proliferation markers, Ki67 and PCNA, were reduced significantly in the MDA-MB-23 cells treated with SN-F11/12. The expression of invasion marker, CCL2, was also found reduced in the treated MDA-MB-231 cells. All these findings highlight the anti-cancer property of SN-F11/12, therefore, the proteins in this fraction can be a potential chemotherapeutic agent for breast cancer treatment.

  15. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition.

    Wilson, Catherine; Nicholes, Katrina; Bustos, Daisy; Lin, Eva; Song, Qinghua; Stephan, Jean-Philippe; Kirkpatrick, Donald S; Settleman, Jeff

    2014-09-15

    Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, "EGFR-addicted" cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT. PMID:25193862

  16. Cancer immunotherapy: the beginning of the end of cancer?

    Farkona, Sofia; Diamandis, Eleftherios P.; Blasutig, Ivan M

    2016-01-01

    These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent succe...

  17. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  18. Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

    Nishino, Mizuki, E-mail: Mizuki_Nishino@DFCI.HARVARD.EDU [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Tirumani, Sree H.; Ramaiya, Nikhil H. [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Hodi, F. Stephen [Department of Medical Oncology and Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women' s Hospital, 450 Brookline Ave., Boston, MA 02215 (United States)

    2015-07-15

    Highlights: • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers. • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events. • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists. - Abstract: The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions.

  19. Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

    Highlights: • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers. • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events. • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists. - Abstract: The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions

  20. Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer.

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Juergens, Heribert; Varnholt, Lena; Hansmeier, Anna; Bollard, Catherine M; Moosmann, Andreas; Bisping, Guido; Rossig, Claudia

    2009-04-01

    The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, gammadelta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human gammadelta T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gammadelta T cells (Vgamma2+Vdelta2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gammadelta T cells pulsed with human leukocyte antigen-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen Bam H1 Z fragment leftward open reading frame or the tumor-associated latent EBV antigen latent membrane protein 2a (LMP2a) with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3CD8 cytolytic effector memory T cells. Furthermore, gammadelta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced gammadelta T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gammadelta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gammadelta T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease. PMID:19242369

  1. Activated human γδ T cells as stimulators of specific CD8+ T cell responses to subdominant Epstein Barr virus (EBV) epitopes: Potential for immunotherapy of cancer

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Juergens, Heribert; Varnholt, Lena; Hansmeier, Anna; Bollard, Catherine M.; Moosmann, Andreas; Bisping, Guido; Rossig, Claudia

    2011-01-01

    The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, γδ T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human γδ T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated γδ T cells pulsed with HLA-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen BZLF-1 or the tumor-associated latent EBV antigen LMP2a with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3+CD8+ cytolytic effector memory T cells. Furthermore, γδ T-APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced γδ T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous γδ T cells to induce LMP2a-specific autologous CTLs was confirmed in two patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human γδ T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease. PMID:19242369

  2. An Approach to Breast Cancer Immunotherapy: The Apoptotic Activity of Recombinant Anti-Interleukin-6 Monoclonal Antibodies in Intact Tumour Microenvironment of Breast Carcinoma.

    Abou-Shousha, S; Moaaz, M; Sheta, M; Motawea, M A

    2016-06-01

    Current work is one of our comprehensive preclinical studies, a new approach to breast cancer (BC) immunotherapy through induction of tumour cell apoptosis. Tumour growth is not just a result of uncontrolled cell proliferation but also of reduced apoptosis. High levels of interleukin-6 (IL-6) are associated with metastatic BC and correlated with poor survival as it promotes growth of tumour-initiating cells during early tumorigenesis protecting these cells from apoptosis. Therefore, this study aims at investigating the potential of anti-IL-6 monoclonal antibodies to suppress IL-6 proliferative/anti-apoptotic activities in intact tumour microenvironment of BC. Fresh sterile tumour and normal breast tissue specimens were taken from 50 female Egyptian patients with BC undergoing radical mastectomy. A unique tissue culture system designed to provide cells of each intact tumour/normal tissue sample with its proper microenvironment either supplemented or not with anti-IL-6 monoclonal antibodies. To evaluate the apoptotic activity of anti-IL-6 as a novel candidate for BC treatment strategy, we compared its effects with those obtained using tumour necrosis-related apoptosis-inducing ligand TRAIL as an established apoptotic agent. Our results revealed that levels of either anti-IL-6- or TRAIL-induced apoptosis in the tumour or normal tissue cultures were significantly higher than those in their corresponding untreated ones (P Recombinant anti-IL-6 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti-apoptotic potential of anti-IL-6 is highly hopeful in IL-6- abundant BC tumour microenvironment. PMID:26971879

  3. RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.

    Xiaohua Song

    Full Text Available Ingenol-3-angelate (I3A is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCδ. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

  4. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF1

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

    2008-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of pu...

  5. Immunotherapy in Melanoma, Gastrointestinal (GI, and Pulmonary Malignancies

    Alexander B. Dillon

    2015-03-01

    Full Text Available Oncologic immunotherapy involves stimulating the immune system to more effectively identify and eradicate tumor cells that have successfully adapted to survive the body's natural immune defenses. Immunotherapy has shown great promise thus far by prolonging the lives of patients with a variety of malignancies, and has added a crucial new set of tools to the oncologists' armamentarium. The aim of this paper is to provide an overview of immunotherapy treatment options that are currently available and under active research for melanoma, gastrointestinal (esophageal, gastric, pancreatic, and colorectal, and pulmonary malignancies. Potential biomarkers that may predict favorable responses to immunotherapies are discussed where applicable, as are future avenues of research in this rapidly evolving field.

  6. [Immunotherapy for Alzheimer's disease].

    Falkentoft, Alexander Christian; Hasselbalch, Steen Gregers

    2016-01-18

    Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. PMID:26815584

  7. CCL21 Cancer Immunotherapy

    Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer

  8. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF1

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

    2008-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years. PMID:18633461

  9. Regulatory activity of azabisphosphonate-capped dendrimers on human CD4+ T cell proliferation enhances ex-vivo expansion of NK cells from PBMCs for immunotherapy

    Caminade Anne-Marie

    2009-09-01

    specificity of the interaction of dendrimers with CD4+ T cell, we hypothesize that regulatory activity may signal through a specific receptor that remains to be indentified. Therefore phosphonate-capped dendrimers constitute not only tools for the ex-vivo expansion of NK cells in immunotherapy of cancers but their mode of action could also lead to further medical applications where T cell activation and proliferation need to be dampened.

  10. Phytochemical, Antioxidant and Anti-Cancer Properties of Euphorbia tirucalli Methanolic and Aqueous Extracts.

    Munro, Benjamin; Vuong, Quan V; Chalmers, Anita C; Goldsmith, Chloe D; Bowyer, Michael C; Scarlett, Christopher J

    2015-01-01

    Euphorbia tirucalli is a succulent shrub or small tree that is native to the African continent, however, it is widely cultivated across the globe due to its use in traditional medicines to treat ailments, ranging from scorpion stings to HIV. Recent studies have identified compounds present in the latex of the plant, including a range of bi- and triterpenoids that exhibit bioactivity, including anticancer activity. This study aimed to optimize water extraction conditions for high-yield total phenolic content recovery, to prepare methanol and aqueous extracts from the aerial sections of the plant, and to test the phytochemical, antioxidant, and anti-cancer properties of these extracts. Water extraction of total phenolic compounds (TPC) was optimized across a range of parameters including temperature, extraction time, and plant mass-to-solvent ratio. The water extract of the E. tirucalli powder was found to contain TPC of 34.01 mg GAE (gallic acid equivalents)/g, which was approximately half that of the methanol extract (77.33 mg GAE/g). The results of antioxidant assays showed a uniform trend, with the methanol extract's antioxidant reducing activity exceeding that of water extracts, typically by a factor of 2:1. Regression analysis of the antioxidant assays showed the strongest correlation between extract TPC and antioxidant activity for the ABTS (2,2-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) and DPPH (2,2-diphenyl-1-picrylhydrazyl) methods. The methanol extract also showed greater growth inhibition capacity towards the MiaPaCa-2 pancreatic cancer cell line. These data suggest that further investigations are required to confirm the source of activity within the E. tirucalli leaf and stems for potential use in the nutraceutical and pharmaceutical industries. PMID:26783950

  11. Phytochemical, Antioxidant and Anti-Cancer Properties of Euphorbia tirucalli Methanolic and Aqueous Extracts

    Benjamin Munro

    2015-10-01

    Full Text Available Euphorbia tirucalli is a succulent shrub or small tree that is native to the African continent, however, it is widely cultivated across the globe due to its use in traditional medicines to treat ailments, ranging from scorpion stings to HIV. Recent studies have identified compounds present in the latex of the plant, including a range of bi- and triterpenoids that exhibit bioactivity, including anticancer activity. This study aimed to optimize water extraction conditions for high-yield total phenolic content recovery, to prepare methanol and aqueous extracts from the aerial sections of the plant, and to test the phytochemical, antioxidant, and anti-cancer properties of these extracts. Water extraction of total phenolic compounds (TPC was optimized across a range of parameters including temperature, extraction time, and plant mass-to-solvent ratio. The water extract of the E. tirucalli powder was found to contain TPC of 34.01 mg GAE (gallic acid equivalents/g, which was approximately half that of the methanol extract (77.33 mg GAE/g. The results of antioxidant assays showed a uniform trend, with the methanol extract’s antioxidant reducing activity exceeding that of water extracts, typically by a factor of 2:1. Regression analysis of the antioxidant assays showed the strongest correlation between extract TPC and antioxidant activity for the ABTS (2,2-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid and DPPH (2,2-diphenyl-1-picrylhydrazyl methods. The methanol extract also showed greater growth inhibition capacity towards the MiaPaCa-2 pancreatic cancer cell line. These data suggest that further investigations are required to confirm the source of activity within the E. tirucalli leaf and stems for potential use in the nutraceutical and pharmaceutical industries.

  12. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).

    Yamamoto, Nobuto; Ushijima, Naofumi; Koga, Yoshihiko

    2009-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years. PMID:19031451

  13. Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.

    Yamamoto, Nobuto; Suyama, Hirofumi; Nakazato, Hiroaki; Yamamoto, Nobuyuki; Koga, Yoshihiko

    2008-07-01

    Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients. PMID:18058096

  14. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF).

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki; Ushijima, Naofumi

    2008-01-15

    Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Patient serum Nagalase activity is proportional to tumor burden. The deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation and immunosuppression. Stepwise incubation of purified Gc protein with immobilized beta-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages treated in vitro with GcMAF (100 pg/ml) are highly tumoricidal to mammary adenocarcinomas. Efficacy of GcMAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of GcMAF (100 ng). As GcMAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase. Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of GcMAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of GcMAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years. PMID:17935130

  15. [Aβ immunotherapy for Alzheimer's disease].

    Sakai, Kenji; Yamada, Masahito

    2013-04-01

    Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, Aβ likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis). According to this hypothesis, Aβ immunization therapies are created to eliminate Aβ from the brain, and to prevent the neurons from damage by these pathogenic proteins. There are two methods for Aβ immunotherapies: active and passive immunization. Previous studies have shown Aβ removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. On the contrary, side effects emerged, such as meningoencephalitis, vasogenic edema, which are currently called amyloid related imaging abnormalities (ARIA)-E and microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, Aβ was removed from the brain parenchyma and phosphorylated-tau was reduced in the neuronal processes. Moreover, deterioration of the cerebral amyloid angiopathy (CAA) and an increase of microhemorrhages and microinfarcts were described. Aβ is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could stem from severe CAA due to dysfunction of the drainage pathway after immunotherapy. Aβ immunization has a potential of cure for AD patients, although the above-described problems must be overcome before applying this therapy in clinical treatment. PMID:23568994

  16. Immunotherapy for B-Cell Lymphoma: Current Status and Prospective Advances

    Hollander, Nurit

    2012-01-01

    Therapy for non-Hodgkin’s lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of r...

  17. Immunotherapy of Cryptococcus infections.

    Antachopoulos, C; Walsh, T J

    2012-02-01

    Despite appropriate antifungal treatment, the management of cryptococcal disease remains challenging, especially in immunocompromised patients, such as human immunodeficiency virus-infected individuals and solid organ transplant recipients. During the past two decades, our knowledge of host immune responses against Cryptococcus spp. has been greatly advanced, and the role of immunomodulation in augmenting the response to infection has been investigated. In particular, the role of 'protective' Th1 (tumour necrosis factor-α, interferon (IFN)-γ, interleukin (IL)-12, and IL-18) and Th17 (IL-23 and IL-17) and 'non-protective' Th2 (IL-4, IL-10, and IL-13) cytokines has been extensively studied in vitro and in animal models of cryptococcal infection. Immunomodulation with monoclonal antibodies against the capsular polysaccharide glucuronoxylomannan, glucosylceramides, melanin and β-glucan and, lately, with radioimmunotherapy has also yielded promising results in animal models. As a balance between sufficiently protective Th1 responses and excessive inflammation is important for optimal outcome, the effect of immunotherapy may range from beneficial to deleterious, depending on factors related to the host, the infecting organism, and the immunomodulatory regimen. Clinical evidence supporting immunomodulation in patients with cryptococcal infection remains too limited to allow firm recommendations. Limited human data suggest a role for IFN-γ. Identification of surrogate markers characterizing patients' immunological status could possibly suggest candidate patients for immunotherapy and the type of immunomodulation to be administered. PMID:22264261

  18. Adherence to Sublingual Immunotherapy.

    Incorvaia, Cristoforo; Mauro, Marina; Leo, Gualtiero; Ridolo, Erminia

    2016-02-01

    Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. PMID:26758865

  19. 在线固相萃取-高效液相色谱系统在高抗癌活性化合物TEB-415药代动力学中的应用%Application of On-line SPE-HPLC System in Pharmacokinetic Study of Highly Active Anti-Cancer Compound TEB-415

    王曼; 温亚彬; 刘康宁; 司戈; 刘磊; 尹正; 卢亚欣

    2014-01-01

    应用在线固相萃取( SPE)-高效液相色谱( HPLC)方法研究TEB-415在小鼠体内的药代动力学。通过在线SPE-HPLC方法结合Ultimate3000系统测定TEB-415血药浓度,使用 Venusil MP C18分析柱(150 mm ×4.6 mm,5μm),乙腈-5mmol/L磷酸盐缓冲液(pH 3.5)为流动相,流速1.0 mL/min,等度洗脱; Capcell MF Ph-1为在线SPE柱(10 mm×4 mm,5μm),水为淋洗液,洗脱剂为水-乙腈,检测波长262 nm。采用WinNonlin5.2软件计算药代动力学参数。血浆中 TEB-415测定的线性范围为100~20000μg/L,定量限( S/N≥10)为20.0μg/L,提取回收率为90.5%~94.6%,日内与日间精密度RSD均小于3.5%,短期稳定性、冻融稳定性及长期稳定性准确度为91.49%~101.96%。 TEB-415口服给药后,在小鼠体内平均达峰时间tmax为5.29 h,平均药峰浓度Cmax为3403μg/L, TEB-415的0~t时间段药时曲线下面积AUC值为AUC0-t=24600μg/L·h,平均半衰期t1/2=3.84 h,体内平均滞留时间MRT =6.56 h,呈现吸收速度适中、吸收程度较高、体内消除速度适中的药代动力学特点。%An on-line solid phase extraction-high performance liquid chromatography ( SPE-HPLC ) system was applied in the plasma pharmacokinetic study of highly active anti-cancer compound tyrosine kinase inhibitors (TEB-415) in mouse. The on-line SPE-HPLC method associated with Ultimate3000 system which was applied to the determination of the blood drug level of TEB-415 in mouse plasma. C18 column ( Venusil MP, 150 mm × 4. 6 mm, 5μm) was used as analytical column and the mobile phase consisted of acetonitrile-5 mmol/L monopotassium phosphate buffer ( pH 3 . 5 ) at a flow rate of 1 . 0 mL/min was used as the isocratic elution. An MF Ph-1 column (10 mm×4 mm, 5 μm) was used as on-line SPE column, and water and water-acetonitrile were used as the washing solvent and elution solvent respectively. The detection wavelength was set at 262 nm. The pharmacokinetic parameters were calculated by WinNonlin 5. 2 software

  20. Inmunoterapia local Local immunotherapy

    E. Lasa

    2003-01-01

    Full Text Available La inmunoterapia específica, junto con la evitación del alergeno y el tratamiento sintomático, forma parte del tratamiento de la patología alérgica. La modalidad más antigua, más conocida y mejor estudiada es la inmunoterapia subcutánea (ITSC, cuya eficacia tanto a corto como a largo plazo, ha sido ampliamente demostrada en numerosos estudios. Sin embargo, a pesar de haberse demostrado segura, no está exenta de efectos adversos y precisa ser administrada bajo supervisión de personal médico. Esto ha animado a buscar nuevas vías de administración de eficacia similar, con un buen perfil de seguridad, y de buena cumplimentación por parte del paciente. De las distintas alternativas estudiadas la más relevante es la inmunoterapia sublingual (ITSL. En ésta, se administra el antígeno en forma de gotas debajo de la lengua. Existen diferentes pautas de administración en función del alergeno implicado. La dosis óptima de tratamiento está aún sin determinar, hallándose en este momento en un rango amplio de dosis respecto a la inmunoterapia subcutánea. Su mecanismo de acción es poco conocido aunque en diversos estudios se han observado cambios inmunológicos. La ITSL ha mostrado un buen perfil de seguridad con escasos efectos secundarios, habitualmente de carácter local. Asimismo se han realizado distintos ensayos clínicos en los que se ha demostrado su eficacia en el tratamiento de la alergia respiratoria tanto en niños como en adultos. Por ello, aunque aún existen datos sin resolver respecto a esta vía de administración de inmunoterapia, ha sido propuesta por la OMS como una alternativa válida a la ITSC.Specific immunotherapy, together with avoidance of the allergen and symptomatic treatment, forms part of the treatment of allergic pathology. The oldest, best known and most studied form is subcutaneous immunotherapy (SCIT, whose efficacy, both in the short and the long term, has been widely demonstrated in numerous studies

  1. Active immunotherapy of allergic asthma with a recombinant human interleukin-5 protein as vaccine in a murine model

    TAN Guang-hong; WANG Cai-chun; HUANG Feng-ying; WANG Hua; HUANG Yong-hao; LIN Ying-ying

    2007-01-01

    Background Eosinophils are highly related to allergic asthma inflammation. Interleukin (IL)-5 is the major chemokine of eosinophils, inhibition of the activity of IL-5 thus seems to be a potential approach to asthma therapy. The current study was performed to determine whether a recombinant human IL-5 protein as a xenogeneic vaccine has the capability of inducing anti-asthma activities.Methods Recombinant human IL-5 was used as a protein vaccine. Mouse asthma model was established to observe the anti-asthma activities. Lung histology was observed; eosinophils in blood and bronchoalveolar lavage were stained and counted. Airway hyperresponsiveness was determined by whole body plethysmograph. Antibody characters and cytokines were detected with enzyme linked immunosorbent assay (ELISA) and Western blot assay.Results Vaccination with recombinant human IL-5 protein as vaccine significantly reduced airway inflammation and airway hyperresponsiveness, and shifted the cytokine production from Th2 (IL-4) to Th1 (INF-γ) in mice allergic-asthma model. Immunization with recombinant human IL-5 protein vaccine bypassed the immunological tolerance and induced production of polyclonal antibodies that were cross-reactive with murine IL-5.Conclusions Active immunization with xenogeneic homologous IL-5 may be a possible therapeutic approach to the treatment of asthma and potentially of other eosinophilic disorders.

  2. Modified immunotherapy for alopecia areata.

    Yoshimasu, Takashi; Furukawa, Fukumi

    2016-07-01

    Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA. PMID:26932732

  3. Double layered hydroxides as potential anti-cancer drug delivery agents.

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  4. Liposomal delivery systems for anti-cancer analogues of vitamin E

    Koudelka, S.; Knotigova, P.T.; Masek, J.; Prochazka, L.; Lukac, R.; Miller, A.D.; Neužil, Jiří; Turanek, J.

    2015-01-01

    Roč. 207, Jun 10 (2015), s. 59-69. ISSN 0168-3659 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Alpha-tocopheryl succinate * Analogues of vitamin E * Anti-cancer drugs Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.705, year: 2014

  5. Homing of radiolabelled recombinant interleukin-2 activated natural killer cells and their efficacy in adoptive immunotherapy against murine fibrosarcoma

    Anuradha Rai; Ashim K Chakravarty

    2007-12-01

    Natural killer (NK) cells are spontaneously cytotoxic against tumour target cells. Their number was found to be four times more in the spleen of tumour-bearing Swiss albino mice. After activation with recombinant interleukin-2 (rIL-2), NK cells were tested and found to seek out the tumour site when injected intravenously in tumour-bearing mice. Their potential for fighting tumours in vivo was further seen following adoptive transfer of rIL-2 activated NK (A-NK) cells in tumour-bearing mice. After surgical removal of tumour load, adoptive transfer of A-NK cells inhibited tumour recurrence in 92.3% cases, thereby suggesting the use of this protocol for therapeutic purposes to obtain a better outcome.

  6. The microenvironment differentially impairs passive and active immunotherapy in Chronic lymphocytic leukemia - Potential therapeutic synergism of CXCR4 antagonists

    Buchner, Maike; Brantner, Philipp; Prinz, Gabriele; Burger, Meike; Baer, Constance; Dierks, Christine; Pfeifer, Dietmar; Mertelsmann, Roland; Gribben, John G.; Veelken, Hendrik; Zirlik, Katja

    2010-01-01

    Abstract Direct contact with stromal cells protects chronic lymphocytic leukemia (CLL) B cells from chemotherapy-induced apoptosis in vitro. Blockade of CXCR4 signaling antagonizes stroma-mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists may also effect efficient mobilization of hematopoetic progenitor cells. Therefore, combinations of CXCR4 blockade with cytoreductive treatment with selective activity on CLL cells may avoid poten...

  7. Conference Scene: novelties in immunotherapy.

    Mitsias, Dimitris I; Kalogiros, Lampros A; Papadopoulos, Nikolaos G

    2013-10-01

    The only method aiming to permanently cure allergic disorders is allergen immunotherapy. Over the last 20 years there has been great progress in understanding the mechanisms that govern allergen immunotherapy in order to meet three basic prerequisites: safety, effectiveness and compliance. In the present summary report from the European Academy of Allergology and Clinical Immunology-World Allergy Organization Congress held last June in Milan, we review key points concerning the main axes as diagnosis, novel modalities, routes and protocols, as well as two important immunotherapy fields: food and insect venom allergy. PMID:24088073

  8. Immunotherapy for nasopharyngeal cancer-a review.

    Jain, Amit; Chia, Whay Kuang; Toh, Han Chong

    2016-04-01

    Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV) and characterized by peritumoral immune infiltrate. Advanced NPC has high lethality. Immunotherapy directed against EBV antigen targets has been previously explored in clinical trials, and is likely to be validated as an important target in NPC as randomized data emerges in the future. Cancer vaccines and adoptive T cell therapy have been explored in the clinic, with the latter showing the greatest success. Recent advances in gene sequencing technology now allow personalized tumor epitope mapping, whilst the advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis offers the opportunity to activate adaptive T cell response in vivo. Anti-PD1 antibodies have shown promising activity in early phase clinical trials, and randomized studies against chemotherapy are underway. As immunotherapy is incorporated into standard treatment paradigms, issues of optimal combinations with targeting agents, immune adjuvants, and sequence with chemotherapy and radiation therapy will need to be addressed. Effective strategies to increase tumor antigenicity, improve immunological memory and reduce immune escape, will need to be developed to improve treatment outcomes. Here we present a brief history of the evolution of immunotherapy in NPC, and highlight key concepts relevant to its further development in the clinic. PMID:27121882

  9. The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo.

    Zheng Wei Lee

    Full Text Available The slow-releasing hydrogen sulfide (H₂S donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS but did not affect survival of normal human lung fibroblasts (IMR90, WI-38 as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122 lacking sulfur and thence not able to release H₂S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 µM in culture medium led to the generation of low (<20 µM concentrations of H₂S sustained over 7 days. In contrast, incubation of NaHS (400 µM in the same way led to much higher (up to 400 µM concentrations of H₂S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 µM incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122 also caused partial G₂/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100-300 mg/kg/day for 14 days significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H₂S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H₂S donors should be investigated further as potential anti-cancer agents.

  10. Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitro study

    Mochizuki Hidetaka

    2001-08-01

    Full Text Available Abstract Background The role of telomerase activation in the expression and/or maintenance of drug resistance is not clearly understood. Therefore, we investigated the relationships, among the telomerase activity, telomere length and the expression of multidrug resistance genes in colorectal cancer cell lines cultivated with anti-cancer drugs. Methods LoVo and DLD-1 cells were continuously grown in the presence of both CDDP and 5-FU for up to 100 days. Cell proliferation, telomerase activity, telomere length and the expression of multidrug resistance genes were serially monitored as the PDL increased. Results The expression of multidrug resistance genes tended to increase as the PDL increased. However, an abnormal aneuploid clone was not detected as far as the cells were monitored by a DNA histogram analysis. Tumor cells showing resistance to anti-cancer drugs revealed a higher cell proliferation rate. The telomere length gradually increased with a progressive PDL. The telomerase activity reached a maximum level at 15 PDL in LoVo cells and at 27 PDL in DLD-1 cells. An increase in the mRNA expression of the telomerase components, especially in hTERT and in hTR, was observed at the same PDLs. Conclusions These results suggest that a high telomerase activity and an elongation of telomeres both appear to help maintain and/or increase drug resistance in colorectal cancer cells. Cancer cells with long telomeres and a high proliferative activity may thus be able to better survive exposure to anti-cancer drugs. This is presumably due to an increased chromosome stability and a strong expression of both mdr-1 and MRP genes.

  11. Imaging Biomarkers in Immunotherapy

    Juergens, Rosalyn A.; Zukotynski, Katherine A.; Singnurkar, Amit; Snider, Denis P.; Valliant, John F.; Gulenchyn, Karen Y.

    2016-01-01

    Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID:26949344

  12. Targeted immunotherapy in Hodgkin lymphoma

    Hutchings, Martin

    2015-01-01

    In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13.......In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13....

  13. Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer

    McDougall Gordon

    2007-01-01

    Full Text Available Abstract Background There is a probable association between consumption of fruit and vegetables and reduced risk of cancer, particularly cancer of the digestive tract. This anti-cancer activity has been attributed in part to anti-oxidants present in these foods. Raspberries in particular are a rich source of the anti-oxidant compounds, such as polyphenols, anthocyanins and ellagitannins. Methods A "colon-available" raspberry extract (CARE was prepared that contained phytochemicals surviving a digestion procedure that mimicked the physiochemical conditions of the upper gastrointestinal tract. The polyphenolic-rich extract was assessed for anti-cancer properties in a series of in vitro systems that model important stages of colon carcinogenesis, initiation, promotion and invasion. Results The phytochemical composition of CARE was monitored using liquid chromatography mass spectrometry. The colon-available raspberry extract was reduced in anthocyanins and ellagitannins compared to the original raspberry juice but enriched in other polyphenols and polyphenol breakdown products that were more stable to gastrointestinal digestion. Initiation – CARE caused significant protective effects against DNA damage induced by hydrogen peroxide in HT29 colon cancer cells measured using single cell microgelelectrophoresis. Promotion – CARE significantly decreased the population of HT29 cells in the G1 phase of the cell cycle, effectively reducing the number of cells entering the cell cycle. However, CARE had no effect on epithelial integrity (barrier function assessed by recording the trans-epithelial resistance (TER of CACO-2 cell monolayers. Invasion – CARE caused significant inhibition of HT115 colon cancer cell invasion using the matrigel invasion assay. Conclusion The results indicate that raspberry phytochemicals likely to reach the colon are capable of inhibiting several important stages in colon carcinogenesis in vitro.

  14. The Study on Acute and Subacute Toxicity and Anti-Cancer Effects of cultivated wild ginseng Herbal acupuncture

    Ki-Rok, Kwon

    2003-06-01

    Full Text Available Objectives : The purpose of this study was to investigate acute and subacute toxicity and sarcoma-180 anti-cancer effects of herbal acupuncture with cultivated wild ginseng (distilled in mice and rats. Methods : Balb/c mice were injected intravenous with cultivated wild ginseng herbal acupuncture for LD50 and acute toxicity test. Sprague-Dawley rats were injected intravenous with cultivated wild ginseng herbal acupuncture for subacute toxicity test. The cultivated wild ginseng herbal-acupuncture was injected at the tail vein of mice. Results : 1. In acute LD50 toxicity test, there was no mortality thus unable to attain the value. 2. Examining the toxic response in the acute toxicity test, there was no sign of toxication. 3. In acute toxic test, running biochemical serum test couldn't yield any differences between the control and experiment groups. 4. In subacute toxicity test, there was no sign of toxication in the experimental groups and didn't show any changes in weight compared to the normal group. 5. In subacute toxicity test, biochemical serum test showed significant increase of Total albumin, Albumin, and Glucose in the experimental group I compared with the control group. Significant decrease of GOT, ALP, GPT, and Triglyceride were shown. In experiment group II, only Glucose showed significant increase compared with the control group. 6. Measuring survival rate for anti-cancer effects of Sarcoma-180 cancer cell line, all the experimental groups showed significant increase in survival rate. 7. Measuring NK cell activity rate, no significant difference was shown throughout the groups. 8. Measuring Interleukin-2 productivity rate, all the experimental groups didn't show significant difference. 9. For manifestation of cytokine mRNA, significant decrease of interleukin-10 was witnessed in the experimental group compared to the control group. Conclusion : According to the results, we can conclude cultivated wild ginseng herbal acupuncture

  15. An Evaluation Of Anti Cancer Potential Of Annona Muricata Linn (Durian Belanda) Tea Product

    Though the number of cancer survivors continues to increase due to the improvements in early detection, cancer incidence and deaths still escalating each year. Even though there are major advancement in medicine technology such as chemotherapy, radiotherapy and nuclear medicine, people in developing countries especially in Asian countries are looking towards natural product as an alternative medicine especially in cancer treatment and prevention; primarily because of the general belief that herbal drugs are without any side effects besides being cheap and locally available. One of them is the leaves of Annona Muricata L. from the Annonaceae family is well known for their anti cancer activity by the local people in Malaysia and is commonly known as Soursoup or in local name of Durian Belanda. In the local market the most of the product of Annona Muricata L. is in the form of tea bag. This present study was aimed to evaluate the anti cancer potential of the extract of Annona Muricata L. The tea bag of Annona Muricata L. was obtain from a local market and was physically identified and confirmed by botanist as the leaves of Annona Muricata L. Sequential extraction was done using hexane, chloroform, methanol and hot aqueous. All of these extracts will be screen for alkaloid, saponin, cardiac glucoside and flavonoid. Then quantitative estimation of phenolics adn flavonoid content was conducted. These extract are also being tested on MDPA-MB-435S (human breast carcinoma cells) and HTB-43 (head and neck cancer) by MTT assay. These extract was also evaluated for their reducing power and DPPH radical scavenging assay. The parameters obtained from the test was IC50 values, a value that produce inhibitory cancer cells by 50 % and a value that produce radical scavenging at 50 % for both MTT assay and DPPH assay. Results revealed that the IC50 of hexane, chloroform, methanol and aqueous extract for MDA-MB-435S (human breast carcinoma cells) was 35.1μg/ml, 26.8 μg/ml, 19.1

  16. Generation and Characterization of a Human/Mouse Chimeric GD2-Mimicking Anti-Idiotype Antibody Ganglidiximab for Active Immunotherapy against Neuroblastoma.

    Christin Eger

    Full Text Available Vaccination with proteins mimicking GD2 that is highly expressed on neuroblastoma (NB cells is a promising strategy in treatment of NB, a pediatric malignancy with poor prognosis. We previously showed efficacy of ganglidiomab in vivo, a murine anti-idiotype (anti-Id IgG1. In order to tailor immune responses to variable regions, we generated a new human/mouse chimeric anti-Id antibody (Ab ganglidiximab by replacing murine constant fragments with corresponding human IgG1 regions. DNA sequences encoding for variable regions of heavy (VH and light chains (VL were synthesized by RT-PCR from total RNA of ganglidiomab-producing hybridoma cells and further ligated into mammalian expression plasmids with coding sequences for constant regions of human IgG1 heavy and light chains, respectively. We established a stable production cell line using Chinese hamster ovarian (CHO cells co-transfected with two expression plasmids driving the expression of either ganglidiximab heavy or light chain. After purification from supernatants, anti-idiotypic characteristics of ganglidiximab were demonstrated. Binding of ganglidiximab to anti-GD2 Abs of the 14.18 family as well as to NK-92tr cells expressing a GD2-specific chimeric antigen receptor (scFv(ch14.18-zeta was shown using standard ELISA and flow cytometry analysis, respectively. Ganglidiximab binding affinities to anti-GD2 Abs were further determined by surface plasmon resonance technique. Moreover, binding of anti-GD2 Abs to the nominal antigen GD2 as well as GD2-specific Ab-mediated cytotoxicity (ADCC, CDC was competitively inhibited by ganglidiximab. Finally, ganglidiximab was successfully used as a protein vaccine in vivo to induce a GD2-specific humoral immune response. In summary, we report generation and characterization of a new human/mouse chimeric anti-Id Ab ganglidiximab for active immunotherapy against NB. This Ab may be useful to tailor immune responses to the paratope regions mimicking GD2

  17. Particle platforms for cancer immunotherapy

    Serda RE

    2013-04-01

    Full Text Available Rita Elena Serda Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA Abstract: Elevated understanding and respect for the relevance of the immune system in cancer development and therapy has led to increased development of immunotherapeutic regimens that target existing cancer cells and provide long-term immune surveillance and protection from cancer recurrence. This review discusses using particles as immune adjuvants to create vaccines and to augment the anticancer effects of conventional chemotherapeutics. Several particle prototypes are presented, including liposomes, polymer nanoparticles, and porous silicon microparticles, the latter existing as either single- or multiparticle platforms. The benefits of using particles include immune-cell targeting, codelivery of antigens and immunomodulatory agents, and sustained release of the therapeutic payload. Nanotherapeutic-based activation of the immune system is dependent on both intrinsic particle characteristics and on the immunomodulatory cargo, which may include danger signals known as pathogen-associated molecular patterns and cytokines for effector-cell activation. Keywords: adjuvant, particle, immunotherapy, dendritic cell, cancer, vaccine

  18. Immunotherapy with GD2 specific monoclonal antibodies

    Targeted immunotherapy focuses anti-tumor activity of antibodies and effector cells, which are actively developed by the host or adoptively transferred, onto tumor cells and into tumor sites. Such tumor selective therapy can be more specific and efficient. The value of such an approach is evident in the classical interaction of antibodies. This paper reports that the ganglioside GD2 is an ideal antigen for specific tumor targeting because of its relative lack of heterogeneity among human neuroblastoma, its high density on tumor cells, its lack of antigen modulation upon binding to antibody, and its restricted distribution in normal tissues

  19. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H.; Pedersen, Peter L.; Goffeau, Andre; Ułaszewski, Stanisław

    2016-01-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of y...

  20. Exploiting developments in nanotechnology for the preferential delivery of platinum-based anti-cancer agents to tumours: targeting some of the hallmarks of cancer.

    Parker, James P; Ude, Ziga; Marmion, Celine J

    2016-01-20

    Platinum drugs as anti-cancer therapeutics are held in extremely high regard. Despite their success, there are drawbacks associated with their use; their dose-limiting toxicity, their limited activity against an array of common cancers and patient resistance to Pt-based therapeutic regimes. Current investigations in medicinal inorganic chemistry strive to offset these shortcomings through selective targeting of Pt drugs and/or the development of Pt drugs with new or multiple modes of action. A comprehensive overview showcasing how liposomes, nanocapsules, polymers, dendrimers, nanoparticles and nanotubes may be employed as vehicles to selectively deliver cytotoxic Pt payloads to tumour cells is provided. PMID:26567482

  1. Immunotherapy for malignant glioma

    Carter M Suryadevara

    2015-01-01

    Full Text Available Malignant gliomas (MG are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM, the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  2. Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy

    Wrzesinski, Claudia; Restifo, Nicholas P

    2005-01-01

    Adoptive T-cell immunotherapy combined with non-myeloablative lymphodepletion has emerged as the most effective immunotherapy treatment for patients with metastatic melanoma (objective response rates of 50%). The mechanisms underlying this major advance in the field of immunotherapy include the elimination of regulatory elements and increased access to activating cytokines. This results in the activation of low-affinity T cells, enabling them to destroy tumors. We propose that a more complete...

  3. Translational approaches targeting the p53 pathway for anti-cancer therapy

    Essmann, Frank; Schulze-Osthoff, Klaus

    2012-01-01

    The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53-based anti-cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gen...

  4. Mitochondrial complex II, a novel target for anti-cancer agents

    Klučková, Katarína; Bezawork-Geleta, A.; Rohlena, Jakub; Dong, L.; Neužil, Jiří

    2013-01-01

    Roč. 1827, č. 5 (2013), s. 552-564. ISSN 0005-2728 R&D Projects: GA ČR(CZ) GAP301/10/1937; GA ČR GAP301/12/1851 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitochondrion * Complex II * Anti- cancer agent Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.829, year: 2013

  5. Cancer cell resistance to AURK-directed therapy: implications for anti-cancer strategies

    Hrabáková, Rita; Kollareddy, M.; Mairychová, Kateřina; Halada, Petr; Hajduch, M.; Kovářová, Hana

    Praha: Institute of Animal Physiology and Genetics ASCR, v. v. i, 2011. s. 23-23. [5th Central and Eastern European Proteomics Conference.. 19.09.2011-22.9.2011, Praha] R&D Projects: GA MŠk LC07017 Institutional research plan: CEZ:AV0Z50450515; CEZ:AV0Z50200510 Keywords : drug resistance * anti-cancer therapy * proteomics * biomarker Subject RIV: CE - Biochemistry

  6. Therapeutic Response in Patients with Advanced Malignancies Treated with Combined Dendritic Cell–Activated T Cell Based Immunotherapy and Intensity–Modulated Radiotherapy

    Hasumi, Kenichiro; Aoki, Yukimasa; Watanabe, Ryuko [Hasumi International Research Foundation, Tokyo Research Center, 1-44-6 Asagaya-kita, Suginami- ku, Tokyo 166-0001 (Japan); Hankey, Kim G.; Mann, Dean L., E-mail: dmann001@umaryland.edu [Department of Pathology, University of Maryland School of Medicine, MSTF Room 700, 10 South Pine Street, Baltimore, Maryland 21040 (United States)

    2011-04-28

    Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

  7. Human synthetic lethal inference as potential anti-cancer target gene detection

    Solé Ricard V

    2009-12-01

    Full Text Available Abstract Background Two genes are called synthetic lethal (SL if mutation of either alone is not lethal, but mutation of both leads to death or a significant decrease in organism's fitness. The detection of SL gene pairs constitutes a promising alternative for anti-cancer therapy. As cancer cells exhibit a large number of mutations, the identification of these mutated genes' SL partners may provide specific anti-cancer drug candidates, with minor perturbations to the healthy cells. Since existent SL data is mainly restricted to yeast screenings, the road towards human SL candidates is limited to inference methods. Results In the present work, we use phylogenetic analysis and database manipulation (BioGRID for interactions, Ensembl and NCBI for homology, Gene Ontology for GO attributes in order to reconstruct the phylogenetically-inferred SL gene network for human. In addition, available data on cancer mutated genes (COSMIC and Cancer Gene Census databases as well as on existent approved drugs (DrugBank database supports our selection of cancer-therapy candidates. Conclusions Our work provides a complementary alternative to the current methods for drug discovering and gene target identification in anti-cancer research. Novel SL screening analysis and the use of highly curated databases would contribute to improve the results of this methodology.

  8. Acquired resistance to immunotherapy and future challenges.

    Restifo, Nicholas P; Smyth, Mark J; Snyder, Alexandra

    2016-02-01

    Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. PMID:26822578

  9. uPAR as anti-cancer target

    Lund, Ida K; Illemann, Martin; Thurison, Tine;

    2011-01-01

    Degradation of proteins in the extracellular matrix is crucial for the multistep process of cancer invasion and metastasis. Compelling evidence has demonstrated the urokinase receptor (uPAR) and its cognate ligand, the urokinase plasminogen activator (uPA), to play critical roles in the concerted...

  10. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

    Li Zhang

    2015-07-01

    Full Text Available Astaxanthin (ATX is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and peroxisome proliferator-activated receptor gamma (PPARγ. Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX.

  11. Anti-cancer Effects of Phyllanthus urinaria and Relevant Mechanisms

    Rong-Chi Yang

    2010-10-01

    Full Text Available Phyllanthus urinaria (P. urinaria, a widely used herbalmedicine, has been reported to possess various biologicalactivities. This report aimed to characterize the whole P. urinariaplant, present the anticancer effects of P. urinaria both invivo and in vitro, and explore relevant mechanisms. The waterextract of P. urinaria not only significantly reduces the cellviability of various cancer cell lines from different origins butalso suppresses tumor development in C57BL/6J mice afterimplantation of Lewis lung carcinoma (LCC cells. The anticanceractivity of P. urinaria extract is mainly due to inducedapoptosis of cancer cells as demonstrated by DNA fragmentationand increased caspase-3 activity through both intrinsic andextrinsic pathways. The decrease in viability with P. urinariatreatment might be partially associated with down-regulationof telomerase activation and induction of the apoptotic process.In addition, P. urinaria also exhibits anti-angiogenic activity that is mediated, at least in part,by suppression of matrix metalloproteinase 2 (MMP-2 secretion and inhibition of MMP-2activity through zinc chelation.

  12. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

    Li Zhang; Handong Wang

    2015-01-01

    Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both i...

  13. Hypoallergenic molecules for subcutaneous immunotherapy.

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focus on the recent advances in a proof of concept study in food allergy, FAST (Food allergy specific immunotherapy), which may increase interest within the biomolecular and pharmaceutical industry to embark on similar projects of immunology driven precision medicine within the allergy field. PMID:26558320

  14. The efficiency of peptide immunotherapy for respiratory allergy.

    Incorvaia, Cristoforo; Montagni, Marcello; Ridolo, Erminia

    2016-06-01

    Allergen immunotherapy (AIT) was introduced more than a century ago and is yet the only disease-modifying treatment for allergy. AIT is currently conducted with whole allergen extracts and several studies clearly support its efficacy in the treatment of respiratory allergies, however the need for a long treatment - that affects costs and patients compliance - and possible IgE-mediated adverse events are still unresolved issues. Peptide immunotherapy is based on the use of short synthetic peptides which represent major T-cell epitopes of the allergen with markedly reduced ability to cross-link IgE and activate mast cells and basophils. Data from clinical trials confirmed the efficacy and tolerability of peptide immunotherapy in patients with cat allergy, with a sustained clinical effect after a short course treatment. Peptide therapy is a promising safe and effective new specific treatment for allergy to be developed for the most important allergens causing rhinitis or asthma. PMID:26901667

  15. Advances in Immunotherapies for Non-small Cell Lung Cancer

    Yuan HE

    2014-03-01

    Full Text Available Globally, Lung cancer is the leading cause of cancer-related death of high morbidity and mortality with poor prognosis, which needs some more effective and less toxic therapies. The immunotherapies offer a novel approach for the treatment of patients with non-small cell lung cancer (NSCLC in both the adjuvant and palliative disease settings. A number of promising immunotherapies based on different mechanism have now been evaluated showing an increasing response rate. Moreover, further phase II/III clinical trials will be indicated to explore its value. These include checkpoint inhibitors (anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, active vaccination (L-BLP25 liposome vaccine, Belagenpumatucel-L vaccine, MAGE-A3 protein vaccine and adoptive vaccination (CIK cells. The purpose of this paper will draw a summary on the theory, clinical trials, toxicity and problems to be solved of the immunotherapies in NSCLC.

  16. Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

    Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules

  17. Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

    Kitamura, Hiroshi, E-mail: hkitamu@sapmed.ac.jp; Tsukamoto, Taiji [Department of Urology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8543 (Japan)

    2011-07-29

    Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8{sup +} T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.

  18. New modalities of cancer treatment for NSCLC: focus on immunotherapy

    Recent advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and are now being tested in lung cancer. The antibody drugs targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unconventional response patterns and immune-related adverse events as a result of their mechanism of action. As these new agents enter the clinic, nurses and other health care providers will require an understanding of the unique efficacy and safety profiles with immunotherapy to optimize potential patient benefits. This paper provides a review of the new immunotherapeutic agents in development for lung cancer, and strategies for managing patients on immunotherapy

  19. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy.

    Fisher, Monte; Yang, Li-Xi

    2002-01-01

    shown to have antioxidant capacity which may allow it to play a role as a normal tissue chemo- and radio-protector when used in combination with adjuvant or definitive chemotherapy and/or radiotherapy in the treatment of cancer, while it may also enable it to defend the host from oxidative stress. Interestingly, studies have also shown that PSK may actually inhibit carcinogenesis by inhibiting the action of various carcinogens on vulnerable cell lines. This action of PSK may play a role in preventing second primary tumors when an inducing agent, such as tobacco or asbestos, is suspected and may also prevent second malignancies due to the carcinogenic effects of radiotherapy and cytotoxic chemotherapy. Another very important aspect of chemoimmunotherapy, in general is that it may be used on debilitated patients such as those with AIDS and the elderly who might otherwise be denied potentially helpful adjuvant cytotoxic chemotherapy. Further determination of the mechanisms of these anti-cancer, immunostimulating and biological response modifying effects of PSK as well as of other protein-bound polysaccharides is certainly warranted. Indeed, with modern cellular and molecular biology techniques, a better understanding of the specific molecular effects of PSK on tumor cells as well as leukocytes may be determined. Much of the research that has been done on PSK is outlined in this paper and may serve as a foundation toward determining the mechanisms of action of this and other protein-bound polysaccharides in the treatment of cancer. This information may open new doors in the development of novel strategies for the treatment of malignancies using adjuvant immunotherapy in combination with surgery, chemotherapy and/or radiotherapy. PMID:12168863

  20. Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma

    Ram Kumar, Ram Mohan, E-mail: rkumar@research.balgrist.ch; Fuchs, Bruno [Laboratory for Orthopaedic Research, Balgrist University Hospital, Sarcoma Center-UZH University of Zurich, Zurich 8008 (Switzerland)

    2015-05-13

    Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome.

  1. ADAM10 as a target for anti-cancer therapy.

    Moss, Marcia L; Stoeck, Alexander; Yan, Wenbo; Dempsey, Peter J

    2008-02-01

    There is a great unmet medical need in the area of cancer treatment. A potential therapeutic target for intervention in cancer is ADAM10. ADAM10 is a disintegrin-metalloproteinase that processes membrane bound proteins from the cell surface to yield soluble forms. Pharmaceutical companies are actively seeking out inhibitors of ADAM10 for treatments in cancer as the enzyme is known to release the ErbB receptor, HER2/ErbB2 from the cell membrane, an event that is necessary for HER2 positive tumor cells to proliferate. ADAM10 is also capable of processing betacellulin indicating that an inhibitor could be used against EGFR/ErbB1 and/or HER4/ErbB4 receptor positive tumor cells that are betacellulin-dependent. ADAM10 is the principle sheddase for several other molecules associated with cancer proliferation, differentiation, adhesion and migration such as Notch, E-cadherin, CD44 and L1 adhesion molecule indicating that targeting ADAM10 with specific inhibitors could be beneficial. PMID:18289051

  2. Characterization of a novel anti-cancer compound for astrocytomas.

    Sang Y Lee

    Full Text Available The standard chemotherapy for brain tumors is temozolomide (TMZ, however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.

  3. Immunotherapy and immunoescape in colorectal cancer

    2007-01-01

    Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNy in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.

  4. Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids

    Tabunoki Hiroko; Saito Naoki; Suwanborirux Khanit; Charupant Kornvika; Satoh Jun-ichi

    2012-01-01

    Abstract Background Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET-770; the compound 1a) and ...

  5. Allergen immunotherapy for allergic rhinoconjunctivitis

    Dhami, Sangeeta; Nurmatov, Ulugbek; Roberts, Graham;

    2016-01-01

    BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Allergic Rhinoconjunctivitis. We seek to critically assess the effectiveness, cost-effectiveness and safety of AI...

  6. Surface functionalization of liposomes with proteins and carbohydrates for use in anti-cancer applications

    Platt, Virginia M.

    Liposomes can be used to exploit the altered biology of cancer thereby increasing delivery of liposome-associated anti-cancer drugs. In this dissertation, I explore methods that utilize the unique cancer expression of the polymeric glycosaminoglycan hyaluronan (HA) and the HA receptor CD44 to target liposomes to tumors, using liposomes functionalized with proteins or oligosaccharides on their surface. To make it easier to prepare protein-functionalized liposomes, a non-covalent protein/liposome association method based upon metal chelation/his 6 interaction was devised and characterized. I evaluated non-covalent attachment of the prodrug converting enzyme yeast cytosine deaminase, the far-red fluorescent protein mKate, two antigens ovalbumin and the membrane proximal region of an HIV GAG and hyaluronidase, a HA-degrading enzyme. In Chapter 2, I describe the synthesis of hyaluronan-oligosaccharide (HA-O) lipid conjugates and their incorporation into liposomes to target CD44-overexpressing cancer cells. HA-O ligands of defined-length, up to 10 monosaccharides, were attached to lipids via various linkers by reductive amination. The HA-lipids were easily incorporated into liposomes but did not mediate binding of liposomes to CD44 overexpressing cells. In Chapter 3, I evaluate the capacity of tris-NTA-Ni-lipids incorporated within a liposome bilayer to associate with his6-tagged proteins. Tris-NTA-lipids of differing structures and avidities were used to associate yeast cytosine deaminase and mKate to the surface of liposomes. Two tris-NTA-lipids and a mono-NTA lipid associated his-tagged proteins to a 1:1 molar ratio in solution. The proteins remained active while associated with the liposome surface. When challenged in vitro with fetal calf serum, tris-NTA-containing liposomes retained his-tagged proteins longer than mono-NTA. However, the tris-NTA/his6 interaction was found to be in a dynamic state; free yeast cytosine deaminase rapidly competed with pre-bound m

  7. Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs

    Sarkar, Fazlul H; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

    2010-01-01

    In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents fo...

  8. Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation.

    Lutterbeck, Carlos Alexandre; Kern, Deivid Ismael; Machado, Ênio Leandro; Kümmerer, Klaus

    2015-09-01

    Anti-cancer drugs are compounds that are of high environmental relevance because of their lack of specific mode of action. They can be extremely harmful to living organisms even at low concentrations. The present study evaluated the toxic effects of four frequently used anti-cancer drugs against plant seedlings, namely Cyclophosphamide (CP), Methotrexate (MTX), 5-Fluorouracil (5-FU) and Imatinib (IM). The phytotoxicity experiments were performed with Lactuca sativa seedlings whereas cytotoxicity, genotoxicity and mutagenicity investigations were performed with the well-established Allium cepa assays. MTX was the most phytotoxic compound, followed by 5-FU, CP and IM. Significant differences in the Mitotic Indexes (MI) were observed in three of the studied compounds (MTX, 5-FU and CP), indicating potential cytotoxic activity of these substances. Chromosome aberrations were registered in cells that were exposed to 5-FU, CP and IM. All the four compounds caused the formation of micronucleated cells indicating mutagenic potential. Besides, the assays performed with MTX samples presented a high number of cell apoptosis (cell death). Although it is unlikely that the pharmaceuticals concentrations measured in the environment could cause lethal effects in plants, the obtained results indicate that these compounds may affect the growth and normal development of these plants. So, both tests can constitute important tools for a fast screening of environmental contamination e.g. in the context of the reuse of treated wastewater and biosolids of agricultural purpose. PMID:26002047

  9. [Response of Pharmaceutical Companies to the Crisis of Post-Marketing Clinical Trials of Anti-Cancer Agents -- Results of Questionnaires to Pharmaceutical Companies].

    Nakajima, Toshifusa

    2016-04-01

    Investigator-oriented post-marketing clinical trials of anti-cancer agents are faced to financial crisis due to drastic decrease in research-funds from pharmaceutical companies caused by a scandal in 2013. In order to assess the balance of research funds between 2012 and 2014, we made queries to 26 companies manufacturing anti-cancer agents, and only 10 of 26 responded to our queries. Decrease in the fund was observed in 5 of 10, no change in 1, increase in 3 and no answer in 1. Companies showed passive attitude to carry out doctor-oriented clinical trials of off-patent drugs or unapproved drugs according to advanced medical care B program, though some companies answered to proceed approved routines of these drugs if clinical trials showed good results. Most companies declined to make comments on the activity of Japan Agency for Medical Research and Development (AMED), but some insisted to produce good corroboration between AMED and pharmaceutical companies in order to improve the quality of trials. Further corroboration must be necessary for this purpose among researchers, governmental administrative organs, pharmaceutical companies, patients' groups, and mass-media. PMID:27220801

  10. Synthesis and evaluation of multi-wall carbon nanotube–paclitaxel complex as an anti-cancer agent

    Ghasemvand, Fariba; Biazar, Esmaeil; Tavakolifard, Sara; Khaledian, Mohammad; Rahmanzadeh, Saeid; Momenzadeh, Daruosh; Afroosheh, Roshanak; Zarkalami, Faezeh; Shabannezhad, Marjan; Hesami Tackallou, Saeed; Massoudi, Nilofar; Heidari Keshel, Saeed

    2016-01-01

    Aim: The aim of this study was to design multi-walled carbon nanotubes (MWCNTs) loaded with paclitaxel (PTX) anti-cancer drug and investigate its anti-cancerous efficacy of human gastric cancer. Background: Carbon nanotubes (CNTs) represent a novel nano-materials applied in various fields such as drug delivery due to their unique chemical properties and high drug loading. Patients and methods: In this study, multi-walled carbon nanotubes (MWCNTs) pre-functionalized covalently with a paclitaxel (PTX) as an anti-cancer drug and evaluated by different analyses including, scanning electron microscope (SEM), particle size analyzer and cellular analyses. Results: A well conjugated of anti-cancer drug on the carbon nanotube surfaces was shown. This study demonstrates that the MWCN-PTX complex is a potentially useful system for delivery of anti-cancer drugs. The flow cytometry, CFU and MTT assay results have disclosed that MWCNT/PTXs might promote apoptosis in MKN-45 gastric adenocarcinoma cell line. Conclusion: According to results, our simple method can be designed a candidate material for chemotherapy. It has presented a few bio-related applications including, their successful use as a nano-carriers for drug transport. PMID:27458512

  11. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy. PMID:26469159

  12. Immunotherapy Treatments of Warm Autoimmune Hemolytic Anemia

    Bainan Liu

    2013-01-01

    Full Text Available Warm autoimmune hemolytic anemia (WAIHA is one of four clinical types of autoimmune hemolytic anemia (AIHA, with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia—sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies.

  13. Benzene-Poly-Carboxylic Acid Complex, a Novel Anti-Cancer Agent Induces Apoptosis in Human Breast Cancer Cells

    Fares, Fuad; Azzam, Naiel; Fares, Basem; Larsen, Stig; Lindkaer-Jensen, Steen

    2014-01-01

    Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog. PMID:24523856

  14. Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology.

    Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

    2016-01-01

    Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin's molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

  15. Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects.

    Liu, Chaoqun; Ho, Paul Chi-Lui; Wong, Fang Cheng; Sethi, Gautam; Wang, Ling Zhi; Goh, Boon Cher

    2015-06-28

    Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer properties. Similarly, in vivo studies in animal models also demonstrated the efficacy of garcinol for the treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play an essential role in translating the preclinical findings of garcinol from cell line models and animal species to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinol's potency and tolerability. This paper reviews the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline. PMID:25796441

  16. Experimental studies of tumor immunotherapy. II. Tumor immunotherapy following tumor extirpation

    Hayashi,Shigeo

    1976-06-01

    Full Text Available In order to approach human cancer immunotherapy, the author carried out the immunotherapy with BCG on mice having homotransplanted cancer, observed the posttransplantation results with lapse of time, conduced daily macrophage inhibition test (MI test and found the immunotherapy to be effective. At the same time the MI test proved to be a useful criterion in determining the course of cancer progress and effectiveness of the immunotherapy.

  17. pH-responsive polymeric micelles with core–shell–corona architectures as intracellular anti-cancer drug carriers

    Polymeric micelles with core–shell–corona nanoarchitecture were designed for intracellular therapeutic anti-cancer drug carriers. Poly(styrene-b-acrylic acid-b-ethylene glycol) (PS-b-PAA-b-PEG) asymmetric triblock copolymer underwent self-assembly in aqueous solution to form spherical micelles with hydrophobic PS core, anionic PAA shell and hydrophilic PEG corona. The anti-cancer drug (doxorubicin, DOX) was successfully incorporated into the polymeric micelles. The in vitro release experiment confirmed that the release of DOX from the micelles was inhibited at pH 7.4. In contrast, an accelerated release of DOX was observed at mildly acidic conditions such as pH 4.5. The excellent biocompatibility of our PS-b-PAA-b-PEG-based micelles made the synthesized nano-carrier best suited for the delivery of anti-cancer drugs. (paper)

  18. In Vitro and Ex Vivo Evaluations of Lipid Anti-Cancer Nanoformulations: Insights and Assessment of Bioavailability Enhancement.

    Jain, Ankitkumar S; Dhawan, Vivek V; Sarmento, Bruno; Nagarsenker, Mangal S

    2016-06-01

    Lipid-based nanoformulations have been extensively investigated for improving oral efficacy of plethora of drugs. Chemotherapeutic agents remain a preferred option for effective management of cancer; however, most chemotherapeutic agents suffer from limitation of poor oral bioavailability that is associated with their physicochemical properties. Drug delivery via lipid-based nanosystems possesses strong rational and potential for improving oral bioavailability of such anti-cancer molecules through various mechanisms, viz. improving their gut solubilisation owing to micellization, improving mucosal permeation, improving lymphatic uptake, inhibiting intestinal metabolism and/or inhibiting P-glycoprotein efflux of molecules in the gastrointestinal tract. Various in vitro characterization techniques have been reported in literature that aid in getting insights into mechanisms of lipid-based nanodevices in improving oral efficacy of anti-cancer drugs. The review focuses on different characterization techniques that can be employed for evaluation of lipid-based nanosystems and their role in effective anti-cancer drug delivery. PMID:27068527

  19. 含黄酮类中药的抗癌抗肿瘤作用研究概况%The General Research on Effects of Flavonoids Ingredients of Chinese Herbs on Anti-cancer

    王博

    2012-01-01

    黄酮类化合物是自然界中广泛存在的一大类化合物,具有多种多样的生物学活性,其抗癌抗肿瘤作用是目前的研究热点,它在中草药中分布,引来国内外学者对中草药中黄酮类成分的研究兴趣,发现其抗癌抗肿瘤作用与抗氧化、抗自由基、抑制癌细胞生长、抗致癌因子、调节免等作用相关.中草药中白花蛇舌草、陈皮、黄芩、夏枯草、半枝莲等含有较高的黄酮类成分,本文将对中草药中黄酮类成分的抗癌抗肿瘤作用进介绍.%Flavonoids is widespread compounds with various biological activities, its anti-cancer effects are the research hot-spot recently. It also has been greatly impressed by considerable domestic and foreign scientists due to the bioactivities of Flavonoids ingredients of Chinese herbs on anti-cancer. Its anti-cancer effect relates to antioxidation, inhibiting proliferation, anti-cancerigenic factor, mediated immune. Flavonoids distribute in many Chinese herbs, such as Hedyotis diffusa, Citrus, Scutellaria, Common Selfheal Fruit-Spike, Sculellaria barbata. This article introduces the effects of Flavonoids ingredients of Chinese herbs on anti-cancer.

  20. Allergen immunotherapy in polysensitized patient.

    Hrubiško, M; Špičák, V

    2016-05-01

    Specific allergen immunotherapy (AIT) is the only therapeutic method with positive impact on natural course of allergic disease - affecting clinical development (including the progression of rhinitis to asthma) and new sensitisations. The actual problem is the increasing number of patients manifesting poly-sensitivity in allergy skin tests and / or in specific IgE tests. Usually, AIT is not recommended in such individuals. The objective we are facing is that in many patients tested as poly-reactive, we have to distinguish in which cases it is a true polysensitization, and when it is due to cross-reactivity of specific IgE antibodies induced by panallergens. This may really determine when AIT may be an appropriate course of action. The article focuses on this problem in more detail, applying the long time Czech and Slovak experience with allergy testing and allergen immunotherapy. PMID:27152601

  1. Emerging immunotherapy in pediatric lymphoma.

    Erker, Craig; Harker-Murray, Paul; Burke, Michael J

    2016-01-01

    Hodgkin and non-Hodgkin lymphoma collectively are the third most common cancer diagnosed in children each year. For children who relapse or have refractory disease, outcomes remain poor. Immunotherapy has recently emerged as a novel approach to treat hematologic malignancies. The field has been rapidly expanding over the past few years broadening its armamentarium which now includes monoclonal antibodies, antibody-drug conjugates and cellular therapies including bispecific T-cell engagers and chimeric antigen receptor-engineered T cells. Many of these agents are in their infancy stages and only beginning to make their mark on lymphoma treatment while others have begun to show promising efficacy in relapsed disease. In this review, the authors provide an overview of current and emerging immunotherapies in the field of pediatric lymphoma. PMID:26616565

  2. Immunotherapy for metastatic colorectal cancer

    Ellebaek, Eva; Andersen, Mads Hald; Svane, Inge Marie;

    2012-01-01

    presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along......Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC and...

  3. New strategies for allergen immunotherapy.

    Carnés, Jerónimo; Robinson, Douglas S

    2008-06-01

    Specific allergen immunotherapy, consisting in the administration of increasing amounts of offending allergens into sensitive patients was first used nearly one hundred years ago and remains in use worldwide for treatment of allergic rhinitis and asthma. It has been recognised as the only effective treatment for type I allergic diseases when the appropriate quantities of allergens are used. The immunological mechanisms by which specific immunotherapy is effective include the modulation of T cells and the response of B-cells and is accompanied by significant decreases of specific IgE and increases in allergen specific IgG antibodies, mainly IgG4. While specific allergen injection immunotherapy is highly effective and the most common way of administration other routes such as oral or intranasal ways have been considered as and alternative to subcutaneous injections. During the last century, allergenic vaccines have been prepared using individual allergens adsorbed to different adjuvant substances. These vaccines have demonstrated efficacy and good results in different clinical trials. However, many novel approaches to allergen immunotherapy have been developed in the last years in order to increase the safety and efficacy of allergenic vaccines. In that way, different and modern vaccines have been prepared including more purified products such as depigmented allergen extracts; allergoids, consisting on big molecules of thousands of kDa, which contain all the individual allergens and show a significant decrease in severe adverse reactions; peptides or small aminoacid sequences; recombinant allergens; hypoallergenic vaccines where the IgE binding sites have been modified; or allergen-CpG fusion molecules. New presentations are under study and new treatments will be developed in the near future with the objective that the prevention of allergic disease may become a reality. The review article also discuss recent patent related to the field. PMID:19075996

  4. New routes for allergen immunotherapy

    Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M.; Senti, Gabriela

    2012-01-01

    IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the a...

  5. Antibody Peptide Based Antifungal Immunotherapy

    Magliani, Walter; Conti, Stefania; Giovati, Laura; Zanello, Pier Paolo; Sperindè, Martina; Ciociola, Tecla; Polonelli, Luciano

    2012-01-01

    Fungal infections still represent relevant human illnesses worldwide and some are accompanied by unacceptably high mortality rates. The limited current availability of effective and safe antifungal agents makes the development of new drugs and approaches of antifungal vaccination/immunotherapy every day more needed. Among them, small antibody(Ab)-derived peptides are arousing great expectations as new potential antifungal agents. In this topic, the search path from the study of the yeast kill...

  6. The immunotherapy of Alzheimer's disease

    Weksler Marc E

    2004-01-01

    Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's d...

  7. Targeting inhibition of Foxp3 by a CD28 2'-Fluro oligonucleotide aptamer conjugated to P60-peptide enhances active cancer immunotherapy.

    Lozano, Teresa; Soldevilla, Mario Martínez; Casares, Noelia; Villanueva, Helena; Bendandi, Maurizio; Lasarte, Juan Jose; Pastor, Fernando

    2016-06-01

    The specific inhibition of Treg function has long been a major technical challenge in cancer immunotherapy. So far no single cell-surface marker has been identified that could be used to distinguish Treg cells from other lymphocytes. The only available specific marker mostly expressed in Treg is Foxp3, which is an intracellular transcription factor. A targeting molecule able to penetrate the membrane and inhibit Foxp3 within the cell is needed. P60-peptide is able to do that, but due to lack of target specificity, the doses are extremely high. In this study we have shown as a proof of concept that P60 Foxp3 inhibitor peptide can be conjugated with a CD28 targeting aptamer to deliver the peptide to CD28-expressing cells. The AptCD28-P60 construct is a clinically feasible reagent that improves the efficacy of the unconjugated P60 peptide very significantly. This approach was used to inhibit Treg function in a vaccination context, and it has shown a significant improvement in the induced immune response, entailing a lower tumor load in an antigen-specific cancer vaccine protocol. PMID:26999456

  8. Novel immunotherapies in lymphoid malignancies.

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE(®)) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  9. New modalities of cancer treatment for NSCLC: focus on immunotherapy

    Davies M

    2014-02-01

    Full Text Available Marianne Davies Smilow Cancer Hospital at Yale-New Haven Hospital, New Haven, CT, USA Abstract: Recent advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and are now being tested in lung cancer. The antibody drugs targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unconventional response patterns and immune-related adverse events as a result of their mechanism of action. As these new agents enter the clinic, nurses and other health care providers will require an understanding of the unique efficacy and safety profiles with immunotherapy to optimize potential patient benefits. This paper provides a review of the new immunotherapeutic agents in development for lung cancer, and strategies for managing patients on immunotherapy. Keywords: immunotherapy, lung cancer, vaccination, nivolumab, ipilimumab, nursing

  10. [Scleroderma related to specific immunotherapy. A report of a case].

    Morfín Maciel, Blanca María; Castillo Morfín, Blanca María

    2009-01-01

    It has been described two main phenotypes of helper T cells. On activation, the immune system develops the most effective Th response. Whereas Th1 cells promote cell-mediate immunity against intracellular pathogens and an over expression could favor autoimmune diseases; Th2 cells develop humoral immunity against extracellular pathogens promoting allergic response. Normally, the two profiles coexist in the same individual with different grades of expression. Recently, it has been described a new subset: Th17, which is related to tissue injury in autoimmune diseases. Then, allergic and autoimmune diseases result from an unbalanced response of the immune system. Allergen-specific immunotherapy is the only curative treatment of a specific allergy, which leads to a life-long tolerance against allergens. There are no controlled studies about the effectiveness or risks associated with allergen-specific immunotherapy in patients with autoimmune disorders. On the other hand, scleroderma is an autoimmune chronic systemic disorder of unknown etiology characterized by excess collagen deposition in the skin and viscera, along with vascular injury. We report a girl with allergic asthma and with a second degree family history of systemic sclerosis who developed localized scleroderma during allergen specific immunotherapy. Because allergy vaccination alter the balance between effector and regulatory T-cell populations, which regulate immune tolerance, a positive family history of autoimmunity in first or second degree, could be a contraindication for allergen-specific immunotherapy. PMID:19768975

  11. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    Stephanie L. Swift

    2016-02-01

    Full Text Available Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system.

  12. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy.

    Swift, Stephanie L; Stojdl, David F

    2016-02-01

    Large-scale assays, such as microarrays, next-generation sequencing and various "omics" technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy-from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse-has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  13. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    Swift, Stephanie L.; Stojdl, David F.

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  14. Biologic Therapy (Immunotherapy) for Kidney Cancer

    ... for kidney cancer Targeted therapies for kidney cancer Biologic therapy (immunotherapy) for kidney cancer Chemotherapy for kidney cancer Pain control for kidney cancer Treatment choices by stage for ...

  15. Immunotherapy for B-cell lymphoma: current status and prospective advances.

    Hollander, Nurit

    2012-01-01

    Therapy for non-Hodgkin's lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radio labeled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect. PMID:22566889

  16. Immunotherapy for B-cell lymphoma: current status and prospective advances

    Nurit eHollander

    2012-01-01

    Full Text Available Therapy for non-Hodgkin's lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radiolabelled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect.

  17. Anti-Cancer Effect of Angelica Sinensis on Women’s Reproductive Cancer

    Hong-Hong Zhu

    2012-06-01

    Full Text Available Objective: Danggui, the root of Angelica Sinensis, has traditionally been used for the treatment of women’s reproductive disorders in China for thousands of years. This study was to determine whether Danggui have potential anti-cancer effect on women’s cancer and its potential mechanism. Methods: Danggui was extracted by ethanol. The Cell Titer 96® Aqueous Non-Radioactive Cell Proliferation Assay was used to compare the effects of Danggui on human breast (MCF-7 and 7368 and cervical (CaSki and SiHa cancer cells with its effects on normal fibroblasts (HTB-125. A revised Ames test was used to test for antimutagenicity. The standard strains of Salmonella typhimarium (TA 100 and 102 were used in the test. Methyl methane sulfonate (MMS and UV light were used as positive mutagen controls and ethanol and double distilled water (DDW as controls. The SAS statistical software was used to analyze the data. Results: Danggui was found to be much more toxic to all cancer cell lines tested than to normal fibroblasts. There was a significant negative dose-effect relationship between Danggui and cancer cell viability. Average viability of MCF-7 was 69.5%, 18.4%, 5.7%, 5.7%, and 5.0% of control for Danggui doses 0.07, 0.14, 0.21, 0.32, and 0.64 ug/ul, respectively, with a Ptrend < 0.0001. Half maximal inhibitory dose (ID50 of Danggui for cancer cell lines MCF-7, CaSki, SiHa and CRL-7368 was 0.10, 0.09, 0.10 and 0.07 ug/ul, Functional Foods in Health and Disease 2012, 2(6:242-250respectively. For the normal fibroblasts, ID50 was 0.58 ug/ul. At a dose of 0.32 ug/ul, Danggui killed over 90% of the cells in each cancer cell line, but at the same dose, only 12.3 % of the normal HTB-125 cells were killed. Revertants per plate of TA 100 decreased with the introduction of increasing doses of Danggui extracts with a Ptrend < 0.0001 when UV light was used as a mutagen. There was no difference in revertants per plate between ethanol and DDW control groups. Conclusions

  18. Immunotherapy of hematological malignancies using dendritic cells.

    Van de Velde, Ann L R; Berneman, Zwi N; Van Tendeloo, Viggo F I

    2008-03-01

    The arsenal of therapeutic weapons against hematological malignancies is constantly growing. Unravelling the secrets of tumor immunobiology has allowed researchers to manipulate the immune system in order to stimulate tumor immunity or to bypass tumor-induced immunosuppression. An area of great interest is active specific immunotherapy where dendritic cell (DC)-based therapeutic vaccines for cancer have definitely grabbed the spotlight. DC are intensively investigated as cellular adjuvants to harness the immune system to fight off cancer by augmenting the number and effector functions of tumor-specific CD8+ cytotoxic T lymphocytes. In the present review we present a comprehensive synopsis and an update of the use of DC in hematological malignancies. In the future, more basic research as well as more clinical trials are warranted to fully establish the value of DC vaccination as an adjuvant therapy for modern hematological oncology. PMID:18390412

  19. Extracellular control of intracellular drug release for enhanced safety of anti-cancer chemotherapy

    Zhu, Qian; Qi, Haixia; Long, Ziyan; Liu, Shang; Huang, Zhen; Zhang, Junfeng; Wang, Chunming; Dong, Lei

    2016-06-01

    The difficulty of controlling drug release at an intracellular level remains a key challenge for maximising drug safety and efficacy. We demonstrate herein a new, efficient and convenient approach to extracellularly control the intracellular release of doxorubicin (DOX), by designing a delivery system that harnesses the interactions between the system and a particular set of cellular machinery. By simply adding a small-molecule chemical into the cell medium, we could lower the release rate of DOX in the cytosol, and thereby increase its accumulation in the nuclei while decreasing its presence at mitochondria. Delivery of DOX with this system effectively prevented DOX-induced mitochondria damage that is the main mechanism of its toxicity, while exerting the maximum efficacy of this anti-cancer chemotherapeutic agent. The present study sheds light on the design of drug delivery systems for extracellular control of intracellular drug delivery, with immediate therapeutic implications.

  20. Glucagon-like peptide-2 (GLP-2) response to enteral intake in children during anti-cancer treatment

    Andreassen, B U; Paerregaard, A; Schmiegelow, K;

    2005-01-01

    BACKGROUND: Intestinal dysfunction is frequent in cancer and during anti-cancer treatment. Glucagon-like peptide-2 (GLP-2) is secreted in a nutrition-dependent manner from the intestinal enteroendocrine L-cells. It accelerates crypt cell proliferation and nutrient absorption, inhibits enterocyte...

  1. Cancer Immunotherapy: A Review

    Anna Meiliana; Nurrani Mustika Dewi; Andi Wijaya

    2016-01-01

    BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy. CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targetin...

  2. Specific repression of mutant K-RAS by 10-23 DNAzyme: Sensitizing cancer cell to anti-cancer therapies

    Point mutations of the Ras family are frequently found in human cancers at a prevalence rate of 30%. The most common mutation K-Ras(G12V), required for tumor proliferation, survival, and metastasis due to its constitutively active GTPase activity, has provided an ideal target for cancer therapy. 10-23 DNAzyme, an oligodeoxyribonucleotide-based ribonuclease consisting of a 15-nucleotide catalytical domain flanked by two target-specific complementary arms, has been shown to effectively cleave the target mRNA at purine-pyrimidine dinucleotide. Taking advantage of this specific property, 10-23 DNAzyme was designed to cleave mRNA of K-Ras(G12V)(GGU → GUU) at the GU dinucleotide while left the wild-type (WT) K-Ras mRNA intact. The K-Ras(G12V)-specific 10-23 DNAzyme was able to reduce K-Ras(G12V) at both mRNA and protein levels in SW480 cell carrying homozygous K-Ras(G12V). No effect was observed on the WT K-Ras in HEK cells. Although K-Ras(G12V)-specific DNAzymes alone did not inhibit proliferation of SW480 or HEK cells, pre-treatment of this DNAzyme sensitized the K-Ras(G12V) mutant cells to anti-cancer agents such as doxorubicin and radiation. These results offer a potential of using allele-specific 10-23 DNAzyme in combination with other cancer therapies to achieve better effectiveness on cancer treatment.

  3. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice

    Pornprom Yoysungnoen; Ponthip Wirachwong; Chatchawan Changtam; Apichart Suksamrarn; Suthiluk Patumraj

    2008-01-01

    AIM: To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2).METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 x 106 human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured.RESULTS: Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%,P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05).CONCLUSION: THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.

  4. Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells

    Ganesh Radhakrishnan

    2012-09-01

    Full Text Available Abstract Background Arachidonic acid metabolite, generated by cyclooxygenase (COX, is implicated in the colorectal cancer (CRC pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2. Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. Methods Three colorectal cancer cell lines (HCA7, HT-29 & LoVo expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor and rofecoxib (COX-2 selective on prostaglandin E2 (PGE2 and leukotriene B4 (LTB4 secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. Results COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P  Conclusions This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.

  5. Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles

    Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

    2016-05-01

    Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 108 particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

  6. Oral Immunotherapy for Food Allergy.

    Burbank, Allison J; Sood, Puja; Vickery, Brian P; Wood, Robert A

    2016-02-01

    Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food-allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut. PMID:26617227

  7. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

    Lambracht-Washington D

    2013-08-01

    Full Text Available Doris Lambracht-Washington, Roger N Rosenberg Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Immunotherapy might provide an effective treatment for Alzheimer's disease (AD. A unique feature of AD immunotherapies is that an immune response against a self-antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focused on two possible targets in this regard. One is the inhibition of accumulation and deposition of amyloid beta 1–42 (Aβ42, which is one of the major peptides found in senile plaques, and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations is already in several stages of clinical trials, tau-based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phosphorylated tau have been found, high interest has again focused on further development of tau-based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. Last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects, as these two pathologies are likely synergistic; this is an approach that has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, and present an overview on halted, ongoing, and upcoming clinical trials together with ongoing preclinical studies targeting tau

  8. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    Swift, Stephanie L.; Stojdl, David F

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and funct...

  9. Construction and characterisation of a stably transfected BHK cell line permanently secreting the canine interleukin 12 as a source for adoptive cancer immunotherapy in dogs

    Kocoski, Vladimir

    2008-01-01

    BACKGROUND AND AIM OF THE STUDY: The dog represents the most important tumor patient in the veterinary medicine. Furthermore, the growing knowledge of tumor biology and immunology in dogs increases the interest of this species as a promising model in studies of tumor immunotherapy in human. Concerning the tumor treatment, one of the latest therapeutical approaches is the tumor immunotherapy, especially the adoptive immunotherapy, which is based on in vitro lymphocyte activation by cytokines. ...

  10. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  11. Radio-immunotherapy

    Radioimmunotherapy (R.I.T.) is a new modality of targeted therapy in which irradiation from radionuclides is delivered to tumor targets using monoclonal antibodies (MAb) directed to tumor-associated antigen. R.I.T. has been developed for more than 20 years. Today, R.I.T. can be used in clinical practice using non-ablative activity of murine anti-CD20 90Y-ibritumomab tiuxetan (Zevalin) for treatment of patients with relapsed or refractory follicular lymphomas (F.L.), with overall response rate of 70 to 80% and 20 to 30% of complete response. Different approaches are explored to improve efficacy of R.I.T. in N.H.L.: myelo-ablative R.I.T. or HD treatment, R.I.T. as consolidation after chemotherapy to target M.R.D., R.I.T. in first-line treatment, fractionated R.I.T., R.I.T. using other Ag targets. For solid tumors, interesting results have been obtained using anti-CEA R.I.T. delivered as consolidation treatment or using pre-targeting system. (authors)

  12. Engineering approaches to immunotherapy.

    Swartz, Melody A; Hirosue, Sachiko; Hubbell, Jeffrey A

    2012-08-22

    As the science of immunology grows increasingly mechanistic, motivation for developing quantitative, design-based engineering approaches has also evolved, both for therapeutic interventions and for elucidating immunological pathways in human disease. This has seeded the nascent field of "immunoengineering," which seeks to apply engineering analyses and design approaches to problems in translational immunology. For example, cell engineers are creating ways to tailor and use immune cells as living therapeutics; protein engineers are devising new methods of rapid antibody discovery; biomaterials scientists are guiding vaccine delivery and immune-cell activation with novel constructs; and systems immunologists are deciphering the evolution and maintenance of T and B cell receptor repertoires, which could help guide vaccine design. The field is multidisciplinary and collaborative, with engineers and immunologists working together to better understand and treat disease. We discuss the scientific progress in this young, yet rapidly evolving research area, which has yielded numerous start-up companies that are betting on impact in clinical and commercial translation in the near future. PMID:22914624

  13. THE JOURNAL OF TROPICAL LIFE SCIENCE OPEN ACCESS Freely available online VOL. 5, NO. 2, pp. 88-91, May, 2015 Isolation of an Anti-Cancer Asperuloside from Hedyotis corymbosa L.

    Nina Artanti; Muhammad Hanafi; Rina Andriyani; Vienna Saraswati; Zalinar Udin; Puspa D. Lotulung; Ken Ichi Fujita; Yoshinosuke Usuki

    2015-01-01

    Hedyotis corymbosa L., with local name rumput mutiara, is an anti-inflammatory, anti-cancer and hepatoprotective traditional medicine. The ethanol extract of H. corymbosa L. shows inhibitory activity to humanYMB-1 breast cancer cell line with an IC50 of 6.51 μg/mL. The methylene chloride fraction shows a potential cytotoxic activity with an IC50 of 2.75 μg/mL. To obtain a lead compound, the extract was further purified by column chromatography. A pure compound is obtained which shows inhibito...

  14. Allergen specific immunotherapy in nasobronchial allergy.

    Joshi S

    2003-12-01

    Full Text Available BACKGROUND: More than one antigen has been used for immunotherapy of allergic disorders. So far less than five antigens have been employed with variable results. AIM: To evaluate effect of multiple antigens up to six in the immunotherapy of nasobronchial allergy. SETTING AND DESIGN: Based on clinical history, symptoms present for at least 3 years with set criteria of immunomodulation for asthma and rhinitis: documented IgE mediated asthma and rhinitis, failure in allergen avoidance and moderate to severe clinical manifestations. MATERIAL AND METHODS: Five hundred cases of various allergic disorders attending allergy clinic of Bombay hospital were screened. Allergen specific immunotherapy was initiated in 131 subjects (56 -rhinitis and 75 asthma with prior consent. Patients suffering from allergic disorders secondary to diseases or drug therapy were excluded. Multiple allergen immunotherapy was given at specific intervals up to a period of one year. Allergen extracts were prepared as per standard technique. For statistical analysis "students′t test" was used. RESULTS AND CONCLUSIONS: Significant improvement in PEFR, reduction in skin sensitivity to allergens used in immunotherapy formulation and symptomatic relief without any untoward reaction show that multiple allergen immunotherapy is as effective as monoallergen immunotherapy in nasobronchial allergy.

  15. Novel Approaches to Pediatric Cancer: Immunotherapy

    Payal A. Shah

    2015-06-01

    Full Text Available From the early 20th century, immunotherapy has been studied as a treatment modality for cancers, including in children. Since then, developments in monoclonal antibodies and vaccine therapies have helped to usher in a new era of cancer immunotherapeutics. However, efficacy of these types of therapies has been limited, mostly in part due to low tumor immunogenicity, cancer escape pathways, and toxicities. As researchers investigate the cellular and molecular components of immunotherapies, mechanisms to improve tumor specificity and overcome immune escape have been identified. The goal of immunotherapy now has been to modulate tumor escape pathways while amplifying the immune response by combining innate and adaptive arms of the immune system. Although several limiting factors have been identified, these recent advances in immunotherapy remain at the forefront of pediatric oncologic therapeutic trials. Immunotherapy is now coming to the forefront of precision treatment for a variety of cancers, with evidence that agents targeting immunosuppressive mechanisms for cancer progression can be effective therapy [1-3]. In this review, we review various types of immunotherapy, including the cellular biology, limitations, recent novel therapeutics, and the application of immunotherapy to pediatric oncology.

  16. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors.

    Terranova-Barberio, Manuela; Thomas, Scott; Munster, Pamela N

    2016-06-01

    Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade. PMID:27197539

  17. Immunotherapy of Metastases Enhances Subsequent Chemotherapy

    Hanna, Michael G.; Key, Marc E.

    1982-07-01

    In many multimodal therapies of cancer, postsurgical chemotherapy is administered before immunotherapy for treatment of micrometastatic disease. This sequence may not be the most efficacious. Experiments in which strain 2 guinea pigs bearing syngeneic L10 hepatocarcinomas were given immunotherapy showed that infiltrating immune effector cells not only were tumoricidal but disrupted the characteristically compact structure of metastatic foci. When cytotoxic drugs were administered at the peak of this inflammatory response, the survival rate of the guinea pigs increased significantly. We conclude that postsurgical immunotherapy can enhance the effect of cytotoxic drugs administered subsequently.

  18. H2S donor, S-propargyl-cysteine, increases CSE in SGC-7901 and cancer-induced mice: evidence for a novel anti-cancer effect of endogenous H2S?

    Kaium Ma

    Full Text Available BACKGROUND: S-propargyl-cysteine (SPRC, an H(2S donor, is a structural analogue of S-allycysteine (SAC. It was investigated for its potential anti-cancer effect on SGC-7901 gastric cancer cells and the possible mechanisms that may be involved. METHODS AND FINDINGS: SPRC treatment significantly decreased cell viability, suppressed the proliferation and migration of SPRC-7901 gastric cancer cells, was pro-apoptotic as well as caused cell cycle arrest at the G(1/S phase. In an in vivo study, intra-peritoneal injection of 50 mg/kg and 100 mg/kg of SPRC significantly reduced tumor weights and tumor volumes of gastric cancer implants in nude mice, with a tumor growth inhibition rate of 40-75%. SPRC also induced a pro-apoptotic effect in cancer tissues and elevated the expressions of p53 and Bax in tumors and cells. SPRC treatment also increased protein expression of cystathione-γ-lyase (CSE in cells and tumors, and elevated H(2S levels in cell culture media, plasma and tumoral CSE activity of gastric cancer-induced nude mice by 2, 2.3 and 1.4 fold, respectively. Most of the anti-cancer functions of SPRC on cells and tumors were significantly suppressed by PAG, an inhibitor of CSE activity. CONCLUSIONS: Taken together, the results of our study provide insights into a novel anti-cancer effect of H(2S as well as of SPRC on gastric cancer through inducing the activity of a new target, CSE.

  19. IMUNODIAGNOSTIC AND IMMUNOTHERAPY OF AUTISM

    Vladimir TRAJKOVSKI

    2000-06-01

    Full Text Available Infantile autism is one of the most disabling illnesses of neurological, emotional and intellectual development. The cause of autism remains unknown. However, recent investigations suggest that this disorder shares several features of established autoimmune disorders.The aim of this article is to describe the news of imunodiagnostic and immunotherapy in autism. Interpretation of data is made by conceptual and methodological differences between studies. The autoimmune response is most likely directed against the brain myelin, perhaps secondary to a viral infection. The idea that autism is an autoimmune disorder is further strengthened by the fact that autistic patients respond well to treatment with immune modulating drugs. Immune interventions can produce immune modulation-state of suppression or stimulation. Immune therapy should always be done in consultation with physicians.

  20. Cancer Immunotherapy Using Engineered Hematopoietic Stem Cells

    Gschweng, Eric Hans

    2015-01-01

    Engineering the immune system against cancer ideally provides surgical precision against the antigen bearing target cell while avoiding the systemic, off-target toxicity of chemotherapy. Successful treatment of patients in the clinic has been achieved by the expression of anti-cancer T-cell receptors (TCR) and chimeric antigen receptors (CAR) in T cells followed by infusion of these cells into cancer patients. Unfortunately, while many patients initially respond showing anti-tumor efficacy, t...

  1. DNA-inorganic hybrid nanovaccine for cancer immunotherapy

    Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

    2016-03-01

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit

  2. Grass pollen immunotherapy: where are we now.

    Würtzen, Peter A; Gupta, Shashank; Brand, Stephanie; Andersen, Peter S

    2016-04-01

    During allergen immunotherapy (AIT), the allergic patient is exposed to the disease-inducing antigens (allergens) in order to induce clinical and immunological tolerance and obtain disease modification. Large trials of grass AIT with highly standardized subcutaneous and sublingual tablet vaccines have been conducted to document the clinical effect. Induction of blocking antibodies as well as changes in the balance between T-cell phenotypes, including induction of regulatory T-cell subtypes, have been demonstrated for both treatment types. These observations increase the understanding of the immunological mechanism behind the clinical effect and may make it possible to use the immunological changes as biomarkers of clinical effect. The current review describes the recent mechanistic findings for subcutaneous immunotherapy and sublingual immunotherapy/tablet treatment and discusses how the observed immunological changes translate into a scientific foundation for the observed clinical effects of grass pollen immunotherapy and lead to new treatment strategies for grass AIT. PMID:26973122

  3. Defining the critical hurdles in cancer immunotherapy

    Fox Bernard A

    2011-12-01

    Full Text Available Abstract Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC, convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

  4. Allergen specific immunotherapy in nasobronchial allergy.

    Joshi S; Tripathi D; Dhar H

    2003-01-01

    BACKGROUND: More than one antigen has been used for immunotherapy of allergic disorders. So far less than five antigens have been employed with variable results. AIM: To evaluate effect of multiple antigens up to six in the immunotherapy of nasobronchial allergy. SETTING AND DESIGN: Based on clinical history, symptoms present for at least 3 years with set criteria of immunomodulation for asthma and rhinitis: documented IgE mediated asthma and rhinitis, failure in allergen avoidance and modera...

  5. Anti-Cancer Effects of Protein Extracts from Calvatia lilacina, Pleurotus ostreatus and Volvariella volvacea

    Jin-Yi Wu

    2011-01-01

    Full Text Available Calvatia lilacina (CL, Pleurotus ostreatus (PO and Volvariella volvacea (VV are widely distributed worldwide and commonly eaten as mushrooms. In this study, cell viabilities were evaluated for a human colorectal adenocarcinoma cell line (SW480 cells and a human monocytic leukemia cell line (THP-1 cells. Apoptotic mechanisms induced by the protein extracts of PO and VV were evaluated for SW480 cells. The viabilities of THP-1 and SW480 cells decreased in a concentration-dependent manner after 24 h of treatment with the protein extracts of CL, PO or VV. Apoptosis analysis revealed that the percentage of SW480 cells in the SubG1 phase (a marker of apoptosis was increased upon PO and VV protein-extract treatments, indicating that oligonucleosomal DNA fragmentation existed concomitantly with cellular death. The PO and VV protein extracts induced reactive oxygen species (ROS production, glutathione (GSH depletion and mitochondrial transmembrane potential (ΔΨm loss in SW480 cells. Pretreatment with N-acetylcysteine, GSH or cyclosporine A partially prevented the apoptosis induced by PO protein extracts, but not that induced by VV extracts, in SW480 cells. The protein extracts of CL, PO and VV exhibited therapeutic efficacy against human colorectal adenocarcinoma cells and human monocytic leukemia cells. The PO protein extracts induced apoptosis in SW480 cells partially through ROS production, GSH depletion and mitochondrial dysfunction. Therefore, the protein extracts of these mushrooms could be considered an important source of new anti-cancer drugs.

  6. Advances in individual markers of interferon in anti-cancer therapy

    Chi Pan; Chenjing Zhang; Jianjin Huang

    2013-01-01

    Interferon (IFN) is a cytokine with various biological functions, including antivirus, immunoregulation and anti-tumor. It has been wildly used in many anti-cancer therapies, including malignant melanoma, hepatocellular carcinoma, ad-vanced renal-cell carcinoma, non-Hodgkin's lymphoma, chronic myelogenous leukemia and AIDS-related Kaposi's sarcoma. However, its effective dose is always very high, which may bring some serious side effects, nevertheless, not all patients can benefit from the IFN therapy. So a problem we have faced is that how to improve the efficiency and sensitivity of IFN? To solve this problem, many studies have been launched to find the effective prognostic factors and individual biomarkers for guiding the treatment better. In addition, further clarifying the anti-tumor mechanisms of IFN is benefit for explaining how the biomark-ers predict prognosis of patients. In recent studies, many IFN associated genes and proteins predicting sensitivity of IFN therapy have been found, which may associate with the progression of cancer, such as IFN regulatory factor (IRF), IFNAR2 mRNA, microRNA, IFITM-1. Some factors in peripheral blood are easier to detect and have the potential to been popularized in clinical practice, such as CD8high CD57+ lymphocyte levels in malignant melanoma, serum IFNAR2 mRNA in mCRC. This review briefly summarized the advances of antitumorally individual markers of IFN.

  7. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

    Alex Matter

    2015-01-01

    This review starts with a brief history of drug discovery&development, and the place of Asia in this worldwide effort discussed. hTe conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. hTe importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. hTe most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. hTe factors to consider before starting a new drug discovery&development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

  8. Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates

    Li, Fei; Zhou, Xiaofei; Zhou, Hongyu; Jia, Jianbo; Li, Liwen; Zhai, Shumei; Yan, Bing

    2016-01-01

    Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID:27467397

  9. RAS GTPase AS THE DRUG TARGET FOR ANTI-CANCER DESIGNING OF DRUG FROM TEMPLATE

    A.S. Krishnapriya and P.K. Krishnan Namboori*

    2013-11-01

    Full Text Available Ras proteins in association with GTP and GDP act as a bio-molecular switch for signaling cell growth, cell survival and signal transduction. The presence of mutated Ras proteins is found to vary in different cancer types and the highest occurrence of about 90% is observed in pancreatic cancer. The Ras GTPase binding site is mainly involved in signal cell proliferation. Hence, this binding site has been considered as a major target. At the same time, targeting a specific protein and designing the drug molecule with respect to that is practically of no use as the target proteins are fast mutating. In this scenario, designing the template from the hot spot of proteins and fitting the template for all the target protein molecules seem to be a promising technique. The templates are initially screened on the basis of pharmacokinetic and pharmacodynamic requirements. Six templates are found to be satisfying conditions like IC50, lipophilic efficiency, ligand efficiency etc. and their efficiencies are compared with standard reference molecules. The computed enrichment factors support these templates to be leads for effective anti-cancer drugs subject to further in vitro and in vivo evaluation.

  10. Spectral and structural studies of the anti-cancer drug Flutamide by density functional theoretical method

    Mariappan, G.; Sundaraganesan, N.

    2014-01-01

    A comprehensive screening of the more recent DFT theoretical approach to structural analysis is presented in this section of theoretical structural analysis. The chemical name of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide is usually called as Flutamide (In the present study it is abbreviated as FLT) and is an important and efficacious drug in the treatment of anti-cancer resistant. The molecular geometry, vibrational spectra, electronic and NMR spectral interpretation of Flutamide have been studied with the aid of density functional theory method (DFT). The vibrational assignments of the normal modes were performed on the basis of the PED calculations using the VEDA 4 program. Comparison of computational results with X-ray diffraction results of Flutamide allowed the evaluation of structure predictions and confirmed B3LYP/6-31G(d,p) as accurate for structure determination. Application of scaling factors for IR and Raman frequency predictions showed good agreement with experimental values. This is supported the assignment of the major contributors of the vibration modes of the title compound. Stability of the molecule arising from hyperconjugative interactions leading to its bioactivity, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. NMR chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. The comparison of measured FTIR, FT-Raman, and UV-Visible data to calculated values allowed assignment of major spectral features of the title molecule. Besides, Frontier molecular orbital analyze was also investigated using theoretical calculations.

  11. Structural characterization and anti-cancerous potential of gallium bioactive glass/hydrogel composites.

    Keenan, T J; Placek, L M; Coughlan, A; Bowers, G M; Hall, M M; Wren, A W

    2016-11-20

    A bioactive glass series (0.42SiO2-0.10Na2O-0.08CaO-(0.40-X)ZnO-(X)Ga2O3) was incorporated into carboxymethyl cellulose (CMC)/dextran (Dex) hydrogels in three different amounts (0.05, 0.10, and 0.25m(2)), and the resulting composites were characterized using transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and (13)C Cross Polarization Magic Angle Spinning Nuclear Magnetic Resonance (CP MAS-NMR). Composite extracts were also evaluated in vitro against MG-63 osteosarcoma cells. TEM confirmed glass distribution throughout the composites, although some particle agglomeration was observed. DSC revealed that glass composition and content did have small effects on both Tg and Tm. MAS-NMR revealed that both CMC and Dex were successfully functionalized, that cross-linking occurred, and that glass addition did slightly alter bonding environments. Cell viability analysis suggested that extracts of the glass and composites with the largest Ga-content significantly decreased MG-63 osteosarcoma viability after 30days. This study successfully characterized this composite series, and demonstrated their potential for anti-cancerous applications. PMID:27561520

  12. Extraction and purification of giant salamander skin mucous glycoprotein and study its anti-cancer activity of lung cancer%大鲵皮肤黏液糖蛋白的提取纯化及抗肺癌活性研究

    徐伟良; 陈德经; 刘宇; 魏泓; 刘青

    2015-01-01

    目的:研究大鲵皮肤黏液糖蛋白提取纯化工艺以及体外对人肺癌细胞A549活性的影响。方法利用碱提取和DEAE-52离子交换层析与Sephadex G-100凝胶层析分离纯化大鲵黏液糖蛋白;并采用MTT比色法体外检测大鲵黏液糖蛋白对人肺癌细胞A549的抑制率。结果黏液糖蛋白中的总糖含量为4.23%,经SDS-PAGE电泳检测,糖蛋白的分子量在30 kDa左右,为单一纯品。随糖蛋白纯品浓度从1、10、20、40μg/mL逐渐增加,糖蛋白对A549细胞的抑制率逐渐增大;当糖蛋白浓度为40μg/mL,作用24 h时,对A549细胞的抑制率可达85.66%,作用48 h时,可达92.32%。与阳性对照紫杉醇相比,大鲵皮肤黏液糖蛋白对人肺癌细胞A549有显著的抑制作用。结论大鲵黏液糖蛋白对人肺癌细胞具有明显的抑制作用,可为抗肺癌药物的开发提供理论依据。%Objective To study the appearance of skin mucous glycoprotein in vitro on the activity of human lung cancer cells A549. Methods Used alkali extraction and DEAE-52 ion exchange chromatography and Sephadex G-100 gel chromatography purification salamander mucous glycoprotein; Salamander mucous glycoprotein inhibition of human lung cancer cells A549 was detected by MTT colorimetric method in vitro.ResuIts It showed that the total sugar content in the appearance of mucus was 4.23%, the relatively pure glycoprotein component, by SDS protein electrophoresis tests, it contained a single glycoprotein component, its molecular weight was about 30 kDa.With glycoprotein pure concentration increased from 1,10, 20,40μg/mL, the glycoprotein inhibition rate of A549 cells increased; when the glycoprotein concentration was 40 μg/mL, for 24 h action, the inhibition rate of A549 cells was up to 85.66 %, while the role of 48 h, the inhibition rate of A549 cells was up to 92.32%.Inhibition effect of mucus glycoprotein on A549 cell compared with positive control

  13. Is immunotherapy an opportunity for effective treatment of drug addiction?

    Zalewska-Kaszubska, Jadwiga

    2015-11-27

    Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. PMID:26432911

  14. Mathematical Model Creation for Cancer Chemo-Immunotherapy

    Lisette de Pillis

    2009-01-01

    Full Text Available One of the most challenging tasks in constructing a mathematical model of cancer treatment is the calculation of biological parameters from empirical data. This task becomes increasingly difficult if a model involves several cell populations and treatment modalities. A sophisticated model constructed by de Pillis et al., Mixed immunotherapy and chemotherapy of tumours: Modelling, applications and biological interpretations, J. Theor. Biol. 238 (2006, pp. 841–862; involves tumour cells, specific and non-specific immune cells (natural killer (NK cells, CD8+T cells and other lymphocytes and employs chemotherapy and two types of immunotherapy (IL-2 supplementation and CD8+T-cell infusion as treatment modalities. Despite the overall success of the aforementioned model, the problem of illustrating the effects of IL-2 on a growing tumour remains open. In this paper, we update the model of de Pillis et al. and then carefully identify appropriate values for the parameters of the new model according to recent empirical data. We determine new NK and tumour antigen-activated CD8+T-cell count equilibrium values; we complete IL-2 dynamics; and we modify the model in de Pillis et al. to allow for endogenous IL-2 production, IL-2-stimulated NK cell proliferation and IL-2-dependent CD8+T-cell self-regulations. Finally, we show that the potential patient-specific efficacy of immunotherapy may be dependent on experimentally determinable parameters.

  15. Immunological Changes on Allergic Response after Beevenom Immunotherapy

    Dong-Ha Han

    2004-12-01

    Full Text Available Beevenom immunotherapy(BVIT in allergic patients is a well-established treatment modality for the prevention of systemic anaphylactic reactions caused by insect stings. BVIT is accompanied by increases in allergen-specific IgG, particularly the IgG4 isotype, which blocks not only IgE-dependent histamine release from basophils but also IgE-mediated antigen presentation to T cells. Inhibition of T cells after BVIT also involves decreased induction of the costimulatory molecule ICOS, which, in turn, seems to be dependent on the presence of IL-10, also associated with the inhibited status of T cells after BVIT. Suppression of T cells by IL-10 is an active process, which depends on the expression and participation of CD28. Immune tolerance in specific allergen immunotherapy might be a consequence of decreased Th2 or increased Th1 response of allergen specific T lymphocytes. BVIT shifted cytokine responses to allergen from a TH-2 to a TH-1 dominant pattern, suggesting direct effects on T cells. Many studies showed that severe side effects due to venom immunotherapy are rare. These results suggest that immunological changes after BVIT may be applied to be therapeutic alternative of general allergic diseases including beevenom allergy.

  16. Adoptive immunotherapy via CD4+ versus CD8+ T cells

    Vy Phan-Lai

    2016-04-01

    Full Text Available The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT. [Biomed Res Ther 2016; 3(4.000: 588-595

  17. Sublingual allergen immunotherapy in HIV-positive patients.

    Iemoli, E; Borgonovo, L; Fusi, A; Magni, C; Ricci, E D; Rizzardini, G; Piconi, S

    2016-03-01

    HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV-infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen-allergic HAART-treated HIV-positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes©) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom-medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT-treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro-immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated. PMID:26228482

  18. A New Approach to Reduce Toxicities and to Improve Bioavailabilities of Platinum-Containing Anti-Cancer Nanodrugs

    Liu, Li; Ye, Qing; Lu, Maggie; Lo, Ya-Chin; Hsu, Yuan-Hung; Wei, Ming-Cheng; Chen, Yu-Hsiang; Lo, Shen-Chuan; Wang, Shian-Jy; Bain, Daniel J.; Ho, Chien

    2015-01-01

    Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help th...

  19. Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models

    HogenEsch, Harm; Yu Nikitin, Alexander

    2012-01-01

    Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinic...

  20. Opening doors to treatment. Exploring the impact of lung cancer specialist nurses on access to anti-cancer treatment: an exploratory case study

    Tod, Angela; McDonnell, Ann; Redman, Judy

    2014-01-01

    This exploratory study examined how different Lung Cancer Nurse Specialists (LCNS) worked within their Multi-disciplinary Teams (MDT) to have a positive impact on patient access to anti-cancer treatment. The study used a mix of qualitative methods including individual and group interviews, observation and documentary analysis. The project was developed in response to the finding from the National Lung Cancer Audit (2010) that 64% of patients who saw a LCNS received anti-cancer treatment, ...

  1. Aptamers: A Feasible Technology in Cancer Immunotherapy

    Villanueva, H.; Pastor, F.

    2016-01-01

    Aptamers are single-chained RNA or DNA oligonucleotides (ODNs) with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy. PMID:27413756

  2. 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).

    Penthala, Narsimha Reddy; Ketkar, Amit; Sekhar, Konjeti R; Freeman, Michael L; Eoff, Robert L; Balusu, Ramesh; Crooks, Peter A

    2015-11-15

    In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 μM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 μM. Analog 7 i also exhibited GI50 values <0.35 μM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 μM and 3.3 μM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. PMID:26602084

  3. [The reaction of the T-immunity system in patients with malignant skin melanoma and stomach cancer to active nonspecific immunotherapy].

    Glinkina, L S; Bruvere, R Zh

    1992-01-01

    Changes in E-receptor-bearing T-lymphocyte level (total and that of active T-lymphocytes) were studied in peripheral blood and resected material obtained from skin malignant melanoma and gastric cancer patients treated with rigvir, an original immunomodulator of the viral origin. Injection of rigvir into peripheral blood was followed by an increase in active T-lymphocyte level and stimulated their migration into tumor. The latter was determined by stage and rate of tumor advancement. PMID:1300766

  4. A SIMPLE METHOD FOR ISOLATION OF SOME BACILLUS STRAINS WITH AN EXPRESSED ANTI-CANCER ACTIVITY

    Francesco Marotta

    2006-02-01

    Full Text Available ABSTRACT:There is now increasing evidence that probiotic bacteria can provide health benefits to humans. In many areas of medicine (gastroenterology, urology, allergology, oncology and others, these sanative microorganisms may be considered as possible and viable alternatives applicable to patient care. Particularly, we have found that oral administration of Bacillus oligonitrophilus KU-1 cells can be used for treatment and prevention of some tumors. Here we present a simple method for isolation of bacteria with anticancer properties from soil.RESUMEN:Está aumentando la evidencia de que hay bacterias probióticas que pueden proporcionar beneficios saludables a los seres humanos. En muchas áreas de la medicina (gastroenterología, urología, alergología, oncología y otras, estos microorganismos pueden considerarse como alternativas posibles y viables aplicables al cuidado del paciente. Particularmente, nosotros hemos encontrado que la administración oral de células KU-1 Bacillus oligonitrophilus puede ser utilizada para el tratamiento y la prevención de algunos tumores. Aquí presentamos un método simple para aislamiento de suelos, de bacterias con características anticáncer.

  5. Synthesis of Thiophene and NO-Curcuminoids for Antiinflammatory and Anti-Cancer Activities

    Kim Drummond Rainsford

    2013-01-01

    Full Text Available In search of better NSAIDs four novel nitric oxide donating derivatives of curcumin (compounds 9a–d, and four thiophene curcuminoids (compounds 10a–c, 11 have been synthesised. The cytotoxic effects of these compounds along with the lead compound curcumin (7 and their effect on the production of the reactive oxygen species nitric oxide and pro-inflammatory cytokines IL-1β, TNF-α and chemokine CXCL-8 were evaluated using human monocytic THP-1 and colon adenocarcinoma CACO-2 cell lines. All of the nitric oxide donating curcuminoids 9a–d and the thiophene curcuminoids 10a–c and 11 were non-cytotoxic to THP-1 cells over a concentration range of 10-100 μM and compared with curcumin compounds 10b and 10c, were more toxic. In CACO-2 cells, 10b and 11 appeared to be non-toxic at 10 to 50 μM, whereas 10a and 10c were non-cytotoxic at 10 μM only. These results clearly indicate that the introduction of a nitroxybutyl moiety to curcumin and replacement of phenyl rings with thiophene units reduces the cytotoxic effect of the parent curcumin, whereas a methyl substituted thiophene increases the cytotoxic effects. In THP-1 cells, drugs 10a and 11 significantly decreased IL-1-β production at their non-cytotoxic concentrations, whereas, they did not decrease TNF-α production in CACO-2 cells. Compound 11 showed a significant decrease in CXCL-8 production.

  6. Preparation and anti-cancer activity of polymer-encapsulated curcumin nanoparticles

    Thu Ha, Phuong; Huong Le, Mai; Nhung Hoang, Thi My; Thu Huong Le, Thi; Quang Duong, Tuan; Tran, Thi Hong Ha; Tran, Dai Lam; Phuc Nguyen, Xuan

    2012-09-01

    Curcumin (Cur) is a yellow compound isolated from rhizome of the herb curcuma longa. Curcumin possesses antioxidant, anti-inflammatory, anti-carcinogenic and antimicrobial properties, and suppresses proliferation of many tumor cells. However, the clinical application of curcumin in cancer treatment is considerably limited due to its serious poor delivery characteristics. In order to increase the hydrophilicity and drug delivery capability, we encapsulated curcumin into copolymer PLA-TPGS, 1,3-beta-glucan (Glu), O-carboxymethyl chitosan (OCMCs) and folate-conjugated OCMCs (OCMCs-Fol). These polymer-encapsulated curcumin nanoparticles (Cur-PLA-TPGS, Cur-Glu, Cur-OCMCs and Cur-OCMCs-Fol) were characterized by infrared (IR), fluorescence (FL), photoluminescence (PL) spectra, field emission scanning electron microscopy (FE-SEM), and found to be spherical particles with an average size of 50–100 nm, being suitable for drug delivery applications. They were much more soluble in water than not only free curcumin but also other biodegradable polymer-encapsulated curcumin nanoparticles. The anti-tumor promoting assay was carried out, showing the positive effects of Cur-Glu and Cur-PLA-TPGS on tumor promotion of Hep-G2 cell line in vitro. Confocal microscopy revealed that the nano-sized curcumin encapsulated by polymers OCMCs and OCMCs-Fol significantly enhanced the cellular uptake (cancer cell HT29 and HeLa).

  7. Potential Anti-cancer and Anti-bacterial Activities of Philippine Echinoderm Extracts

    Rodyl J. Layson; Maria Criselda A. Rodil; Elmer-Rico E. Mojica; Custer C. Deocaris

    2014-01-01

    In high-throughput search for bioactive compounds under resource-limited settings from Philippine echinoderms, the aqueous, methanol, chloroform and hexane extracts of seven Philippine echinoderms namely Holothuria nobilis (sea cucumber), Bohadscia marmorata (sea cucumber), Stichopus chloronatus (sea cucumber), Holothuria axiologa (sea cucumber), Linckia laevigata (starfish), Oreaster nodusus (starfish) and Ophiocoma ochoenleinii (brittle star) were screened for antitumor and antibacterial a...

  8. Preparation and anti-cancer activity of polymer-encapsulated curcumin nanoparticles

    Curcumin (Cur) is a yellow compound isolated from rhizome of the herb curcuma longa. Curcumin possesses antioxidant, anti-inflammatory, anti-carcinogenic and antimicrobial properties, and suppresses proliferation of many tumor cells. However, the clinical application of curcumin in cancer treatment is considerably limited due to its serious poor delivery characteristics. In order to increase the hydrophilicity and drug delivery capability, we encapsulated curcumin into copolymer PLA-TPGS, 1,3-beta-glucan (Glu), O-carboxymethyl chitosan (OCMCs) and folate-conjugated OCMCs (OCMCs-Fol). These polymer-encapsulated curcumin nanoparticles (Cur-PLA-TPGS, Cur-Glu, Cur-OCMCs and Cur-OCMCs-Fol) were characterized by infrared (IR), fluorescence (FL), photoluminescence (PL) spectra, field emission scanning electron microscopy (FE-SEM), and found to be spherical particles with an average size of 50–100 nm, being suitable for drug delivery applications. They were much more soluble in water than not only free curcumin but also other biodegradable polymer-encapsulated curcumin nanoparticles. The anti-tumor promoting assay was carried out, showing the positive effects of Cur-Glu and Cur-PLA-TPGS on tumor promotion of Hep-G2 cell line in vitro. Confocal microscopy revealed that the nano-sized curcumin encapsulated by polymers OCMCs and OCMCs-Fol significantly enhanced the cellular uptake (cancer cell HT29 and HeLa). (paper)

  9. Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress-mediated apoptosis in non-small cell lung cancer cells

    Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC

  10. Enhanced osteoblast adhesion on nanostructured selenium compacts for anti-cancer orthopedic applications

    Phong Tran

    2008-10-01

    Full Text Available Phong Tran1, Thomas J Webster21Physics Department; 2Division of Engineering and Department of Orthopedics, Brown University, Providence, USAAbstract: Metallic bone implants possess numerous problems limiting their long-term efficacy, such as poor prolonged osseointegration, stress shielding, and corrosion under in vivo environments. Such problems are compounded for bone cancer patients since numerous patients receive orthopedic implants after cancerous bone resection. Unfortunately, current orthopedic materials were not originally developed to simultaneously increase healthy bone growth (as in traditional orthopedic implant applications while inhibiting cancerous bone growth. The long-term objective of the present research is to investigate the use of nano-rough selenium to prevent bone cancer from re-occurring while promoting healthy bone growth for this select group of cancer patients. Selenium is a well known anti-cancer chemical. However, what is not known is how healthy bone cells interact with selenium. To determine this, selenium, spherical or semispherical shots, were pressed into cylindrical compacts and these compacts were then etched using 1N NaOH to obtain various surface structures ranging from the micron, submicron to nano scales. Changes in surface chemistry were also analyzed. Through these etching techniques, results of this study showed that biologically inspired surface roughness values were created on selenium compacts to match that of natural bone roughness. Moreover, results showed that healthy bone cell adhesion increased with greater nanometer selenium roughness (more closely matching that of titanium. In this manner, this study suggests that nano-rough selenium should be further tested for orthopedic applications involving bone cancer treatment.Keywords: selenium, nano-rough, osteoblast, cancer, chemopreventive

  11. Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions

    Boss, Anna; Bishop, Karen S.; Marlow, Gareth; Barnett, Matthew P. G.; Ferguson, Lynnette R.

    2016-01-01

    The traditional Mediterranean diet (MD) is associated with long life and lower prevalence of cardiovascular disease and cancers. The main components of this diet include high intake of fruit, vegetables, red wine, extra virgin olive oil (EVOO) and fish, low intake of dairy and red meat. Olive oil has gained support as a key effector of health benefits and there is evidence that this relates to the polyphenol content. Olive leaf extract (OLE) contains a higher quantity and variety of polyphenols than those found in EVOO. There are also important structural differences between polyphenols from olive leaf and those from olive fruit that may improve the capacity of OLE to enhance health outcomes. Olive polyphenols have been claimed to play an important protective role in cancer and other inflammation-related diseases. Both inflammatory and cancer cell models have shown that olive leaf polyphenols are anti-inflammatory and protect against DNA damage initiated by free radicals. The various bioactive properties of olive leaf polyphenols are a plausible explanation for the inhibition of progression and development of cancers. The pathways and signaling cascades manipulated include the NF-κB inflammatory response and the oxidative stress response, but the effects of these bioactive components may also result from their action as a phytoestrogen. Due to the similar structure of the olive polyphenols to oestrogens, these have been hypothesized to interact with oestrogen receptors, thereby reducing the prevalence and progression of hormone related cancers. Evidence for the protective effect of olive polyphenols for cancer in humans remains anecdotal and clinical trials are required to substantiate these claims idea. This review aims to amalgamate the current literature regarding bioavailability and mechanisms involved in the potential anti-cancer action of olive leaf polyphenols. PMID:27548217

  12. Oncolytic viruses: a step into cancer immunotherapy

    Pol JG

    2011-12-01

    Full Text Available Jonathan G Pol, Julien Rességuier, Brian D LichtyMcMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, CanadaAbstract: Oncolytic virotherapy is currently under investigation in phase I–III clinical trials for approval as a new cancer treatment. Oncolytic viruses (OVs selectively infect, replicate in, and kill tumor cells. For a long time, the therapeutic efficacy was thought to depend on the direct viral oncolysis (virocentric view. The host immune system was considered as a brake that impaired virus delivery and spread. Attention was paid primarily to approaches enhancing virus tumor selectivity and cytotoxicity and/or that limited antiviral responses. Thinking has changed over the past few years with the discovery that OV therapy was also inducing indirect oncolysis mechanisms. Among them, induction of an antitumor immunity following OV injection appeared to be a key factor for an efficient therapeutic activity (immunocentric view. Indeed, tumor-specific immune cells persist post-therapy and can search and destroy any tumor cells that escape the OVs, and thus immune memory may prevent relapse of the disease. Various strategies, which are summarized in this manuscript, have been developed to enhance the efficacy of OV therapy with a focus on its immunotherapeutic aspects. These include genetic engineering and combination with existing cancer treatments. Several are currently being evaluated in human patients and already display promising efficacy.Keywords: oncolytic virus, cancer immunotherapy, tumor antigen, cancer vaccine, combination strategies

  13. Melanoma immunotherapy dominates the field.

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  14. Immunotherapy in Sarcoma: Future Horizons.

    Burgess, Melissa; Gorantla, Vikram; Weiss, Kurt; Tawbi, Hussein

    2015-11-01

    Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions. From Coley's toxin to cytokine-based therapies to adoptive cell therapy, there have been numerous immunotherapeutic investigations in this patient population. A promising strategy includes adoptive T cell therapy which has been studied in small cohorts of synovial sarcoma, a subtype that is known to widely express the cancer testis antigen, NY-ESO-1. Additionally, recent data in metastatic melanoma and renal cell carcinoma demonstrate the utility and tremendous efficacy of immune checkpoint blockade with increased rates of durable responses compared to standard therapies. Responses in traditionally "non-immunogenic" tumors, such as lung and bladder cancers, provide ample rationale for the study of immune checkpoint inhibitors in sarcoma. While immunotherapy has induced some responses in sarcomas, further research will help clarify optimal patient selection for future clinical trials and new combinatorial immunotherapeutic strategies. PMID:26423769

  15. Mechanisms of subcutaneous allergen immunotherapy.

    Soyer, Ozge U; Akdis, Mubeccel; Akdis, Cezmi A

    2011-05-01

    Allergen-specific immunotherapy (SIT) is the only curative approach in the treatment of allergic diseases defined up-to-date. Peripheral T-cell tolerance to allergens, the goal of successful allergen-SIT, is the primary mechanism in healthy immune responses to allergens. By repeated administration of increased doses of the causative allergen, allergen-SIT induces a state of immune tolerance to allergens through the constitution of T regulatory (Treg) cells, including allergen-specific interleukin (IL)-10-secreting Treg type 1 cells and CD4(+)CD25(+)Treg cells; induction of suppressive cytokines, such as IL-10 and transforming growth factor β; suppression of allergen-specific IgE and induction of IgG4 and IgA; and suppression of mast cells, basophils, eosinophils, and inflammatory dendritic cells. This review summarizes the current knowledge on the mechanisms of allergen-SIT with emphasis on the roles of Treg cells in allergen-SIT. PMID:21530813

  16. New routes for allergen immunotherapy.

    Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M; Senti, Gabriela

    2012-10-01

    IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review. PMID:23095873

  17. Immunotherapy in renal cell carcinoma.

    Bukowski, R M

    1999-06-01

    Patients with metastatic renal cell carcinoma continue to present a therapeutic challenge. Current therapeutic approaches involve surgery and various types of immunotherapy. The rationale for this latter form of therapy include the observations of spontaneous tumor regression, the presence of a T-cell-mediated immune response, and the tumor responses observed in patients receiving cytokine therapy. Analysis of prognostic factors in these patients demonstrates that clinical responses occur most frequently in individuals with good performance status. The cytokines interleukin-2 (IL-2, aldesleukin [Proleukin], interferon-alfa (Intron A, Roferon-A), or the combination produce responses in 15% to 20% of patients. Randomized trials suggest that administration of interferon-alfa may result in a modest improvement in median survival. Investigation of the molecular genetics of renal cell carcinoma and the presence of T-lymphocyte immune dysregulation have suggested new therapeutic strategies. Further preclinical and clinical studies investigating inhibitors of angiogenesis or pharmacologic methods to reverse immune dysregulation are ongoing. Therapeutic results in patients with renal cell carcinoma remain limited, and investigational approaches are warranted. PMID:10378218

  18. The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not qualitatively superior to that of other IgG subclasses

    Ejrnaes, Anne M; Bødtger, Uffe; Larsen, Jørgen N; Svenson, Morten

    2004-01-01

    for the clinical efficacy of SIT. In this study, fractionated serum samples from 14 SIT-treated birch pollen allergic individuals enabled determination of the inhibitory capacity of IgG4 alone versus non-IgG4 IgG. Allergen-binding activities of IgG and the IgG-mediated inhibition of allergen binding...... to autologous IgE were detected using 125I-labelled rBet v 1.2801, a recombinant variant of the major allergen of Betula verrucosa pollen. Results show that IgG4-depletion resulted in equivalent reductions in binding and blocking activities. In contrast, a significant but less than two-fold higher...

  19. Towards immunotherapy with redirected T cells in a large animal model: Ex vivo activation, expansion, and genetic modification of canine T cells

    Mata, Melinda; Vera, Juan; Gerken, Claudia; Rooney, Cliona M; Miller, Tasha; Pfent, Catherine; Wang, Lisa L.; Wilson-Robles, Heather M.; Gottschalk, Stephen

    2014-01-01

    Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising anti-tumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells we developed expans...

  20. Monocyte-derived dendritic cells are essential for CD8+ T cell activation and anti-tumor responses after local immunotherapy

    Sabine eKuhn; Jianping eYang; F eRonchese

    2015-01-01

    Tumors harbor several populations of dendritic cells with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate anti-tumor immune responses, and is associated with the appearance of a population of monocyte-derived dendritic cells in the tumor and tumor-draining lymph node. Here we use dendr...

  1. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

    Yamamoto, N; Naraparaju, V R

    1997-06-01

    Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90

  2. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers.

    Bao, Bin; Azmi, Asfar S; Ali, Shadan; Zaiem, Feras; Sarkar, Fazlul H

    2014-06-01

    Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. PMID:25333034

  3. Current Studies of Immunotherapy on Glioblastoma.

    Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N; DeCandio, Michele L; Vandergrift, W Alex; Varma, Abhay K; Patel, Sunil J; Banik, Naren L; Lindhorst, Scott M; Giglio, Pierre; Das, Arabinda

    2014-04-01

    Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it's in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials. PMID:25346943

  4. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    Sergio Arancibia

    Full Text Available Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH. This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH and the Concholepas hemocyanin (CCH. FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4(+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer

  5. Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

    Chi Zhang

    2015-01-01

    Full Text Available Background: Metabotropic glutamate receptors (mGluRs are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.

  6. Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells

    Hossain, Md. Motarab [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States); Banik, Naren L. [Department of Neurosciences, Medical University of South Carolina, Charleston, SC (United States); Ray, Swapan K., E-mail: swapan.ray@uscmed.sc.edu [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States)

    2012-08-01

    network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. -- Highlights: Black-Right-Pointing-Pointer Survivin shRNA + EGCG controlled growth of human malignant neuroblastoma cells. Black-Right-Pointing-Pointer Survivin knockdown induced neuronal differentiation in neuroblastoma cells. Black-Right-Pointing-Pointer Survivin shRNA + EGCG induced morphological and biochemical features of apoptosis. Black-Right-Pointing-Pointer Combination therapy inhibited invasion, proliferation, and angiogenesis as well. Black-Right-Pointing-Pointer So, combination therapy showed multiple anti-cancer mechanisms in neuroblastoma.

  7. A case of malignant melanoma of the maxilla treated by adoptive immunotherapy after fast neutron therapy

    A 77-year-old male patient with malignant melanoma was treated by fast neutron therapy and immunotherapy. Total dose of fast neutron applied to the primary lesion was 1905 cGy per 21 fractionation for 46 days. For adoptive immunotherapy, lymphocytes were collected from the peripheral blood drawn from the patient 2 days after the injection of cyclophosphamide. T cells were further purified by passing the lymphocytes through nylon wool. Cytotoxic T cells were induced by incubating the T cells mixed with allogeneic malignant melanoma cells and a small number of patient's adherent cells, and activated with recombinant interleukin-2 (γ IL-2). Our patient and the patient from whom stimulating melanoma cells were derived shared A locous 24 and B locous 51 of MHC class I antigens in common. Thus prepared cytotoxic T cells were inoculated to the patient via the maxillary artery, 3 to 4 times a week for one month. Total amount of cells transferred was 5.6 x 108 (97% lymphocytes). Primary lesion reduced markedly by the therapies. During adoptive immunotherapy, increase in natural killer cells and decrease in both suppressor/inducer T-cells and macrophages were observed. However, lung metastases appeared 3 months after adoptive immunotherapy. While the nonspecific immunotherapy (OK-432 injection) was being conducted thereafter, growth of the metastatic lesions of the lung was kept gentle but became obvious after the suspension of the treatment. (author)

  8. New Concepts in Tumor Antigens: Their Significance in Future Immunotherapies for Tumors

    Fan Yang; Xiao-Feng Yang

    2005-01-01

    The identification and molecular characterization of self-antigens expressed by human malignancies that are capable of elicitation of anti-tumor immune responses in patients have been an active field in tumor immunology.More than 2,000 tumor antigens have been identified, and most of these antigens are self-antigens. These significant progresses have led to the renaissance of tumor immunology and studies on anti-tumor immunotherapy.However, despite of the progress in the identification of self-tumor antigens, current antigen-specific immunotherapies for tumors are far less satisfied than expected, which reflects the urgent need to improve our understanding on self-tumor antigens. In order to develop more effective antigen specific anti-tumor immunotherapies and to monitor the responses to these immunotherapies in patients with tumors, many important fundamental questions need to be addressed. We propose for the first time that the studies in addressing the characteristics of self-tumor antigens and autoantigens are grouped as a new subject termed "antigenology". In this brief review, we would outline the progress in the identification of tumor antigens in solid tumors and hematologic malignancies, and overview the new concepts and principles of antigenology and their significance for future immunotherapies to these malignancies. Cellular & Molecular Immunology.

  9. Bioinformatics for cancer immunotherapy target discovery

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein;

    2014-01-01

    cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline......The mechanisms of immune response to cancer have been studied extensively and great effort has been invested into harnessing the therapeutic potential of the immune system. Immunotherapies have seen significant advances in the past 20 years, but the full potential of protective and therapeutic...... and co-targets for single-epitope and multi-epitope strategies. We provide examples of application to the well-known tumor antigen HER2 and suggest bioinformatics methods to ameliorate therapy resistance and ensure efficient and lasting control of tumors....

  10. Immunotherapy of murine sarcomas using lymphokine activated killer cells: optimization of the schedule and route of administration of recombinant interleukin-2

    Interleukin-2 (IL-2) at high doses or at low doses in concert with lymphokine-activated killer (LAK) cells can produce regression of established pulmonary and hepatic metastases from a variety of tumors in mice. IL-2 appears to mediate its antitumor effect through the generation of LAK cells in vivo from endogenous lymphocytes and by the stimulation of host and transferred LAK cell proliferation in tissues. In this paper we have investigated different strategies for IL-2 administration to determine which regimen produced maximal in vivo proliferation and optimal immunotherapeutic efficacy of LAK cells. Tissue expansion of lymphoid cells was assessed using an assay of in vivo labeling of dividing cells by the thymidine analogue, 5-[125I]iododeoxyuridine. The therapeutic effect of the different IL-2 administration protocols was determined by evaluating their efficacy in the treatment of established, 3-day pulmonary metastases from sarcomas in mice. The selection of IL-2 injection regimens for evaluation was based upon pharmacokinetic studies of IL-2 in mice. A single i.v. or i.p. dose yielded high peak IL-2 levels that could be measured for only a few hours after injection, while IL-2 given i.p. thrice daily produced titers that were detectable throughout the study periods (greater than or equal to 6 units/ml of serum after 100,000 units of IL-2 i.p. thrice daily). Using the proliferation and therapy models, we tested the same cumulative daily doses of IL-2 administered by i.v. or i.p. once daily, or i.p. thrice daily regimens. The i.p. thrice daily protocol stimulated greater lymphoid cell proliferation in the lungs, for example, than did the other regimens

  11. Assays for predicting and monitoring responses to lung cancer immunotherapy

    Teixidó, Cristina; Karachaliou, Niki; González-Cao, Maria; Morales-Espinosa, Daniela; Rosell, Rafael

    2015-01-01

    Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting ...

  12. Strategies of mucosal immunotherapy for allergic diseases

    Yi-Ling Ye; Ya-Hui Chuang; Bor-Luen Chiang

    2011-01-01

    Incidences of allergic disease have recently increased worldwide.Allergen-specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases.Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT),there remains a risk of severe and sometimes fatal anaphylaxis.Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration and lower side-effect profile.This study reviews recent progress in mucosal immunotherapy for allergic diseases.Administration routes,antigen quality and quantity,and adjuvants used are major considerations in this field.Also,direct uses of unique probiotics,or specific cytokines,have been discussed.Furthermore,some researchers have reported new therapeutic ideas that combine two or more strategies.The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation,which includes continuous searching for efficient adjuvants,collecting more information about dominant T-cell epitopes of allergens,and having the proper combination of each.In clinics,when compared to other mucosal routes,sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration,although local and systemic side effects have been reported.Additionally,not every allergen has the same beneficial effect.Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults.Data collected from large,well-designed,double-blind,placebo-controlled,and randomized trials,with post-treatment follow-up,can provide robust substantiation of current evidence.

  13. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2016-03-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

  14. Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

    Coelho, Rui Moura; Lemos, João Miranda; Alho, Irina; Valério, Duarte; Ferreira, Arlindo R; Costa, Luís; Vinga, Susana

    2016-02-21

    Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength. PMID:26657065

  15. Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells.

    Chon, Hae Jung; Lee, Yura; Bae, Kyoung Jun; Byun, Byung Jin; Kim, Soon Ae; Kim, Jiyeon

    2016-07-01

    Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase family. TNIK was first identified as a kinase that is involved in regulating cytoskeletal organization in many types of cells, and it was recently proposed as a novel therapeutic target in several types of human cancers. Although previous studies suggest that TNIK plays a pivotal role in cancer cell survival and prognosis, its function in hematological cancer cell survival has not been investigated. Here we investigated the relationship between TNIK function and cell viability in multiple myeloma IM-9 cells using TNIK small interfering RNA (siRNA) transfection and dovitinib treatment. Treatment of IM-9 cells with TNIK siRNA and dovitinib treatment reduced cell proliferation. The ATP competing kinase assay and western blot analysis showed that dovitinib strongly inhibited both the interaction of TNIK with ATP (K i, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induced caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs. Our results provide new evidence that TNIK may be involved in the proliferation of multiple myeloma IM-9 cells and in the anti-cancer activity of dovitinib via inhibition of the endogenous Wnt signaling pathway. PMID:26995282

  16. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies

  17. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    Tucker, Jo A.; Jochems, Caroline [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Gulley, James L. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Schlom, Jeffrey, E-mail: js141c@nih.gov; Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2012-12-11

    Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies.

  18. Simultaneous determination of the novel thiosemicarbazone anti-cancer agent, Bp4eT, and its main phase I metabolites in plasma: application to a pilot pharmacokinetic study in rats.

    Stariat, Ján; Suprunová, Vlasta; Roh, Jaroslav; Šesták, Vít; Eisner, Tomáš; Filipský, Tomáš; Mladěnka, Přemysl; Nobilis, Milan; Šimůnek, Tomáš; Klimeš, Jiří; Kalinowski, Danuta S; Richardson, Des R; Kovaříková, Petra

    2014-05-01

    Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 μM for Bp4eT, 0.02-0.37 μM for both M1-E and M1-Z, and 0.10-1.60 μM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. PMID:24254882

  19. The biochemical aftermath of anti-amyloid immunotherapy

    Nicoll James AR

    2010-10-01

    Full Text Available Abstract Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP transgenic mice and Alzheimer's Disease (AD patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792 and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques

  20. Benzene-Poly-Carboxylic Acid Complex, a Novel Anti-Cancer Agent Induces Apoptosis in Human Breast Cancer Cells

    Fares, Fuad; Azzam, Naiel; Fares, Basem; Larsen, Stig; Lindkaer-Jensen, Steen

    2014-01-01

    Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and ap...

  1. Immunomodulating anti-cancer chemotherapy based on HPMA conjugates with pH-controlled release of doxorubicin

    Mrkvan, Tomáš; Etrych, Tomáš; Chytil, Petr; Šírová, Milada; Strohalm, Jiří; Plocová, Daniela; Ulbrich, Karel; Říhová, Blanka

    Washington : Verlag, 2006, s. 1311-1311. [Annual Meeting 2006 American Association for Cancer Research /97./. Washington (US), 01.04.2006-05.04.2006] R&D Projects: GA ČR GD310/03/H147; GA ČR GA305/02/1425; GA AV ČR IAA4050201 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : anti-tumor immunity * anti- cancer therapy * doxorubicin Subject RIV: EE - Microbiology, Virology

  2. Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer

    Wei, Tzu-Tang; Lin, Yu-Chin; Lin, Pei-Hua; Shih, Jin-Yuan; Chou, Chia-Wei; Huang, Wei-Jan; Yang, Yu-Chih; Hsiao, Pei-Wen; Chen, Ching-Chow

    2015-01-01

    Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens. HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl. Ectopic expression of c-Cbl induced decreased EGFR, inhibited growth in NSCLC cells. Knockdown of EGFR inhibited NSCLC growth. Mutation of EGFR at Y1045 decreased WJ-induced growth inhibition as well as in vivo anti-cancer effect and EGFR degradation medi...

  3. Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055.

    Dueregger, Andrea; Guggenberger, Fabian; Barthelmes, Jan; Stecher, Günther; Schuh, Markus; Intelmann, Daniel; Abel, Gudrun; Haunschild, Jutta; Klocker, Helmut; Ramoner, Reinhold; Sampson, Natalie

    2013-11-15

    This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport. PMID:23972793

  4. Role of IL-2 in cancer immunotherapy.

    Jiang, Tao; Zhou, Caicun; Ren, Shengxiang

    2016-06-01

    Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL-2 in cancer immunotherapy. PMID:27471638

  5. Sublingual Immunotherapy for Allergic Fungal Sinusitis.

    Melzer, Jonathan M; Driskill, Brent R; Clenney, Timothy L; Gessler, Eric M

    2015-10-01

    Allergic fungal sinusitis (AFS) is a condition that has an allergic basis caused by exposure to fungi in the sinonasal tract leading to chronic inflammation. Despite standard treatment modalities, which typically include surgery and medical management of allergies, patients still have a high rate of recurrence. Subcutaneous immunotherapy (SCIT) has been used as adjuvant treatment for AFS. Evidence exists to support the use of sublingual immunotherapy (SLIT) as a safe and efficacious method of treating allergies, but no studies have assessed the utility of SLIT in the management of allergic fungal sinusitis. A record review of cases of AFS that are currently or previously treated with sublingual immunotherapy from 2007 to 2011 was performed. Parameters of interest included serum IgE levels, changes in symptoms, Lund-McKay scores, decreased sensitization to fungal allergens associated with AFS, and serum IgE levels. Ten patients with diagnosed AFS were treated with SLIT. No adverse effects related to the use of SLIT therapy were identified. Decreases in subjective complaints, exam findings, Lund-McKay scores, and serum IgE levels were observed. Thus, sublingual immunotherapy appears to be a safe adjunct to the management of AFS that may improve patient outcomes. PMID:25902841

  6. Steroids vs immunotherapy for allergic rhinitis

    Aasbjerg, Kristian; Backer, Vibeke

    2014-01-01

    Treatment for seasonal allergic rhinitis induced by airborne allergens can be divided into two major groups: symptom-dampening drugs, such as antihistamines and corticosteroids, and disease-modifying drugs in the form of immunotherapy. It has been speculated that depot-injection corticosteroids g...

  7. Topical immunotherapy with diphenylcyclopropenone-induced vitiligo.

    Kutlubay, Zekayi; Engin, Burhan; Songur, Abdullah; Serdaroglu, Server; Tuzun, Yalcin

    2016-08-01

    Topical immunotherapy made by diphenylcyclopropenone (DPCP) is an alternative treatment that can be used safely and efficaciously in recalcitrant alopecia areata patients. DPCP-induced vitiligo is a rare, but documented, unwanted side effect. The real mechanism of DPCP-induced vitiligo is not well known. PMID:26963903

  8. Plasma Onco-Immunotherapy: Novel Approach to Cancer Treatment

    Fridman, Alexander

    2015-09-01

    Presentation is reviewing the newest results obtained by researchers of A.J. Drexel Plasma Institute on direct application of non-thermal plasma for direct treatment of different types of cancer by means of specific stimulation of immune system in the frameworks of the so-called onco-immunotherapy. Especial attention is paid to analysis of depth of penetration of different plasma-medical effects, from ROS, RNS, and ions to special biological signaling and immune system related processes. General aspects of the plasma-stimulation of immune system are discussed, pointing out specific medical applications. Most of experiments have been carried out using nanosecond pulsed DBD at low power and relatively low level of treatment doses, guaranteeing non-damage no-toxicity treatment regime. The nanosecond pulsed DBD physics is discussed mostly regarding its space uniformity and control of plasma parameters relevant to plasma medical treatment, and especially relevant to depth of penetration of different plasma medical effects. Detailed mechanism of the plasma-induced onco-immunotherapy has been suggested based upon preliminary in-vitro experiments with DBD treatment of different cancer cells. Sub-elements of this mechanism related to activation of macrophages and dendritic cells, specific stressing of cancer cells and the immunogenic cell death (ICD) are to be discussed based on results of corresponding in-vitro experiments. In-vivo experiments focused on the plasma-induced onco-immunotherapy were carried out in collaboration with medical doctors from Jefferson University hospital of Philadelphia. Todays achievements and nearest future prospective of clinical test focused on plasma-controlled cancer treatment are discussed in conclusion.

  9. THE JOURNAL OF TROPICAL LIFE SCIENCE OPEN ACCESS Freely available online VOL. 5, NO. 2, pp. 88-91, May, 2015 Isolation of an Anti-Cancer Asperuloside from Hedyotis corymbosa L.

    Nina Artanti

    2015-05-01

    Full Text Available Hedyotis corymbosa L., with local name rumput mutiara, is an anti-inflammatory, anti-cancer and hepatoprotective traditional medicine. The ethanol extract of H. corymbosa L. shows inhibitory activity to humanYMB-1 breast cancer cell line with an IC50 of 6.51 μg/mL. The methylene chloride fraction shows a potential cytotoxic activity with an IC50 of 2.75 μg/mL. To obtain a lead compound, the extract was further purified by column chromatography. A pure compound is obtained which shows inhibitory activities against YMB-1, HL60 and KB human cell lines with IC50 values of 0.7; 11.0 and 104.2 μg/mL, respectively. Based on the 1D and 2D FT-NMR data, the isolated compound is an asperuloside.

  10. Anti-cancer drug loaded iron-gold core-shell nanoparticles (Fe@Au) for magnetic drug targeting.

    Kayal, Sibnath; Ramanujan, Raju Vijayaraghavan

    2010-09-01

    Magnetic drug targeting, using core-shell magnetic carrier particles loaded with anti-cancer drugs, is an emerging and significant method of cancer treatment. Gold shell-iron core nanoparticles (Fe@Au) were synthesized by the reverse micelle method with aqueous reactants, surfactant, co-surfactant and oil phase. XRD, XPS, TEM and magnetic property measurements were utilized to characterize these core-shell nanoparticles. Magnetic measurements showed that the particles were superparamagnetic at room temperature and that the saturation magnetization decreased with increasing gold concentration. The anti-cancer drug doxorubicin (DOX) was loaded onto these Fe@Au nanoparticle carriers and the drug release profiles showed that upto 25% of adsorbed drug was released in 80 h. It was found that the amine (-NH2) group of DOX binds to the gold shell. An in vitro apparatus simulating the human circulatory system was used to determine the retention of these nanoparticle carriers when exposed to an external magnetic field. A high percentage of magnetic carriers could be retained for physiologically relevant flow speeds of fluid. The present findings show that DOX loaded gold coated iron nanoparticles are promising for magnetically targeted drug delivery. PMID:21133071

  11. {sup 99m}Tc-HYNIC-Annexin A5 in Oncology: Evaluating Efficacy of Anti-Cancer Therapies

    Schaper, Frédéric L.W.V.J.; Reutelingsperger, Chris P., E-mail: c.reutelingsperger@maastrichtuniversity.nl [Department of Biochemistry, Cardiovascular Research Institute Maastricht, MUMC, Universiteitssingel 50, 6200 MD Maastricht (Netherlands)

    2013-05-15

    Evaluation of efficacy of anti-cancer therapy is currently performed by anatomical imaging (e.g., MRI, CT). Structural changes, if present, become apparent 1–2 months after start of therapy. Cancer patients thus bear the risk to receive an ineffective treatment, whilst clinical trials take a long time to prove therapy response. Both patient and pharmaceutical industry could therefore profit from an early assessment of efficacy of therapy. Diagnostic methods providing information on a functional level, rather than a structural, could present the solution. Recent technological advances in molecular imaging enable in vivo imaging of biological processes. Since most anti-cancer therapies combat tumors by inducing apoptosis, imaging of apoptosis could offer an early assessment of efficacy of therapy. This review focuses on principles of and clinical experience with molecular imaging of apoptosis using Annexin A5, a widely accepted marker for apoptosis detection in vitro and in vivo in animal models. {sup 99m}Tc-HYNIC-Annexin A5 in combination with SPECT has been probed in clinical studies to assess efficacy of chemo- and radiotherapy within 1–4 days after start of therapy. Annexin A5-based functional imaging of apoptosis shows promise to offer a personalized medicine approach, now primarily used in genome-based medicine, applicable to all cancer patients.

  12. 99mTc-HYNIC-Annexin A5 in Oncology: Evaluating Efficacy of Anti-Cancer Therapies

    Evaluation of efficacy of anti-cancer therapy is currently performed by anatomical imaging (e.g., MRI, CT). Structural changes, if present, become apparent 1–2 months after start of therapy. Cancer patients thus bear the risk to receive an ineffective treatment, whilst clinical trials take a long time to prove therapy response. Both patient and pharmaceutical industry could therefore profit from an early assessment of efficacy of therapy. Diagnostic methods providing information on a functional level, rather than a structural, could present the solution. Recent technological advances in molecular imaging enable in vivo imaging of biological processes. Since most anti-cancer therapies combat tumors by inducing apoptosis, imaging of apoptosis could offer an early assessment of efficacy of therapy. This review focuses on principles of and clinical experience with molecular imaging of apoptosis using Annexin A5, a widely accepted marker for apoptosis detection in vitro and in vivo in animal models. 99mTc-HYNIC-Annexin A5 in combination with SPECT has been probed in clinical studies to assess efficacy of chemo- and radiotherapy within 1–4 days after start of therapy. Annexin A5-based functional imaging of apoptosis shows promise to offer a personalized medicine approach, now primarily used in genome-based medicine, applicable to all cancer patients

  13. 99mTc-HYNIC-Annexin A5 in Oncology: Evaluating Efficacy of Anti-Cancer Therapies

    Chris P. Reutelingsperger

    2013-05-01

    Full Text Available Evaluation of efficacy of anti-cancer therapy is currently performed by anatomical imaging (e.g., MRI, CT. Structural changes, if present, become apparent 1–2 months after start of therapy. Cancer patients thus bear the risk to receive an ineffective treatment, whilst clinical trials take a long time to prove therapy response. Both patient and pharmaceutical industry could therefore profit from an early assessment of efficacy of therapy. Diagnostic methods providing information on a functional level, rather than a structural, could present the solution. Recent technological advances in molecular imaging enable in vivo imaging of biological processes. Since most anti-cancer therapies combat tumors by inducing apoptosis, imaging of apoptosis could offer an early assessment of efficacy of therapy. This review focuses on principles of and clinical experience with molecular imaging of apoptosis using Annexin A5, a widely accepted marker for apoptosis detection in vitro and in vivo in animal models. 99mTc-HYNIC-Annexin A5 in combination with SPECT has been probed in clinical studies to assess efficacy of chemo- and radiotherapy within 1–4 days after start of therapy. Annexin A5-based functional imaging of apoptosis shows promise to offer a personalized medicine approach, now primarily used in genome-based medicine, applicable to all cancer patients.

  14. 99mTc-HYNIC-Annexin A5 in Oncology: Evaluating Efficacy of Anti-Cancer Therapies.

    Schaper, Frédéric L W V J; Reutelingsperger, Chris P

    2013-01-01

    Evaluation of efficacy of anti-cancer therapy is currently performed by anatomical imaging (e.g., MRI, CT). Structural changes, if present, become apparent 1-2 months after start of therapy. Cancer patients thus bear the risk to receive an ineffective treatment, whilst clinical trials take a long time to prove therapy response. Both patient and pharmaceutical industry could therefore profit from an early assessment of efficacy of therapy. Diagnostic methods providing information on a functional level, rather than a structural, could present the solution. Recent technological advances in molecular imaging enable in vivo imaging of biological processes. Since most anti-cancer therapies combat tumors by inducing apoptosis, imaging of apoptosis could offer an early assessment of efficacy of therapy. This review focuses on principles of and clinical experience with molecular imaging of apoptosis using Annexin A5, a widely accepted marker for apoptosis detection in vitro and in vivo in animal models. 99mTc-HYNIC-Annexin A5 in combination with SPECT has been probed in clinical studies to assess efficacy of chemo- and radiotherapy within 1-4 days after start of therapy. Annexin A5-based functional imaging of apoptosis shows promise to offer a personalized medicine approach, now primarily used in genome-based medicine, applicable to all cancer patients. PMID:24216991

  15. Prospects in the development of natural radioprotective therapeutics with anti-cancer properties from the plants of Uttarakhand region of India.

    Painuli, Sakshi; Kumar, Navin

    2016-03-01

    Radioprotective agents are substances those reduce the effects of radiation in healthy tissues while maintaining the sensitivity to radiation damage in tumor cells. Due to increased awareness about radioactive substances and their fatal effects on human health, radioprotective agents are now the topic of vivid research. Scavenging of free radicals is the most common mechanism in oncogenesis that plays an important role in protecting tissues from lethal effect of radiation exposure therefore radioprotectors are also good anti-cancer agents. There are numerous studies indicating plant-based therapeutics against cancer and radioprotection. Such plants could be further explored for developing them as promising natural radioprotectors with anti-cancer properties. This review systematically presents information on plants having radioprotective and anti-cancer properties. PMID:27240731

  16. Advances in immunotherapy for non-small cell lung cancer.

    Reckamp, Karen L

    2015-12-01

    In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy. PMID:27058851

  17. Devitalization as a special surgical tumour treatment inducing anti-cancer response - sn experimental study in two animal models

    Horák, Vratislav; Morávková, Alena; Strnádel, Ján; Hradecký, Jan; Usvald, Dušan; Vannucci, Luca

    Mainz : Association for Immunotherapy of Cancer , 2008. s. 65-65. [Annual Meeting of CIMT /6./. 15.05.2008-16.05.2008, Mainz] R&D Projects: GA ČR GA524/04/0102; GA AV ČR IAA600450601 Institutional research plan: CEZ:AV0Z50450515 Keywords : devitalization Subject RIV: FD - Oncology ; Hematology

  18. [Psychological aspects of immunotherapies in the treatment of malignant melanoma].

    Kovács, Péter; Pánczél, Gitta; Melegh, Krisztina; Balatoni, Tímea; Pörneczy, Edit; Lõrincz, Lenke; Czirbesz, Kata; Gorka, Eszter; Liszkay, Gabriella

    2016-03-01

    Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires

  19. Evolutionary relationships of Aurora kinases: Implications for model organism studies and the development of anti-cancer drugs

    Patrick Denis R

    2004-10-01

    Full Text Available Abstract Background As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. Results Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. Conclusions In

  20. Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

    Forero Ivan

    2012-05-01

    Full Text Available Abstract Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1 the most promising combinations found in the laboratory; 2 early success of combination immunotherapy in clinical trials; 3 industry perspectives on combination approaches, and 4 relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer

  1. Workshop on immunotherapy combinations. Society for Immunotherapy of Cancer annual meeting Bethesda, November 3, 2011.

    Martinez Forero, Ivan; Okada, Hideho; Topalian, Suzanne L; Gajewski, Thomas F; Korman, Alan J; Melero, Ignacio

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace. PMID

  2. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

    Eliška Potůčková

    Full Text Available Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT, demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma, non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1 promote the redox cycling of iron; (2 bind and mobilize iron from labile intracellular pools; and (3 prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.

  3. Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions

    Montoya, Iván D.

    2008-01-01

    Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders. PMID:18551223

  4. Potentiating Cancer Immunotherapy Using Papaya Mosaic Virus-Derived Nanoparticles.

    Lebel, Marie-Ève; Chartrand, Karine; Tarrab, Esther; Savard, Pierre; Leclerc, Denis; Lamarre, Alain

    2016-03-01

    The recent development of novel immunotherapies is revolutionizing cancer treatment. These include, for example, immune checkpoint blockade, immunomodulation, or therapeutic vaccination. Although effective on their own, combining multiple approaches will most likely be required in order to achieve the maximal therapeutic benefit. In this regard, the papaya mosaic virus nanoparticle (PapMV) has shown tremendous potential as (i) an immunostimulatory molecule, (ii) an adjuvant, and (iii) a vaccine platform through its intrinsic capacity to activate the innate immune response in an IFN-α-dependent manner. Here, we demonstrate that intratumor administration of PapMV significantly slows down melanoma progression and prolongs survival. This correlates with enhanced chemokine and pro-inflammatory-cytokine production in the tumor and increased immune-cell infiltration. Proportions of total and tumor-specific CD8(+) T cells dramatically increase following PapMV treatment whereas those of myeloid-derived suppressor cells (MDSC) concomitantly decrease. Moreover, systemic PapMV administration prevents metastatic tumor-implantation in the lungs. Importantly, PapMV also synergistically improves the therapeutic benefit of dendritic cell (DC)-based vaccination and PD-1 blockade by potentiating antitumor immune responses. This study illustrates the immunostimulatory potential of a plant virus-derived nanoparticle for cancer therapy either alone or in conjunction with other promising immunotherapies in clinical development. PMID:26891174

  5. Immunotherapy with irradiated tumour cells and BCG in experimental osteosarcoma

    The effects of immunotherapy with irradiated tumour cells and BCG were studied in a non-metastasizing variety of the Dunn osteosarcoma transplantable in mice. Experimental animals which had been preimmunized with three injections of 0.7 to 1.4 x 106 irradiated tumour cells each 1 to 3 weeks before administration of 1 x 106 living tumour cells, showed a tumour incidence of 23 per cent. This was significantly (P<0.005) lower than the 92 per cent tumour incidence in the control animals. Non-specific immunotherapy with BCG given subcutaneously at a dose of 1.0 mg of dry-weight bacterial mass three times at 3-weeks intervals was found to have no protective effect against the osteosarcoma. The tumour incidence was 90 per cent for BCG-treated and 94 per cent for control animals. The osteosarcomas were studied light and electron microscopically and also with regard to the histochemical alkaline phosphatase activity. No structural difference was found between the tumours of the various groups. The demonstrated immunotherapeutic response is in contrast o the low degree of immunogenicity of the osteosarcoma, which we will report elsewhere. (author)

  6. Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells.

    Kim, Jinkyoung; Lee, Jiyun; Kim, Chungyeul; Choi, Jinhyuk; Kim, Aeree

    2016-05-01

    Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti-tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose- and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-β1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-β1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3. PMID:26581908

  7. Fulvic acid promotes extracellular anti-cancer mediators from RAW 264.7 cells, causing to cancer cell death in vitro.

    Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Kang, Chang-Hee; Lee, Seungheon; Choi, Yung Hyun; Jeong, Yong Kee; Kim, Gi-Young

    2016-07-01

    Fulvic acid (FA) is known to promote electrochemical balance as a donor or a receptor possessing many biomedical functions. Nevertheless, the effect of FA on the anti-cancer activity has not been elucidated. In the current study, we first isolated FA from humus and investigated whether FA regulates immune-stimulating functions, such as production of nitric oxide (NO), in RAW 264.7 cells. Our data showed that FA slightly enhances cell viability in a dose-dependent manner and secretion of NO from RAW 264.7 cells. It upregulated the protein and mRNA expression of inducible NO synthesis (iNOS). In addition, FA enhanced the DNA-binding activity of nuclear factor-κB (NF-κB) in RAW 264.7 cells; the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) effectively attenuated the expression of FA-stimulated iNOS, suggesting that FA stimulates NF-κB to promote iNOS and NO production. Finally, FA-stimulated culture media (FA-CM) from RAW 264.7 cells were collected and MCA-102 fibrosarcoma cells were cultured in this media. The FA-CM augmented MCA-102 fibrosarcoma cell apoptosis; however, an NO inhibitor N(G)-monomethyl-l-arginine (NMMA) slightly inhibited the FA-CM-mediated MCA-102 fibrosarcoma cell apoptosis, which was accompanied by low levels of NO. In the present study, we found that FA induces the generation of NO and iNOS in RAW 264.7 cells by inducing NF-κB activation; however, NO did not significantly stimulate MCA-102 fibrosarcoma cell apoptosis in the current study. In addition, FA-CM enhanced cell death in various human cancer cells such as Hep3B, LNCaP, and HL60. Taken together, FA most likely stimulates immune-modulating molecules such as NO and induces cancer cell apoptosis. PMID:27177083

  8. Advances of Immunotherapy in Small Cell Lung Cancer

    Jingjing LIU

    2014-06-01

    Full Text Available Small cell lung cancer (SCLC is complex heterogeneous due to unclear biological characteristics in terms of cell origin, pathogenesis and driver genes etc. Diagnosis and treatment of SCLC has been slowly improved and few breakthroughs have been discovered up to now. Therefore new strategies are urgently needed to improve the efficacy of SCLC treatment. Tumor immunotherapy has potential to restore and trigger the immune system to recognize and eliminate tumor cells, notably it has only minimal adverse impact on normal tissue. Cancer vaccine, adoptive immunotherapy, cytokines and checkpoint inhibitors have now been launched for clinical treatment of SCLC. Ipilimumab is the most promising medicine of immunotherapy. Immunotherapy is expected to bring new vision to the treatment of SCLC. And further researches are needed on such problems affecting efficacy of immunotherapy as the heterogeneity of SCLC, the uncertainty of target for immunotherapy, the immune tolerance, etc.

  9. Development of PROSTVAC immunotherapy in prostate cancer.

    Singh, Parminder; Pal, Sumanta K; Alex, Anitha; Agarwal, Neeraj

    2015-01-01

    PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID:26235179

  10. RNA-Based Vaccines in Cancer Immunotherapy

    Megan A. McNamara

    2015-01-01

    Full Text Available RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy.

  11. Coinhibitory Pathways in Immunotherapy for Cancer.

    Baumeister, Susanne H; Freeman, Gordon J; Dranoff, Glenn; Sharpe, Arlene H

    2016-05-20

    The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer. PMID:26927206

  12. ATMPs for Cancer Immunotherapy: A Regulatory Overview.

    Galli, Maria Cristina

    2016-01-01

    This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described. PMID:27033211

  13. Local immunotherapy in experimental murine lung inflammation

    sprotocols

    2015-01-01

    Authors: Caroline Uebel, Sonja Koch, Anja Maier, Nina Sopel, Anna Graser, Stephanie Mousset & Susetta Finotto ### Abstract Innovative local immunotherapy for severe lung diseases such as asthma, chronic obstructive pulmonary disease or lung cancer requires a successful delivery to access the desired cellular target in the lung. An important route is the direct instillation into the airways in contrast to delivery through the digestive tract. This protocol details a method to deliv...

  14. Adoptive immunotherapy for cancer: building on success

    Gattinoni, Luca; Powell, Daniel J.; Rosenberg, Steven A.; Restifo, Nicholas P

    2006-01-01

    Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the u...

  15. Multivalent glycomimetics in experimental anticancer immunotherapy

    Vannucci, Luca; Pospíšil, Miloslav; Krist, Pavel; Křen, Vladimír; Huliková, Katarína; Luptovcová, Martina; Svoboda, Jan; Kuldová, Markéta; Bezouška, Karel; Rossmann, Pavel; Difato, Francesco; Mosca, F.; Fišerová, Anna

    Praha : Blackwell Publishing, 2006, s. 51-51. [Annual Meeting of the European Society for Clinical Investigation /40./. Prague (CZ), 15.03.2006-18.03.2006] R&D Projects: GA ČR GA524/04/0102; GA AV ČR IAA500200509 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z50110509 Keywords : immunotherapy * lectin-like receptors Subject RIV: EE - Microbiology, Virology

  16. Molecular biomarkers for grass pollen immunotherapy

    Popescu, Florin-Dan

    2014-01-01

    Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or wher...

  17. Allergen-Specific Immunotherapy in Food Anaphylaxis

    Kerzl, Regina; Mempel, Martin; Ring, Johannes

    2008-01-01

    Specific immunotherapy (SIT) protocols for nutritional allergens have only recently been established with a focus on oral allergy syndrome because of pollen cross-reacting antibodies. For these patients, a substantial number of studies have been published suggesting benefits from SIT. The situation in true anaphylaxis to food allergens such as peanut allergy is more complex, and therapeutic strategies are based on individual protocols rather than controlled studies. However, in defined cases,...

  18. Prostate cancer immunotherapy: beyond immunity to curability.

    Simons, Jonathan W

    2014-11-01

    Metastatic prostate cancer is the second leading cause of death from cancer in the United States. It is the first prevalent cancer in which overall survival in advanced disease is modestly, but objectively, improved with outpatient delivered dendritic cell-based immunotherapy. More prostate cancer patients have enrolled through Facebook and trusted-site Internet searches in clinical trials for prostate cancer vaccine-based immunotherapy than in immunotherapy trials for lung, breast, colon, pancreas, ovarian, and bladder cancer combined in the past 7 years. Exceptional responses to anti-CTLA-4 treatment have been documented in clinics, and prostate cancer neoantigen characterization and T-cell clonotyping are in their research ascendancy. The prostate is an accessory organ; it is not required for fertility, erectile function, or urinary continence. The true evolutionary advantage of having a prostate for male mammalian physiology is a topic of speculation in seminar rooms and on bar stools, but it remains unknown. Hundreds of prostate lineage-unique proteins (PLUP) exist among the >37,000 normal human prostate lineage-unique open reading frames that can be targeted for immunologic ablation of PLUP(+) prostate cancer cells by prostate-specific autoimmunity. This bioengineered graft-versus-prostate disease is a powerful strategy that can eliminate deaths from prostate cancer. Immunologic tolerance to prostate cancer can be overcome at every clinical stage of presentation. This Cancer Immunology at the Crossroads article aims to present advances in the past two decades of basic, translational, and clinical research in prostate cancer, including bioengineering B-cell and T-cell responses, and ongoing prostate cancer immunotherapy trials. PMID:25367978

  19. Review on Immunotherapies for Lung Cancer

    Sha JIN

    2012-10-01

    Full Text Available Lung cancer is a highly malignant disease with poor prognosis, most cases are diagnosed at a very late stage. More effective medications or therapies should be developed to improve its prognosis. The advancement of tumor immunity and tumor immunosuppression facilitated the feasibility of immunotherapies for lung cancer. Ipilimumab, antibody to Programmed death-1 (PD-1, Toll-like receptor agonists, liposomal BLP25 (L- BLP25, belagenpumatucel-L, melanoma-associated antigen A3 (MAGE-A3 vaccine and talactoferrin have been proved to be effective for lung cancer through early clinical trials, most of the drugs have moved forward to phase III trials, so as to collect much higher level evidence to support the immunotherapies incorporated into the multidisciplinary treatment of lung cancer. The selection of target patients at appropriate stages, breaking down of tumor immunosuppression as well as the objective measurement of tumor response to the therapy are major challenges for the development of immunotherapies for lung cancer. The clarifying of the mechanism of immune escape led to the above drug development, and immune-senescence has already become the hotspot in this field.

  20. Laser immunotherapy of canine and feline neoplasia

    Woods, J. P.; Bartels, Kenneth E.; Davidson, Ellen B.; Ritchey, Jerry W.; Lehenbauer, Terry W.; Nordquist, Robert E.; Chen, Wei R.

    1998-07-01

    The major cause of treatment failure in human and veterinary cancer patients is tumor invasion and metastasis. The inability of local therapy (surgery, radiation, photodynamic therapy) to eradicate a metastatic cancer presents a challenge in the therapy of residual or micrometastatic disease. Because of its local therapy limitations, chromophore-enhanced selective photothermal laser treatment has been augmented with a superimposed laser-induced systemic photobiological reaction, laser immunotherapy. Laser immunotherapy is a novel cancer treatment consisting of: (1) a laser in the infrared wavelength range (i.e. 805 nm solid state laser); (2) a photosensitizer of the corresponding absorption peak [i.e. indocyanine green (ICG)]; and (3) an immunoadjuvant [i.e. glycated chitosan gel (GCG)]. The intratumor injection of the photosensitizer (ICG) and immunoadjuvant (GCG) solution is followed by noninvasive laser irradiation. The laser energy causes tumor cell destruction by photothermal interaction to reduce the tumor burden and at the same time exposes tumor antigens. The immunoadjuvant concomitantly stimulates the host to mount a systemic anti-tumor immune response against the remaining cells of the tumor and to induce a long-term, tumor-specific immunity. This study investigates the feasibility of utilizing laser immunotherapy as an adjunctive therapy for the control of feline fibrosarcoma in future.

  1. Immunotherapy with the storage mite lepidoglyphus destructor.

    Armentia-Medina, A; Tapias, J A; Martín, J F; Ventas, P; Fernández, A

    1995-01-01

    We carried out a double-blind clinical trial of immunotherapy on 35 patients sensitized to the storage mite Lepidoglyphus destructor (Ld). Before and after 12 months of specific hyposensitization (Abelló Lab., Spain) we performed in vivo (skin tests with Ld, methacholine and challenge tests), and in vitro tests (specific IgE, IgG, IgG1 and IgG4 to Ld and specific IgE, IgG, IgG1 and IgG4 to their major allergen Lep dI). We also monitored the efficacy and safety of the immunotherapy with clinical and analytical controls (symptoms and medication score, detection of immune complexes). After therapy we found a significant decrease in specific skin reactivity, dose of positive challenge tests, and hyperresponsiveness to methacholine. Sputum eosinophilia decreased. Specific IgE to Ld was increased and we also observed an increase in specific IgG1 and IgG4 to Ld and Lep DI. The placebo group showed no changes in these variables. There were no severe secondary reactions after treatment with the extract. Patients-self-evaluation was favourable and their labour absence decreased. No development of circulating immune complexes was associated with this immunotherapy. PMID:8526179

  2. Sublingual immunotherapy in children: facts and needs

    Frati Franco

    2009-10-01

    Full Text Available Abstract Allergen specific immunotherapy (SIT is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects, and is the only treatment targeting the causes of hypersensitivity and not only the symptoms, as done by drugs. The traditional, subcutaneous immunotherapy (SCIT was burdened by the problem of systemic reactions which may be sometimes severe and - though very rarely - even fatal. This was the background to develop non injections routes for SIT and particularly sublingual immunotherapy (SLIT, that emerged as a real treatment option for respiratory allergy. A number of studies was conducted to evaluate efficacy and safety of SLIT, the first meta-analysis - including 22 placebo-controlled trials - concluded for positive results in both issues, but the number of studies on children was too low to draw definite conclusions. Since then, many other studies became available and make possible to analyze SLIT in children in its well defined aspects as well as in sides still requiring more solid data.

  3. Application of Proteomics in the Search for Novel Proteins Associated with the Anti - cancer Effect of the Synthetic Cyclin - dependent Kinases Inhibitor, Bohemine

    Kovářová, Hana; Halada, Petr; Man, P.; Dzubak, P.; Hajduch, M.

    2002-01-01

    Roč. 1, č. 4 (2002), s. 247-256. ISSN 1533-0346 R&D Projects: GA ČR GA301/02/0475; GA ČR GA303/02/0875; GA AV ČR KSK5052113 Keywords : anti cancer effect * proteomics Subject RIV: FD - Oncology ; Hematology

  4. Screening of Drug Metabolizing Enzymes for the Ginsenoside Compound K In Vitro: An Efficient Anti-Cancer Substance Originating from Panax Ginseng.

    Jian Xiao

    Full Text Available Ginsenoside compound K (CK, a rare ginsenoside originating from Panax Ginseng, has been found to possess unique pharmacological activities specifically as anti-cancers. However, the role of cytochrome P450s (CYPs in the metabolism of CK is unclear. In this study, we screened the CYPs for the metabolism of CK in vitro using human liver microsomes (HLMs or human recombinant CYPs. The results showed that CK inhibited the enzyme activities of CYP2C9 and CYP3A4 in the HLMs. The Km and Vmax values of CK were 84.20±21.92 μM and 0.28±0.04 nmol/mg protein/min, respectively, for the HLMs; 34.63±10.48 μM and 0.45±0.05 nmol/nmol P450/min, respectively, for CYP2C9; and 27.03±5.04 μM and 0.68±0.04 nmol/nmol P450/min, respectively, for CYP3A4. The IC50 values were 16.00 μM and 9.83 μM, and Ki values were 14.92 μM and 11.42μM for CYP2C9 and CYP3A4, respectively. Other human CYP isoforms, including CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP2C19, showed minimal or no effect on CK metabolism. The results suggested that CK was a substrate and also inhibitors for both CYP2C9 and CYP3A4. Patients using CK in combination with therapeutic drugs that are substrates of CYP2C9 and CYP3A4 for different reasons should be careful, although the inhibiting potency of CK is much poorer than that of enzyme-specific inhibitors.

  5. Dendritic cell-tumor cell hybrids and immunotherapy

    Cathelin, Dominique; Nicolas, Alexandra; Bouchot, André;

    2011-01-01

    Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation...... still require optimization. An alternative technique for providing antigens to DC consists of the direct fusion of dendritic cells with tumor cells. These resulting hybrid cells may express both major histocompatibility complex (MHC) class I and II molecules associated with tumor antigens and the...... appropriate co-stimulatory molecules required for T-cell activation. Initially tested in animal models, this approach has now been evaluated in clinical trials, although with limited success. We summarize and discuss the results from the animal studies and first clinical trials. We also present a new approach...

  6. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: Ensuing energetic and oxidative stress implications

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca2+ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. - Graphical abstract: Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death Display Omitted Highlights: → We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. → GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. → These actions could be

  7. Preclinical Assessment of Vernonia amygdalina Leaf Extracts as DNA Damaging Anti-cancer Agent in the Management of Breast Cancer

    Ernest Izevbigie

    2008-12-01

    Full Text Available Breast cancer is the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Fortunately, the mortality rate from breast cancer has decreased in recent years due to an increased emphasis on early detection and more effective treatments. Despite early detection, conventional and chemotherapeutic methods of treatment, about 7% of women still died every year. Hence, the aim of the present study was to assess the therapeutic efficacy of Vernonia amygdalina (VA leaf extracts as anti-cancer agent against human breast cancer in vitro using the MTT [3-(4, 5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide] and alkaline single cell gel electrophoresis (Comet assays, respectively. In this experiment, human breast adenocarcinoma (MCF-7 cells were treated with different doses of VA leaf extracts for 48 hours. Data obtained from the MTT assay showed that VA significantly ((P < 0.05 reduced the viability of MCF-7 cells in a dose-dependent manner upon 48 hours of exposure. Data generated from the comet assay also indicated a slight dose-dependent increase in DNA damage in MCF-7 cells associated with VA treatment. We observed a slight increase in comet tail-length, tail arm and tail moment, as well as in percentages of DNA cleavage at all doses tested, showing an evidence that VA-induced minimal genotoxic damage in MCF-7 cells. Taken together, our findings suggest that VA treatment moderately (P < 0.05 reduces cellular viability and induces minimal DNA damage in MCF-7 cells. These findings provide evidence that VA extracts represent a DNA-damaging anti-cancer agent against breast cancer and its mechanisms of action functions, at least in part, through minimal DNA damage and moderate toxicity in tumors cells.

  8. Clinical and laboratory 2-year outcome of oral immunotherapy in patients with cow's milk allergy.

    Elizur, A; Appel, M Y; Goldberg, M R; Yichie, T; Levy, M B; Nachshon, L; Katz, Y

    2016-02-01

    Studies examining the long-term effect of oral immunotherapy in food-allergic patients are limited. We investigated cow's milk-allergic patients, >6 months after the completion of oral immunotherapy (n = 197). Questionnaires, skin prick tests, and basophil activation assays were performed. Of the 195 patients contacted, 180 (92.3%) were consuming milk protein regularly. Half experienced adverse reactions, mostly mild. Thirteen patients (6.7%) required injectable epinephrine. Higher reaction rate after immunotherapy was associated with more anaphylactic episodes before treatment and a lower starting dose (OR = 2.1, P = 0.035 and OR = 2.3, P = 0.035, respectively). Reaction rate in patients who were 6-15 months, 15-30 months, or >30 months post-treatment decreased from 0.28/month to 0.21/month to 0.15/month, respectively (P Milk-induced %CD63 and %CD203c expression was significantly lower in patients >24 months vs in patients <24 months post-treatment (P = 0.038 and P = 0.047, respectively). In conclusion, many patients experience mild adverse reactions after completing oral immunotherapy and some require injectable epinephrine. Progressive desensitization, both clinically and in basophil reactivity, occurs over time. PMID:26482941

  9. Advance of Cellular Immunotherapy in Clinical and Translational Medicine of Lung Cancer

    YAN Fei; YU Shao-rong; FENG Ji-feng

    2016-01-01

    Lung cancer is one of the most common cancers and ranks the ifrst in the mortality worldwide. The core of immunotherapy, especially cellular immunotherapy, is to activate the T cell-mediated tumor-killing effect in patients with tumors, so as to increase their anti-tumor effect. Surgery and radio- and chemotherapy cannot radically eliminate cancerous cells, but immunotherapy is an important supplementary method in killing tumor stem cells and non-proliferating cells. Cellular immunotherapy contains dendritic cells (DC), cytokine-induced killer (CIK), DC-CIK, natural killer T cells (NKT) and γδ T cells, which provides new techniques for the comprehensive treatment of lung cancer. Using CIK combined with DC, radiochemotherapy, radiofrequency ablation and monomers of Chinese medicine to induce CIK cells that directionally migrate to cancerous nest can increase tumor-killing ability and immunoregulatory ability of CIK cells, reduce adverse and toxic reactions and increase patients’ quality of life, and NKT cell and γδ T cell therapies have also been gradually perfected and promoted in clinical translation. This study mainly introduced the clinical translation of DC vaccines, CIK cells and DC-CIK treatment for lung cancer, hoping to provide new pathways and reference for the clinical treatment of lung cancer.

  10. The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

    Mira A. Patel

    2014-09-01

    Full Text Available The current standard of care for glioblastoma (GBM is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ. As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

  11. The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

    Patel, Mira A.; Kim, Jennifer E.; Ruzevick, Jacob [Department of Neurosurgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Phipps Building Rm 123, Baltimore, MD 21287 (United States); Li, Gordon [Department of Neurosurgery, Stanford University Medical Center, 1201 Welch Rd., P309 MSLS, Stanford, CA 94305 (United States); Lim, Michael, E-mail: mlim3@jhmi.edu [Department of Neurosurgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Phipps Building Rm 123, Baltimore, MD 21287 (United States)

    2014-09-29

    The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

  12. The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

    The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care

  13. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.

    Calderon, Moises A; Demoly, Pascal; Gerth van Wijk, Roy; Bousquet, Jean; Sheikh, Aziz; Frew, Anthony; Scadding, Glenis; Bachert, Claus; Malling, Hans J; Valenta, Rudolph; Bilo, Beatrice; Nieto, Antonio; Akdis, Cezmi; Just, Jocelyne; Vidal, Carmen; Varga, Eva M; Alvarez-Cuesta, Emilio; Bohle, Barbara; Bufe, Albrecht; Canonica, Walter G; Cardona, Victoria; Dahl, Ronald; Didier, Alain; Durham, Stephen R; Eng, Peter; Fernandez-Rivas, Montserrat; Jacobsen, Lars; Jutel, Marek; Kleine-Tebbe, Jörg; Klimek, Ludger; Lötvall, Jan; Moreno, Carmen; Mosges, Ralph; Muraro, Antonella; Niggemann, Bodo; Pajno, Giovanni; Passalacqua, Giovanni; Pfaar, Oliver; Rak, Sabina; Senna, Gianenrico; Senti, Gabriela; Valovirta, Erkka; van Hage, Marianne; Virchow, Johannes C; Wahn, Ulrich; Papadopoulos, Nikolaos

    2012-01-01

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a

  14. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

    Calderon Moises A

    2012-10-01

    Full Text Available Abstract Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in

  15. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    Whelan, M C; Casey, G; MacConmara, M; Lederer, J A; Soden, D; Collins, J K; Tangney, M; O'Sullivan, G C

    2010-07-01

    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development. PMID:20186173

  16. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    Whelan, M C

    2012-01-31

    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

  17. The Anti-cancer Drug Chlorambucil as a Substrate for the Human Polymorphic Enzyme Glutathione Transferase P1-1: Kinetic Properties and Crystallographic Characterisation of Allelic Variants

    Parker, Lorien J.; Ciccone, Sarah; Italiano, Louis C.; Primavera, Alessandra; Oakley, Aaron J.; Morton, Craig J.; Hancock, Nancy C.; Bello, Mario Lo; Parker, Michael W. (SVIMR-A); (Melbourne); (Rome)

    2008-08-04

    The commonly used anti-cancer drug chlorambucil is the primary treatment for patients with chronic lymphocytic leukaemia. Chlorambucil has been shown to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues. The allelic variants of GST P1-1 are associated with differing susceptibilities to leukaemia and differ markedly in their efficiency in catalysing glutathione (GSH) conjugation reactions. Here, we perform detailed kinetic studies of the allelic variants with the aid of three representative co-substrates. We show that the differing catalytic properties of the variants are highly substrate-dependent. We show also that all variants exhibit the same temperature stability in the range 10 C to 45 C. We have determined the crystal structures of GST P1-1 in complex with chlorambucil and its GSH conjugate for two of these allelic variants that have different residues at positions 104 and 113. Chlorambucil is found to bind in a non-productive mode to the substrate-binding site (H-site) in the absence of GSH. This result suggests that under certain stress conditions where GSH levels are low, GST P1-1 can inactivate the drug by sequestering it from the surrounding medium. However, in the presence of GSH, chlorambucil binds in the H-site in a productive mode and undergoes a conjugation reaction with GSH present in the crystal. The crystal structure of the GSH-chlorambucil complex bound to the *C variant is identical with the *A variant ruling out the hypothesis that primary structure differences between the variants cause structural changes at the active site. Finally, we show that chlorambucil is a very poor inhibitor of the enzyme in contrast to ethacrynic acid, which binds to the enzyme in a similar fashion but can act as both substrate and inhibitor.

  18. Zn-Driven Discovery of a Hydrothermal Vent Fungal Metabolite Clavatustide C, and an Experimental Study of the Anti-Cancer Mechanism of Clavatustide B

    Panpan Ye

    2014-05-01

    Full Text Available A naturally new cyclopeptide, clavatustide C, was produced as a stress metabolite in response to abiotic stress elicitation by one of the hydrothermal vent fluid components Zn in the cultured mycelia of Aspergillus clavatus C2WU, which were isolated from Xenograpsus testudinatus. X. testudinatus lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. The known compound clavatustide B was also isolated and purified. This is the first example of a new hydrothermal vent microbial secondary metabolite produced in response to abiotic Zn treatment. The structures were established by spectroscopic means. The regulation of G1-S transition in hepatocellular carcinoma cell lines by clavatustide B was observed in our previous study. The purpose of the present study was to verify these results in other types of cancer cell lines and elucidate the possible molecular mechanism for the anti-cancer activities of clavatustide B. In different human cancer cell lines, including pancreatic cancer (Panc-1, gastric cancer (MGC-803, colorectal cancer (SW-480, retinoblastoma (WERI-Rb-1 and prostate cancer (PC3, clavatustide B efficiently suppressed cell proliferations in a dose-dependent manner. Although different cancer cell lines presented variety in Max effect dose and IC50 dose, all cancer cell lines showed a lower Max effect dose and IC50 dose compared with human fibroblasts (hFB (p < 0.05. Moreover, significant accumulations in G1 phases and a reduction in S phases (p < 0.05 were observed under clavatustide B treatment. The expression levels of 2622 genes including 39 cell cycle-associated genes in HepG2 cells were significantly altered by the treatment with 15 μg/mL clavatustide B after 48 h. CCNE2 (cyclin E2 was proved to be the key regulator of clavatustide B-induced G1-S transition blocking in several cancer cell lines by using real-time PCR.

  19. Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

    Serena Meraviglia

    2011-12-01

    Full Text Available The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.

  20. Microsatellite instability as a predictive factor for immunotherapy in malignant melanoma.

    Kubecek, Ondrej; Trojanova, Petronela; Molnarova, Veronika; Kopecky, Jindrich

    2016-08-01

    Immunotherapy has attracted attention as a novel treatment modality for malignant melanoma. Although the use of immunotherapy in metastatic melanoma has shown promising results, there remains a lack of predictive biomarkers indicating treatment benefit from immunotherapy. There is growing evidence suggesting that microsatellite instability (MSI) as a product of DNA mismatch repair deficiency, may be one of possible predictive markers in malignant melanoma. It has been proposed that the immunogenicity of some tumors might be determined by mutational heterogeneity and could be the key to the success of immune therapies. This is also supported by the fact that tumors with the highest amount of somatic mutations, such as malignant melanoma have showed positive results with immune checkpoint inhibitors. There are promising data regarding the association between MSI status and immunogenicity from studies with colorectal cancer, where MSI is linked to improved prognosis compared to microsatellite stable cancers. MSI in colon cancer is linked to a significant increase of immunocompetent cells responsible for the antitumor activity - CD3(+), CD8(+), CD45RO(+), and T-bet(+) lymphocytes and decrease of inhibition factors such as Foxp3, IL-6, IL-17, and TGF-β. On the other hand, taking into account the progression-dependent accumulation of somatic mutations in MSI tumors and consequent high levels of neo-antigens, the possible drug resistance of MSI tumors to traditional treatment, and the presence of inhibition checkpoints within the MSI tumors, there is a solid rationale for the use of novel therapeutic strategies such as immunotherapy in MSI melanomas. We presume that the MSI phenotype in malignant melanoma might be helpful to identify patients, who would be more likely to profit from immunotherapy than from conventional therapy. PMID:27372860

  1. Regulatory T cell effects in antitumor laser immunotherapy: a mathematical model and analysis

    Dawkins, Bryan A.; Laverty, Sean M.

    2016-03-01

    Regulatory T cells (Tregs) have tremendous influence on treatment outcomes in patients receiving immunotherapy for cancerous tumors. We present a mathematical model incorporating the primary cellular and molecular components of antitumor laser immunotherapy. We explicitly model developmental classes of dendritic cells (DCs), cytotoxic T cells (CTLs), primary and metastatic tumor cells, and tumor antigen. Regulatory T cells have been shown to kill antigen presenting cells, to influence dendritic cell maturation and migration, to kill activated killer CTLs in the tumor microenvironment, and to influence CTL proliferation. Since Tregs affect explicitly modeled cells, but we do not explicitly model dynamics of Treg themselves, we use model parameters to analyze effects of Treg immunosuppressive activity. We will outline a systematic method for assigning clinical outcomes to model simulations and use this condition to associate simulated patient treatment outcome with Treg activity.

  2. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit. PMID:26250412

  3. Indoleamine 2, 3-dioxygenase: potential in cancer immunotherapy

    Indoleamine 2, 3-dioxygenase (IDO) is a potent immunosuppressive enzyme that has a significant role in different types of cancers. There is evidence that shows its involvement in a number of infectious diseases and auto-immune disorders. In vitro and in vivo studies indicate that 1-methyl tryptophan, being a competitive inhibitor, has shown to actively control the conditions in which IDO is over-expressed. Dendritic cells are the natural site of secretion of IDO in the host immune system. However, the expression takes place only in the presence of tolerogenic signals that lead to suppression of T-cell mediated immunogenic responses. Different therapies are being designed by employing the role of IDO in conditions such as stress, depression, cancer, pregnancy, and organ transplant, which reflect the promising role of this new target in cancer immunotherapy. (author)

  4. A mathematical model of the dynamics of antitumor laser immunotherapy

    Dawkins, Bryan A.; Laverty, Sean M.

    2014-02-01

    We use a mathematical model to describe and predict the population dynamics of tumor cells, immune cells, and other immune components in a host undergoing laser immunotherapy treatment against metastatic cancer. We incorporate key elements of the treatment into the model: a function describing the laser-induced primary tumor cell death and parameters capturing the role and strength of the primary immunoadjuvant, glycated chitosan. We focus on identifying conditions that ensure a successful treatment. In particular, we study the patient response (i.e., anti-tumor immune dynamics and treatment outcome) in two different but related mathematical models as we vary quantitative features of the immune system (supply, proliferation, death, and interaction rates). We compare immune dynamics of a `baseline' immune model against an `augmented' model (with additional cell types and antibodies) and in both, we find that using strong immunoadjuvants, like glycated chitosan, that enhance dendritic cell activity yields more promising patient outcomes.

  5. Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

    Bot, Adrian; Chiriva-Internati, Maurizio; Cornforth, Andrew; Brian J Czerniecki; Ferrone, Soldano; Geles, Kenneth; Greenberg, Philip D.; Hurt, Elaine; Koya, Richard C.; Masoud H Manjili; Matsui, William; Morgan, Richard A.; Palena, Claudia M; Powell Jr, Daniel J; Restifo, Nicholas P

    2014-01-01

    Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.

  6. Specific allergen immunotherapy attenuates allergic airway inflammation in a rat model of Alstonia scholaris pollen induced airway allergy.

    Datta, Ankur; Moitra, Saibal; Hazra, Iman; Mondal, Somnath; Das, Prasanta Kumar; Singh, Manoj Kumar; Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Tripathi, Santanu Kumar; Chaudhuri, Swapna

    2016-01-01

    Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcɛRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcɛRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities. PMID:26667977

  7. INTRAPLEURAL IMMUNOTHERAPY FOR METASTATIC PLEURISIES IN PATIENTS WITH BREAST CANCER

    K. S. Titov; L. V. Demidov; M. V. Kiselevsky; I. N. Mikhailova; I. Zh. Shubina; A. N. Gritsai; I. E. Sinelnikov; L. M. Rodionova

    2009-01-01

    Intrapleural immunotherapy for metastatic pleurisies demonstrates a high efficiency in the treatment of patients with breast cancer (BC). This immunotherapy modality is regarded as one of the stages of complex treatment in patients with disseminated BC and allows its capabilities to be extended for their further management.

  8. Immunotherapy and Immune Evasion in Prostate Cancer

    Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

    2013-05-24

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

  9. Immunotherapy and Immune Evasion in Prostate Cancer

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies

  10. Mechanisms of allergen-specific immunotherapy

    Fujita Hiroyuki; Soyka Michael B; Akdis Mübeccel; Akdis Cezmi A

    2012-01-01

    Abstract Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a ro...

  11. Prolonged local persistence of cisplatin-loaded gelatin microspheres and their chemoembolic anti-cancer effect in rabbits

    Purpose: To confirm prolonged cisplatin release from drug-loaded gelatin microspheres (GMSs) and their improved chemoembolic anti-cancer effect against VX2 liver tumors in rabbits. Materials and methods: Two groups of twelve rabbits each were treated intraarterially either with 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) or 0.04 mg/kg cisplatin solution by administering them into the right renal artery. Platinum concentrations within the renal parenchyma were analyzed immediately following infusion (day 0) and on days 1, 3, and 7 using the atomic absorption method. In a second experiment four groups of five rabbits each with implanted VX2 liver tumors were treated intraarterially through the hepatic artery with the following drugs: 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) (group I), 2 mg/kg GMSs without any drug (group II), 1.5 mg/kg cisplatin solution (group III) and saline (group IV). Tumor volumes were analyzed pre-injection and 7 days after with MRI allowing calculating the relative tumor growth rate (%). Degree of liver cell necrosis was assessed on the histopathological specimens. Results: The renal parenchymal platinum concentrations (μg/ml) with 4.51 ± 2.25 (day 0), 1.59 ± 0.70 (day 1), 0.72 ± 0.10 (day 3) and 0.20 ± 0.06 (day 7) were significantly more pronounced after cisplatin-loaded GMS on days one and three compared to cisplatin with 1.99 ± 0.55, 0.08 ± 0.03, 0.18 ± 0.01 and 0.10 ± 0.07, respectively. Relative tumor growth rates resulted in 84.5% ± 26.4 (group I); 241.4% ± 145.1 (II); 331.9% ± 72.2 (III), and 413.6% ± 103.6 (IV) with statistical significant differences between groups I and III, and groups I and IV. Similar degrees of necrosis were observed in both GMSs treated groups, while ballooning of hepatocytes was highest in cisplatin-loaded GMSs. Conclusions: With cisplatin-loaded GMSs more pronounced and prolonged local parenchymal cisplatin concentrations may be achieved offering the advantage of an

  12. Hepatitis B immunopathogenesis and immunotherapy.

    Golsaz-Shirazi, Forough; Shokri, Fazel

    2016-04-01

    Worldwide there are over 248 million chronic carriers of HBV of whom about a third eventually develop severe HBV-related complications. Due to the major limitations of current therapeutic approaches, the development of more effective strategies to improve therapeutic outcomes in chronic hepatitis B (CHB) patients seems crucial. Immune activation plays a critical role in spontaneous viral control; therefore, new modalities based on stimulation of the innate and adaptive immune responses could result in the resolution of infection and are promising approaches. Here, we summarize the HBV immunopathogenesis, and discuss the encouraging results obtained from the promising immune-based innovations, such as therapeutic vaccination, cytokine therapy, cell-based therapies and blocking inhibitory receptors, as current and future immunotherapeutic interventions. PMID:26973127

  13. Melittin-MIL-2 fusion protein as a candidate for cancer immunotherapy

    Liu, Mingjun; Wang, Haitao; Liu, Linjie; Wang, Bin; Sun, Guirong

    2016-01-01

    Background Cytokine fusion protein that modulates the immune response holds great potential for cancer immunotherapy. IL-2 is an effective treatment against advanced cancers. However, the therapeutic efficacy of IL-2 is limited by severe systemic toxicity. Several mutants recombinant IL-2 can increase antitumor activity and minimize systemic toxicity. Melittin is an attractive anticancer candidate because of its wide-spectrum lytic properties. We previously generated a bifunctional fusion pro...

  14. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

    Klebanoff, Christopher A.; Khong, Hung T.; Antony, Paul A.; Douglas C Palmer; Restifo, Nicholas P

    2005-01-01

    Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine ‘sinks’ for homeostatic γC-cytoki...

  15. Immunotherapy of Cancer: Towards a New Era

    John B.A.G. Haanen

    2014-11-01

    Full Text Available In the past two decades, immunotherapy of cancer has developed into an established treatment option. At first, the development of monoclonal antibodies – targeting overexpressed cell surface molecules on tumour cells – resulted in improved survival when combined with standard chemotherapy or radiotherapy. More recently, T cell immunotherapy has impacted on survival of certain cancer types. In melanoma especially, but now also in renal cell cancer and non-small cell lung cancer, immune checkpoint inhibitors, such as cytotoxic T lymphocyte–associated antigen-4 (anti-CTLA4 and blockade of programmed death receptor-1-PD- ligand 1 (PD1-PD-L1 interaction, represent a completely new treatment paradigm, lowering the threshold for an anticancer immune response and breaking self-tolerance. Adoptive T cell transfer using tumour- infiltrating lymphocytes or genetically modified T cells are under development, but have shown impressive clinical efficacy in several Phase II studies. These emerging but highly promising treatments can give rise to durable tumour control in diseases that were lethal in all patients only a few years ago.

  16. A stochastic model for immunotherapy of cancer.

    Baar, Martina; Coquille, Loren; Mayer, Hannah; Hölzel, Michael; Rogava, Meri; Tüting, Thomas; Bovier, Anton

    2016-01-01

    We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understand the resistance of tumours to therapeutic approaches and may have non-trivial consequences on tumour treatment protocols. This is supported through numerical simulations. PMID:27063839

  17. Personalized cancer immunotherapy using Systems Medicine approaches.

    Gupta, Shailendra K; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio

    2016-05-01

    The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma. PMID:26174229

  18. Immunological mechanisms of allergen-specific immunotherapy.

    Jutel, Marek; Akdis, C A

    2011-06-01

    The studies on the mechanisms of specific immunotherapy (SIT) point out its targets that decide on the efficacy of SIT and hence might be used for its further improvement. Several mechanisms have been proposed to explain the beneficial effects of immunotherapy. The knowledge of the mechanisms underlying allergic diseases and curative treatment possibilities has experienced exciting advances over the last three decades. Studies in several clinical trials in allergen-SIT have demonstrated that the induction of a tolerant state against allergens in many ways represents a key step in the development of a healthy immune response against allergens. Several cellular and molecular mechanisms have been demonstrated: allergen-specific suppressive capacities of both inducible subsets of CD4(+) CD25(+) forkhead box P3(+) T-regulatory and IL-10-secreting type 1 T-regulatory cells increase in peripheral blood; suppression of eosinophils, mast cells, and basophils; Ab isotype change from IgE to IgG4. This review aims at the better understanding of the observed immunological changes associated with allergen SIT. PMID:21466562

  19. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    Gastaldi, Matteo; Thouin, Anaïs; Vincent, Angela

    2016-01-01

    Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  20. Peptide immunotherapy in experimental autoimmune encephalomyelitis

    Stephen M Anderton

    2015-06-01

    Full Text Available We now have potent drugs available to treat the inflammatory component of multiple sclerosis (MS. However, not all patients respond, the drugs are not curative, and the associated risks to beneficial immune surveillance are considerable. A more desirable approach is to specifically target those comparatively rare T lymphocytes that are orchestrating the autoimmune attack. Using the autoantigen itself to instill immune tolerance in those cells remains a holy grail of immunotherapy. Peptide immunotherapy (PIT is highly effective at silencing autoimmune responses in experimental autoimmune encephalomyelitis (EAE, and clinical trials of PIT are underway in MS. This review discusses the current paradigms for PIT-induced tolerance in naïve T cells. It highlights the need for better understanding of the mode of action of PIT upon memory and effector T cells that are responsible for driving/sustaining ongoing autoimmune pathology. Recent studies in EAEsuggest genetic and epigenetic changes in these pathogenic T-cell populations in response to PIT. Finally, future challenges to effective translation of PIT to the clinic are considered.