Progress of Immunotherapy Combined with Anti-Angiogenesis Therapy in Lung Cancer

Lung cancer is the most prevalent and fatal cancer in China and even around the world, and many patients are found in the late stage of lung cancer. For the treatment of advanced lung cancer, in addition to traditional chemotherapy modalities, many emerging treatments are increasingly significant, such as immunotherapy, anti-angiogenic therapy, and targeted therapy. An increasing number of studies have now shown that anti-angiogenic therapy improves the immune microenvironment by enhancing tumor immunity through normalization of tumor vessels. Immunization combined with anti-angiogenic therapy can exert synergistic effects and improve the prognosis of patients. This article summarizes the extent of benefit, current clinical study data, and future prospects of immunotherapy combined with anti-angiogenic agents in the treatment of advanced NSCLC.

Anti-tumor effect of matrine combined with cisplatin on rat models of cervical cancer

Objective:To observe the anti-tumor effect of matrine combined with cisplatin on U14 rat models of cervical cancer.Methods:A total of 80 female Kunming rats were used to establish U14 rat models of cervical cancer and then divided into groups Ⅰ,Ⅱ,Ⅲ and Ⅳ,with 20 rats in each.For Group Ⅰ,the control group,injection of normal saline was given around the tumors.For Group Ⅱ,injection of 2 mg/kg cisplatin was given around the tumors.For Group Ⅲ,injection of 75 mg/kg matrine was given around the tumors while the combined injection of matrine and cisplatin was given for Group Ⅳ with the same doses as Groups Ⅱand Ⅲ.The animals were sacrificed 10 d after the injection and tumors were taken out for the comparisons of tumor weights after injection and calculation of anti-tumor rates,while thymus and spleen were taken for thymus index and spleen index.Blood in eyeball was collected for determination of changes in serum creatinine and urea nitrogen levels.Sections of tumor issue were prepared and morphological changes in tumor tissue cells were observed by using immunohistochemistry technique.Results:After injection,the thymus index and spleen index in Groups Ⅲ and Ⅳ were significantly higher than those in Groups Ⅰ and Ⅱ(P<0.05)while the two indexes in Group Ⅱ were significantly lower than Group Ⅰ(P<0.05).The tumor weights in Groups Ⅱ and Ⅳ were significantly smaller than those in Groups Ⅰ and Ⅲ(P<0.05) with significantly higher anti-tumor rates than Groups Ⅰ and Ⅲ(P<0.05).The serum creatinine and urea nitrogen levels in Groups Ⅲ and Ⅳ were significantly lower than Group Ⅱ(P<0.05) and the two indicators in Group Ⅲ were significantly lower than those in Group Ⅳ(P<0.05).The observation under the histological microscope showed densely arranged tumor cells in Group Ⅰ,growing as a crumby structure and diffuse appearance,with hyperchromatic and large nuclei,and abundant cytoplasm.In the case of Group Ⅱ,it showed less tumor cells,with extensive degenerative necrosis,sparse arrangement and karyopyknosis as well as karyoclasis.For Group Ⅲ,necrosis of tumor cells in different sizes and heterogeneous color in nuclei were observed.For Group Ⅳ,the number of tumor cells was significantly smaller than Groups Ⅰ and Ⅲ and the tumor cells presented an appearance of crumby structure as cancer nests,with more proliferation of connective tissue.Conclusions:The treatment of matrine combined with cisplatin can significantly improve the anti-tumor effect on U14 rats with cervical cancer,which can be a new option for the treatment for cervical cancer.

3D-QSAR Studies on the Anti-tumor Activity of N-Aryl-salicylamide Derivatives

In the present work,comparative molecular field analysis(CoMFA)techniques were used to perform three-dimensional quantitative structure-activity relationship(3D-QSAR)studies on the anti-tumor activity(pHi,i=1,2,3,4)of N-aryl-salicylamide derivatives against four cancer cell lines,including A549,MCF-7,SGC-7901,and Bel-7402.12 compounds were randomly selected as the training set to establish the prediction models,which were verified by the test set of 5 compounds containing template molecule.The contributions of steric and electrostatic fields to pH1,pH2,pH3,and pH4 were 23.8% and 76.2%,20.1% and 79.9%,18.7% and 81.3%,and 14.3%and 85.7%,respectively.The cross-validation(Rcv 2)and non-cross-validation coefficients(R2)were 0.826 and 0.963 for pH1,0.867 and 0.974 for pH2,0.941 and 0.989 for pH3,and 0.797 and 0.961 for pH4,respectively.The CoMFA models were then used to predict the activities of the compounds,and it was found that the models had strong stability and good predictability.Based on the CoMFA contour maps,some key structural factors responsible for the anticancer activity of the series of compounds were revealed.The results provide some useful theoretical references for understanding the mechanism of action,designing new N-aryl-salicylamide derivatives with high anti-tumor activity,and predicting their activities.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy:A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.

Extraction, Purification and Anti-tumor Activity of Polysaccharide from Mycelium of Mutant Cordyceps Militaris

A water-soluble polysaccharide（named MCMP） was isolated from the mycelium with high yield mutation Cordyceps militaris by hot-water extraction, deproteinization by sevage, alcohol precipitation, anion-exchange and gel filtration chromatography CL-6B. The polysaccharide contained mannose, rhamnose, galactose and glucose in a molar ratio of 59.36：1：8.31：39.50, of which the average molecular weight is 8100. In our research, Hep-G2 cells, Hela cells and mesangial cells were chosen to determine the anti-tumor activity of the polysaccharide. The results of MTT assay show that polysaccharides of the mutant strain presented inhibitory activity on the cells proliferation after 48 h incubation.

Synthesis and Anti-tumor Activity of Novel Amide Derivatives of Ursolic Acid

Ursolic acid was modified at C3 and C28 position to obtain fourteen derivatives including twelve novel compounds, and their chemical structures were characterized by IR, ^1H NMR and MS. Cell growth inhibitory effects of the derivatives against Hela cell were evaluated by MTT assay. All these derivatives were found to have stronger cell growth inhibitory than their parent compound, ursolic acid. The derivatives with a substituted acetyl group at C3 hydroxyl group show better activities than those with an unsubstituted hydroxyl group.

Experimental Research on Anti-tumor Metastasis Effect of Basil Polysaccharide in vivo

Objective: To study the effects of basil polysaccharide (BP) in inhibiting tumor growth and metastasis in vivo. Methods: One hundred and fifty mice were randomly divided into five groups to observe the effect on tumor growth after H22 cancer cells had been transplanted subcutaneously into their right armpit region and treated with different dosages (5 mg/kg, 2. 5 mg/kg and 1. 25 mg/kg) of BP for 14 days, with Mi-tomycin (Mit-C) used as control. Another 150 mice were randomly divided into three groups, models of tumor metastasis in the lung by various paths (lymphatic, blood circulatory and spontaneous) were established respectively. They were treated with BP or Mit-C to observe the influence of treatments on tumor metastasis by various paths. Results: BP of various dosages showed no effect on tumor growth, but in high and middle dosage, it could significantly reduce the number or metastasis nodules ( P<0. 05). Conclusion: BP has a tumor metastasis inhibitory effect, which might be one of the candidates for new anti-tumor metastasis agents. Its mechanism may be blocking the function of platelets in the tumor metastasis progress.

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.

Two-year delay in ulcerative colitis diagnosis is associated with anti-tumor necrosis factor alpha use

BACKGROUND Ulcerative colitis(UC)is an uncommon inflammatory bowel disease(IBD).However,its incidence has recently increased in South Korea.Moreover,UC diagnoses are frequently delayed,and the relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.AIM To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.METHODS Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed;167 cases were excluded because the first symptom date was unknown.We evaluated the relationship between the prognosis and a diagnostic delay of 3,6,12,18,and 24 mo by comparing the prognostic factors[anti-tumor necrosis factor(TNF)-αuse,admission history due to acute flare-ups,frequent admission due to flare-ups,surgery associated with UC,and the clinical remission state at the latest followup]at each diagnostic interval.RESULTS The mean diagnostic interval was 223.3±483.2 d(median,69 d;75th percentile,195 d).Among the prognostic factors,anti-TNFαuse was significantly increased after a diagnostic delay of 24 mo.Clinical risk factors predictive of a 24-mo diagnostic delay were age<60 years at diagnosis[odd ratio(OR)=14.778,95%confidence interval(CI):1.731-126.121],smoking history(OR=2.688,95%CI:1.239-5.747,P=0.012),and misdiagnosis of hemorrhoids(OR=11.066,95%CI:3.596-34.053).Anti-TNFαuse was associated with extensive UC at diagnosis(OR=3.768,95%CI:1.860-7.632)and 24-mo diagnostic delay(OR=2.599,95%CI:1.006-4.916).CONCLUSION A diagnostic delay>24 mo was associated with increased anti-TNFαuse.Age<60 years at diagnosis,smoking history,and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.

STUDY ON THE ANTI-TUMOR EFFICACY INDUCED BY HEAT SHOCK PROTEIN 70-PEPTIDE COMPLEXES DERIVED FROM TUMOR CELLS

OBJECTIVE: To study the efficacy and explore the mechanism of the anti-tumor immunity elicited by heat shock protein 70-peptide complexes (HSP70-PC) derived from tumor cells. METHODS: Cells culture, flow cytometric analysis, affinity chromatography for protein purification, SDS-PAGE, Western-blotting and animal experiment were used. RESULTS: HSP70-PC immunization rendered protective effect to both naive tumorl-bearing mice. All of the naive mice obtained complete resistance to Hcaf cell attack; 40% of the tumor-bearing mice survived for over 90 days, whereas the mice of control group died within 2 weeks (P

Radiofrequency ablation,heat shock protein 70 and potential anti-tumor immunity in hepatic and pancreatic cancers:a minireview

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive surgical procedure which has widespread popularity in the treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA stimulates anti-tumor immunity, possibly through the induction heat shock protein 70 (HSP70) expression. HSP70 has the capacity to affect the immunogenicity of tumor cells, to chaperone antigenic peptides and deliver these into antigen presentation pathways within antigen-presenting cells, and to activate and regulate innate and adaptive immunity, which makes it useful in immunotherapeutic strategies for the treatment of cancers. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1991-2010) on anti-tumor immunity, heat shock protein 70, radiofrequency ablation, hepatic cancer, pancreatic cancer, and other related subjects. RESULTS: RFA has an increasing application in the surgical treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA can induce the expression of HSP70 which possesses properties that enable it to influence a variety of immunological processes. Tumor-derived HSP70 is regarded as a potent adjuvant facilitating presentation of tumor antigens and induction of anti-tumor immunity. CONCLUSIONS: This review addresses the potential association of RFA, HSP70, and anti-tumor immunity in treatment of hepatic and pancreatic cancers. To establish direct evidence of a potential association of RFA, HSP70, and anti-tumor immunity in hepatic and pancreatic cancers, further investigations should be conducted.

Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients

AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor(TNF)therapy and evaluate for any serologic and genetic associations.METHODS This study was a retrospective review of patients attending the inflammatory bowel disease(IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.RESULTS Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients(21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the antiTNF agent. In total: n = 66(5%) infusion reactions; n = 49(4%) allergic/serum sickness reactions; n = 19(1.5%) lupus-like reactions, n = 52(4%) rash, n = 18(1.4%) infections. In Crohn's disease, Ig A ASCA(P = 0.04) and Ig G-ASCA(P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions(P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT(Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic, and pathways associations.

Characterization and Anti-tumor Activity of Glycopeptides from Ganoderma sinensis

The water-soluble part（GS） of Ganoderma sinense Zhao, Xu et Zhang was divided into high molecular（GS-H） and low molecular（GS-L） parts by Cellulose Super Filtration, and GS was also fractionated into four fractions, GS-1, 2, 3, and 4 by ethanol precipitation according to their molecular weights. Chemical analysis shows that GS and GS-1, 2, 3, 4 were complexes of polysaccharide and peptide. The fractions with molecular weights over 4000, GS-1, 2, 3, and GS-H show anti-tumor activities, however, the fractions with molecular weights lower than 4000, GS-4, and GS-L have no anti-tumor activity, indicating that the anti-tumor activity of Ganoderma Sinensis was caused by glucopeptides with molecular weight ranging from 4000 to 20000. Two purified glucopeptides, GS-6b and GS-7b were obtained from GS-H by ion-exchange and gel-permeation chromatography. Their molecular weights, glycosidic linkages, and configurations were detected by means of IR spectrum, sugar composition analysis, and methylation analysis. The polysaccharide parts of GS-6b and GS-7b had glucan backbone consisting of β-1→3 Glc, and side chain containing glucosyl, mannosyl, fucosyl, xylosyl, galactosyl, and glucuronic acid residues attached on 1-2, 1-4, 1-6 positions of the backbone of GS-6b, or 1-6, 1-4 positions of the backbone of GS-7b. The peptide parts in GS-6b and GS-7b were composed of 10 kinds of amino acids, including Asp, Ser, Arg, Gly, Thr, Pro, Ala, Val, Met, and Lys.

Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease

Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.

Anti-tumor Effects of a Recombinant Fowlpox Virus Expressing Apoptin on Human Cervical Carcinoma in Vivo and in Vitro

Apoptin is a chicken anemia virus-derived,p53-independent,bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis of various human tumor cells,but not of normal diploid cells.To explore the application of apoptin in tumor gene therapy,we used a recombinant fowlpox virus expressing apoptin protein （vFV-Apoptin） to investigate the anti-tumor effectes of vFV-Apoptin on human cervical carcinoma（HeLa） cells in vivo and in vitro through 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide（MTT） assay,acridine orage/ethidium bromide（AO/EB） and annexin V staining test,respectively.The results show that vFV-Apoptin inhibites the proliferation of HeLa cells in vitro through inducing the apoptosis of HeLa cells,and the inhibition effect of vFV-Apoptin has a dose-effect and time-effect relationship.The results of animal models show that vFV-Apoptin significantly inhibits tumor growth,extends the lifespan of animals and improves the mean survival.Experimental results indicate that vFV-Apoptin has a potential application in the tumor gene therapy.

Phenylquinolinones with antitumor activity from the Indian Ocean-derived fungus Aspergillus versicolor Y31-2

Two phenylquinolinones,including one new compound(1) and a previously isolated compound(2),were isolated from the ethyl acetate extracts of the fungus Aspergillus versicolor Y31-2,which was obtained from seawater samples collected from the Indian Ocean.The structures of these compounds were established by spectroscopic analyses.4-(3-Hydroxyphenyl)-3-methoxyquinolin-2(1H)-one(1) exhibited moderate cytotoxicity against MCF-7(human breast carcinoma cell line) and SMMC-7721(human liver cancer cell line) cells with IC_(50) values of 16.6 and 18.2 μmol/L,respectively.To the best of our knowledge,this study represents the first reported account of the isolation of compounds 1 and 2 as the secondary metabolites of the seawater derived fungus Aspergillus versicolor from the Indian Ocean.

Synthesis and Primary Research on Antitumor Activity of Three New Panaxadiol Fatty Acid Esters

For making use of Ginseng resources that exhibit an antitumor activity and for finding new anticancer drugs, three new fatty acid ester compounds： 3/β-acetoxy panaxadiol （ Ⅰ ）, 3β-palmitic acid aceloxy panaxadiol （ Ⅱ ） , and 3β-octadecanoic acid aceloxy panaxadiol（ Ⅰ , Ⅱ, and m） were synthesized with panaxadiol, diacetyl oxide, palmityl chloride and stearyl chloride, and their structures were determined via MS, ^13C NMR, IR, TLC, and so on. The molar yields of the three compounds are 75.14%, 79. 08%, and 72. 57%, respectively. Meanwhile, the antitumor activity of the three new panaxadiol fatty acid ester derivatives and panaxadiol was compared by using the method of MTT. Tumor cell used was Vero cell line. Positive control was 5-FU, blank was an RPMI1640 culture medium, negative control was an RPMI1640 culture medium and the solvent for drugs to be tested. Compound Ⅰ has the strongest antitumor activity followed by panaxadiol; compounds Ⅱ and Ⅲ have similar and weakest antitumor activities. Furthermore, the antitumor activities of the panaxadiol fatty acid ester derivatives show positive correlation with the concentration of the test group, but show no relationship with the molecular weight of fatty acid. The methods that are used to synthesize the three compounds with high yields and strong antitumor activities are simple and show a great potential for meeting the needs of industrial manufacture of these drugs.

Screening of Anti-tumor Effective Extracts from Sedum bulbiferum Makino and HPLC Determination of Quercetin and Kaempferol in This Herbal Medicine

[Objectives] To investigate the anti-tumor activity of Sedum bulbiferum Makino in vitro,and establish a HPLC method for determination of quercetin and kaempferol in S. bulbiferum. [Methods] The inhibitory activities of different extracts and total flavonoids of S. bulbiferum on proliferation of three kinds of cancer cells( Hep G2,EC109,SW480) were tested by MTT assay. HPLC method for determination of quercetin and kaempferol in S. bulbiferum was established. [Results]The growth and proliferation of the three kinds of cancer cells were all significantly inhibited by ethyl acetate fraction and total flavonoids isolated from S. bulbiferum. With each extraction concentration increasing,stronger anti-tumor activity was found. The linear ranges of quercetin and kaempferol were 0. 03-0. 36 μg( R = 0. 999 9) and0. 08-0. 96 μg( R = 0. 999 9),and the average recoveries were 98. 90%( RSD = 1. 15%) and 98. 27%( RSD = 1. 70%),respectively.[Conclusions]S. bulbiferum has significant anti-tumor activity in vitro. The HPLC method established was accurate,reproducible,and could be used for quality control of this crude drug.

Anti-tumor activities and apoptotic mechanism of ribosome-inactivating proteins

Ribosome-inactivating proteins(RIPs) belong to a family of enzymes that attack eukaryotic ribosomes and potently inhibit cellular protein synthesis.RIPs possess several biomedical properties,including anti-viral and anti-tumor activities.Multiple RIPs are known to inhibit tumor cell proliferation through inducing apoptosis in a variety of cancers,such as breast cancer,leukemia/lymphoma,and hepatoma.This review focuses on the anti-tumor activities of RIPs and their apoptotic effects through three closely related pathways:mitochondrial,death receptor,and endoplasmic reticulum pathways.

Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.