2 has an anti-tumoreffect because of its immune-regulat- ing function , TNF-α had an anti-tumor activity against sarcoma 180. In addition to direct cytotoxicity against tumor cells, TNF induced a host-mediated factor which contributed to the anti-tumor effects . Rychly J et al.  also demonstrated that TNF-α induced strong necrosis in sarcoma 180 in vivo and showed total regres- sion. The infiltration of inflammatory cells was observed in the sarcoma 180 tumor. Their result suggested that cell infiltration may be of importance for tumor regression. A synergistic anti-tumoreffect has been observed when TNF-α is combined with IL-2 . We demonstrate that liqi can stimulate the production and activity of IL-2 and TNF-α in mouse Sarcoma 180 tumor-bearing mice.
Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC- 1,-3A,-3B). In contrast, the anti-tumoreffect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDH high CD44 high ) in vitro, and prevented paclitaxel-induced increase
Pancreatic carcinoma is one of the malignant tumors in digestive system in the USA. It is the fourth leading cause of the cancer-related death and the 5 years survival rate is about 6% [23, 24]. While in all the newly discov- ered cancer patients in the world, there are more than 2% cancer patients are pancreatic cancer patients . In China, the numbers of the pancreatic cancer patient was increased year by year, and the trend of the patients’ age was younger and younger. Although the radiother- apy, chemotherapy and other therapy means have cer- tain effect to prolong the survival period of the patient, the overall survival is still less than 24 month . In addition, there has a certain resistance to conventional chemotherapy (eg. gemcitabine) for pancreatic cancer [27, 28]. Therefore, there is an urgent need to find an ef- fective drug treatment and treatment strategies. For in vivo anti-tumoreffect evaluation, the xenografts of the mice are one of the important models. While the im- munodeficiency mice often used as the tumor growth vector. In this study, we used nude mice and constructed the human pancreatic cancer xenografts in nude mice and studied the related treatment mechanism of elemene in vivo and in vitro.
To determine the anti-tumoreffect of HJC0152 in vivo, nude mice were subcutaneously inoculated with MKN45 cells and treated with HJC0152 (7.5 mg/kg) or PBS. As exhibited in Figure 3A–C, the tumor volumes (P < 0.001) and tumor weight (P < 0.01) were significantly lower in the HJC0152-treated group compared with the control group. Furthermore, the mice of both groups had similar body weights indicating that HCJ0152 had no parent side effects (Figure 3D). The tumor tissues were analyzed histo-pathologically by H&E staining, and the proportion of Ki-67 positive cells was significantly reduced in the HJC0152-treated mice compared with the con- trol mice (Figure 3E, F). Taken together, HJC0152 retarded tumor growth in vivo by inhibiting the proliferative capacity of the tumor cells.
In this study, a drug delivery system based on NPs with loaded THA was successfully developed and its anti-tumoreffect was evaluated both in vivo and in vitro. The obtained nanoparticles exhibited a spherical morphology, monodis- persity, and negative zeta potential. In vitro drug release experiments demonstrated that THA was released from the nanoparticles both long-term and with a sustained-release pattern. THA-NPs exhibited a concentration-dependent cytotoxicity against A549 cells and also increased the cellular uptake via passive endocytosis in vitro. Based on tumor volume measurements, the medium survival time and PET/CT imaging on the A549 xenograft mice indi- cated that THA-NPs featured a superior in vivo anti-tumor activity. Furthermore, a potentially promising therapeutic applicability was demonstrated due to the material’s abilities to induce cell apoptosis, cell cycle arrest at G1 phase, and inhibition of cell proliferation and microvessel generation. In summary, THA-NPs may find potential applications in pulmonary carcinoma therapy as well as therapeutic resis- tance and radiotherapy sensitization.
DOI: 10.4236/oalib.1105271 11 Open Access Library Journal   . c-Myc gene is involved in both cell dying and development of various tumors. When c-Myc gene expression is down-regulated, cells stop in G1 phase and stop proliferating; when c-Myc expression is enhanced, it will pro- mote cell malignant transformation. Lead to the occurrence of tumors . E2F1 is one of the transcription factors. This protein has an additional cyc- lin-binding domain. The decrease in expression can block the cell cycle from G1 to S phase and inhibit cell proliferation . Moreover, E2F1 has a synergistic effect with c-Myc. E2F1 has been confirmed as a target gene of c-Myc, which can reduce the expression of c-Myc by down-regulating E2F1, thereby inhibiting the proliferation of tumor cells . The results of this study showed that the pro- tein levels of c-Myc, E2F1 and NF- κ B in BGC-823 cells decreased after PN treatment. Moreover, studies have shown that the STAT3 signaling pathway may be involved in the regulation of c-Myc expression . In normal cells, STAT phosphorylation is transient, and in many cancer cell lines or in primary tumors, STAT3 is continuously phosphorylated , becoming an activated transcrip- tion factor activation form, entering the nucleus and binding to target genes. Promote its transcription . The results showed that the STAT3 phosphoryla- tion was decreased, indicating that PN can block the phosphorylation of STAT3, thereby preventing its entry into the nucleus. This result is consistent with the results of studies in a variety of tumor cell lines, suggesting that PN may exert its anti-tumoreffect in BGC-823 by inhibiting STAT3-c-Myc-E2F1 cascade.
Chitosan- sodium deoxycholate nanoparticles containing 5-fluorouracil (5-FU) was prepared via a simple electrostatic interaction between oppositely charged particles using different weight ratios between chitosan and sodium deoxycholate. The objective of this work is to characterize and estimate the antitumor activity of the prepared chitosan- sodium deoxycholate nanoparticles loaded with 5-FU.The prepared nanoparticles were characterized in-vitro and in-vivo. The in-vitro characterizations were investigated by entrapment efficiency % (EE %), particle size analysis, zeta potential measurement, in-vitro release and Transmission Electron Microscopy (TEM). 5- FU loaded CS- DS nanoparticles showed EE% ranging from (14.54 ±1.35 to 22.43 ±2.12), reasonable mean particle sizes (165.65 ±17.23 to 318.47 ±25.86) and zeta potential (35.57 ±3.05 to 48.86 ±3.57 mV). The in- vitro release of nanoparticles exhibited an initial burst effect followed by a sustained drug release with approximately 90 % of the drug being released over 6 hrs. In-vivo anti-tumoreffect was studied on solid ehrlich carcinoma (SEC) tumor bearing Swiss albino mice.The anti- tumor activity of 5-FU loaded in CS- DS nanoparticles was evaluated comparatively to control and plain formula. The results revealed that 5-FU loaded CS- DS nanoparticles effectively decreased tumor volume and showed significantly (p<0.05) lower tumor volume compared to control group and plain formula.
We and others have shown that angiostatic drugs can enhance the effect of RTx in preclinical studies [3, 17-19]. Part of this effect has been linked to vessel normalization which transiently improves tumor oxygenation during angiostatic therapy. The short window of normalization observed in mice, i.e. a few days [8, 9, 12, 33], suggests that it only plays a limited role during fractionated RTx regimes that last for several weeks. In addition, whether vessel normalization occurs in patients receiving angiostatic therapy as well as the duration of this normalization remains to be established. Moreover, angiostatic therapy can also be beneficial when given during or after RTx [5, 34]. The latter was confirmed in the current study further suggesting that mechanisms other than vessel normalization contribute to the interaction between RTx and angiostatic therapy. Here, we provide evidence for such an alternative mechanism. By applying DCE-MRI as a non-invasive method to monitor the tumor vascular function we found that RTx FR enhanced
Among the molecule-targeting drugs for unresectable advanced recurrent colorectal cancer that are listed in the current NCCN’s Guidelines for Treatment of Colorectal Cancer, many of the angiogenesis- related drugs target VEGF-associated molecules. Three types are listed as efficacious drugs. Bevacizumab has a VEGF-neutralizing effect and a vascular normalization which improves the delivery and effectiveness of chemotherapeutics[14,21,42]. Ziv-Aflibercept is a receptor-antibody complex consisting of VEGF-binding portions from the extracellular domains of VEGF Receptors 1 and 2 and fused to human immunoglobulin IgG1Fc. Regorafenib targets VEGFR1-3, TIE2,
even remarkably cured one tumor among 7 tumors (Fig 5A-B, S2A, Table 1). Since the single dose TRT showed notable tumor regression until day 20, the two dose regimen might be optimized by extending dosing interval to 20 days to get prolonged therapy efficacy. It could be further improved by introducing more repeated doses in the multiple dose regimen as well. The vasculature destruction and tumor cell pro- liferation inhibition of 177 Lu-3PRGD 2 TRT resulted in
C-Src activation has been documented in upwards of 50% of tumors derived from the colon, liver, lung, breast and pancreas [6,7]. C-Src activity increases with pro- gressive stages of disease in colon cancer and is thought to be predictive of poor clinical prognosis suggesting that c-Src activation confers growth and/or survival advan- tages to metastatic colon tumor cells [8-10]. It has been postulated that c-Src activation may contribute to colon tumor progression and metastasis by activating Akt- mediated survival pathways that decrease sensitivity of detached cells to anoikis . C-Src has also been shown to be over-expressed and activated in a high proportion of ovarian cancers  and inhibition of c-Src sensitizes ovarian cancer cells to chemotherapeutic agents such as paclitaxel and cisplatin .
Metformin (1, 1-dimethylbiguanide hydrochloride), an oral biguanide agent, derived from the herb Galega officinalis (French lilac), has been widely used for the treatment of type 2 diabetes. Metformin also displays significant growth inhibitory effects in several cancer cell and mouse tumor models. According to a study conducted by the Indian council of medical research in 2013, lung cancer constitutes 6.9 per cent of all new cancer cases and 9.3 per cent of all cancer related deaths in both sexes. In India, gastric cancer is the fifth most common cancer among males and seventh most common cancer among females. Every year in India, 122,844 women are diagnosed with cervical cancer and 67,477 die from the disease. A study by an international team of doctors, reported that only 4% of liver cancer patients survive for five years in India compared to 10% to 20% elsewhere. Observational data including registries of patients with type II diabetes have suggested that use of metformin may be associated with a decreased cancer incidence. The knowledge gained from the molecular mechanisms of metformin action could lead to the development of novel therapies. Therefore, metformin has become an attractive stand-all agent for molecular chemoprevention with an extra significant benefit when combined with common chemo or radiation therapy.
alone. In an earlier study we have also demonstrated that targeting EGFR using cetuximab improved the efficacy of PDT treatment in a human bladder cancer model. Increased apoptosis and downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT and cetuximab . Inhibition of EGFR signalling can lead to increased PDT cytotoxicity through a mechanism that involves increased apoptotic cell death . Similarly, PDT + C225, an EGFR inhibitor, produced synergistic reductions in mean tumor burden when compared with PDT only or C225. Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group . Inhibition of EGFR has been shown to increase the antitumor activity of radiotherapy and chemotherapy in preclinical and clinical studies [49, 50]. In an in vivo study on head and neck xenograft model in nude mice, combination of PDT and chemotherapy drug carboplatin reduced the tumor size. Though the difference in the tumor size was not significant between the PDT and combination therapy groups, a difference in the expression of EGFR was observed between these two groups . In our studies we observed that PDT and nimotuzumab synergistically delayed tumor growth. Similarly, del Carmen and colleagues  also presented evidence that intraperitoneal administration of C225 (cetuximab) and benzoporphyrin derivative monoacid-A (BPD)-PDT act synergistically to prevent or inhibit tumor cell growth and extend survival in a murine model of ovarian cancer peritoneal metastasis. Another study reported that ERK1/2 and EGFR-PI3K-Akt pathways seem to be involved in cellular survival after PDT and EGFR inhibitors and PDT act synergistically to reduce malignant tumors effectively . Treatment of U87MG brain tumours with nimotuzumab and radiation has also shown enhanced inhibition of EGFR-signalling activation . Such inhibition was not apparent for tumors treated with radiation alone, suggesting a rationale for combined treatment with anti-EGFR mAbs and radiotherapy.
benefit from the addition of cetuximab to first-line che- motherapy seems to be restricted to patients with the wild-type KRAS gene; with the best outcomes being observed in those with unmutated forms of both the KRAS and BRAF genes [6-8]. A detailed understanding of the mechanisms controlling cetuximab antitumor activity is necessary to optimize its therapeutic efficacy and to identify those patients who are likely to benefit from the treatment. Although KRAS and BRAF gene status has been considered as a meaningful biomarker, EGFR signaling can also be regulated by several ligands, receptors and cross-talk with other pathways. Hence, these gene mutations may contribute to individual tumors in varying degrees. Moreover, EGFR signaling could change in minutes order so it is crucial to moni- tor the dynamics of signal transduction to understand the intrinsic biological entity of tumor growth, in addi- tion to the representative gene mutation status. To understand such signaling kinetics and tumor growth suppression in response to cetuximab administration, we used a colorectal cancer cell line, HT29, which expressed the highest EGFR level of 6 colorectal cancer cell lines tested. Here, we report the signaling alteration of the EGFR/MAPK pathway initiated by three types of growth factors in the presence/absence of cetuximab in vitro. The protein phosphorylation status of the xeno- graft tumor treated with cetuximab will also be discussed.
mRNA was also enhanced in iNOS-KO mice treated with GalCer (Figure 4). CXCL9 is known as the T-cell chemoattractant, which is induced by IFN-γ. The up- regulation of CXCL9 in the lung might be involved in the increase of CD8+ cells in BALF of tumor-bearing iNOS-mice treated with GalCer. Moreover, we found that the frequency of CD11b+/Ly6G+ cells in iNOS-KO mice treated with GalCer was lower than that in WT mice treated with GalCer (Figures 3A and 6A). MDSCs are broadly defined as CD11b+/Ly6G+ cells. Several previous reports demonstrated that MDSCs were involved in the impairment of host immune systems at tumor-bearing animals [28, 29]. Recent studies demonstrated that iNOS enhanced the recruitment and induction of functional MDSCs [30, 31]. The present data also indicated that the frequency of MDSCs in the tumor was significantly decreased in iNOS-KO mice compared to that in WT mice. Moreover, CFSE-based proliferation assay revealed that BALF cells and CD11b+ cells from GalCer-treated WT mice had an ability to suppress the proliferation of T cells (Figures 3B and 6B). These suppressions were reduced in BALF cells and CD11b+ cells from GalCer- treated iNOS-KO mice. The absent of iNOS activity failed the induction of functional MDSCs after the treatment of GalCer. The decrease of functional MDSCs might be involved in the enhancement of anti-tumoreffect in iNOS- KO mice treated with GalCer.
Given the ubiquitous expression of CD47 on normal cells, tumor-specific delivery of CD47 blockade would generate better anti-tumoreffect with fewer side effects than sys- temic administration. Indeed, the possibility of attack against healthy self cells warrants a concern. For example, patients, especially those under chronic inflammatory conditions or infection, may become severely anemic upon CD47 blockade . Thus, how to block CD47- SIRPα inside the tumor tissues specifically becomes the challenge. Tumor-targeting antibodies may be conjugated with anti-CD47 or SIRPα-Ig to increase specificity . In the selection of a conjugation partner, two kinds of part- ners can be exploited. One is pro-phagocytic Fc receptor (FcR)-activating antibodies, such as the anti-CD20 anti- body, since CD47-SIRPα interruption can synergize with antibody-dependent cellular phagocytosis [20, 44]. The other partner can be adaptive check point blockade anti- bodies including anti-programmed death ligand 1 (PDL1) for unleashing both an innate and adaptive anti-tumor re- sponse . While cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death protein 1 (PD1) blockade monotherapy has gained enormous atten- tion for its potential to result in a durable clinical response and prolonged overall survival with tolerable toxicity com- pared to standard chemotherapy, not all patients respond . Discovery that nivolumab and ipilimumab dual ther- apy is more efficacious than ipilimumab monotherapy in patients with untreated metastatic melanoma highlights the importance of combination therapy and search for other molecular targets . It is possible that combin- ation therapy of anti-CD47 antibody, which increases the tumor cell phagocytosis and priming of anti-tumor CD8 + T cell responses, and anti-CTLA4/PD1, which reinvigo- rates exhausted T cells, may give greater synergism by improving different steps to generating effective anti- tumor immunity. Such idea that tumor-targeted delivery of the CD47 checkpoint antagonist can work as a potential booster to synergize with other tumor-targeting antibodies for better cancer immunotherapy is being actively investi- gated, as reflected by phase I clinical trials testing its com- bination therapy with cetuximab or rituximab (Table 1).
topic; scutellaria methanol extract can inhibit leukemia cell line THP-1 and human osteogenic sarcoma cell line HOS cell proliferation  .The vitro experiments shows that injection of mouse bladder cancer cell line MBT-2 of C3H/HeN mice, Scutellaria had played an anti-tumoreffect  . Scutellariabaicalensis extract, but also inhibit the growth of liver cancer cells HepG2  .
mice, thereby providing the basis for high titer viral therapy. The New York City Board of Health vaccine (Wyeth) strain is TK gene deleted (VACV:JX-594), and it expresses granulocyte- macrophage colony-stimulating factor (GM-CSF). 30 It has shown good host tolerance in a Phase I clinical trial, and longer survival in a Phase II trial, after both intra-tumoral and intrave- nous injections. 31–33 However, this vaccine has a poorer anti- tumoreffect in vitro compared to the wild-type (WT) strain. 34 Recombinant VACV has shown therapeutic effects in several murine tumor models, including those of glioblastoma, pancrea- tic cancer, and melanoma. 35 – 38 Interestingly, we found that both WT and recombinant VACV were less replicative in the murine triple-negative breast cancer (TNBC) cell line 4T1, which shows high levels of TTP, 39 both in vitro and in vivo. Furthermore, TNBC cells from different species differ in terms of TTP expression, which affects the replication of recom- binant VACV.
are somatostatin analogs. Somatostatin (SST) is a group of cyclic peptide hormones secreted by D cells. The somatostatin receptor (SSTR) has been regarded as one of markers for geno- type of cancers to which increasing attention has been paid. The bioeffects of SST are medi- ated by the SSTR on cell membrane. Studies have confirmed that lung cancer of all types has high expression of SSTR, and the expres- sion of SSTR and its affinity to SST are mark- edly increased when compared with normal tis- sues. In addition, semi-quantitative analysis showed the SSTR expression in NSCLC was higher than that in SCLC (P<0.01). Thus, SSTR can be used as a target for the diagnosis and treatment of NSCLC. The endogenous SST is instable and susceptible to degradation. In recent years, investigators have developed a series of somatostatin analogs (SSTA) by alter- ing the non-essential amino acids in SST. These SSTAs have characteristics similar to SST but are not susceptible to degradation and easily to be labeled with radionuclides. Depreotide, a new SSTA, is a disulfide-bond-free cyclic SSRA which avoids the fracture of disulfide bonds due to reduction during the labeling. Thus, depreotide has been a hot topic in researches. Recently, increasing studies have been con- ducted to investigate the anti-tumoreffect of radionuclide labeled SSTA, for which the ratio- nales include: 1) SSTA can bind to specific SSTR to exert direct anti-tumoreffect, inhibit the pro- duction of hormones and cytokines which are essential for the cancer growth or angiogenesis in cancers or induce the apoptosis of cancer cells exerting anti-tumoreffect; 2) the cytotoxic radionuclides may enter cells via the binding between SSTA and SSTR, and the α ray, β ray, Auger electron and internal-conversion elec- tron produced during the disintegration of radionuclides may exert direct killing effect on cancer cells. Thus, radionuclide mediated ther- apy has been a novel and promising strategy for the treatment of cancers.
Rhabdomyosarcoma (RMS) is a common soft tissue sar- coma which is considered relevant in the skeletal muscle lineage of childhood. It is with an incidence of 4.5 cases per 1 million children every year, which making it the third most prevalent extracranial solid tumor in children [1, 2]. RMS has four distinct histopathological subtypes: embryonal rhabdomyosarcoma (ERMS), alveolar rhabdo- myosarcoma (ARMS), pleomorphic rhabdomyosarcoma, and sclerosing/spindle rhabdomyosarcoma. About 70– 80% of RMS patients belong to either ERMS or ARMS [3–5]. ERMS are characterized by RAS gene mutations and account for about two thirds of RMS and have a 73% 5-year overall survival rate. ARMS are characterized by PAX/FOXO1 or related fusion oncogenes and ac- count for about 20% of RMS and have a 48% 5-year overall survival rate [1, 6]. Recurrence, metastasis and drug resistance are the main causes of treatment failure resulting a survival rate of 40% for ERMS [7–9] and 10– 30% for ARMS [9, 10] in patients with metastatic dis- ease. Despite the development of conventional treat- ment, such as surgery, chemotherapy, radiotherapy, immunotherapy, the survival rate in recurrent and meta- static RMS is still less than 20% . Thus more effective treatment strategies are urgently needed for the RMS patients.