Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current systemic chemotherapy in the treatment of solid tumors inevitably induces various systemic adverse effects. Locally injected chemotherapy is expected to overcome this limitation of systemic therapy. We evaluated by luminescence imaging the effects of chemotherapy administered locally by means of a biodegradable thermosensitive hydrogel polymer. The human gastric cancer cell line HSC44Luc was used for tumor induction, and it was confirmed to be sensitive to doxorubicin by MTT assay. Cells were injected subcutaneously into Balb/c-nude mice. When the mean volume of tumor reached 400 mm(3), we divided the mice into 6 groups (5 per group) according to treatment: 1) control (intratumor injection of PBS), 2) systemic injection of doxorubicin, 3) intratumor injection of polymer gel, 4) intratumor injection of polymer gel physically mixed with a low dose of doxorubicin, 5) intratumor injection of polymer gel physically mixed with a high dose of doxorubicin, 6) intratumor injection of conjugated polymer gel with doxorubicin. Body weight and tumor volume were measured every 2 or 3 days for 30 days after treatment. One mouse in each group was sacrificed for histopathologic examination every week. Reductions in body weight were not significantly different among groups. The relative rate of tumor growth was 774% in Group 1, 267% in Group 2, 813% in Group 3, -186% in Group 4, and 155% in Group 6, respectively. Thus the relative rate of tumor growth in the groups treated with polymer gel mixed with doxorubicin and the groups treated with conjugated polymer gel with doxorubicin were lower than that in the control group. Locally injectable chemotherapy using a thermosensitive hydrogel polymer with doxorubicin can suppress tumor growth effectively without severe systemic toxicity.
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PMID:Suppression of in vivo tumor growth by using a biodegradable thermosensitive hydrogel polymer containing chemotherapeutic agent. 1938 56

Melanoma is one of the most chemo-resistant cancers. The remission rate of current therapy remains low. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of antitumor antibiotics that binds to N2 of guanine to form a DNA adduct. However, significant cardiotoxicity hampers their clinical use. We have previously synthesized a PBD indole conjugate (IN6CPBD) that induced apoptosis in several cancer cell lines. The purpose of this study was to assess the efficacy and safety of the IN6CPBD for established murine melanoma cells in vivo. IN6CPBD induced more apoptosis than DC-81 as evidenced by sub-G1 distribution, annexin V positivity, and decrease mitochondrial membrane potential (DeltaPsi(mt)). The melanomas were established in C57BL/6 mice by injecting B16F10 cells via the tail vein. Three courses of therapy were instituted after day 5 and the mice were sacrificed at day 20. The tumor growth rate in the foot pad was significantly reduced in IN6CPBD-treated mice than that in DC-81- and PBS-treated mice. The tumor burden in the lungs was also reduced significantly in IN6CPBD-treated mice accompanied with the most prominent TUNEL staining. Renal function, and cardiac enzymes were not altered significantly by IN6CPBD or DC-81, however, robust deterioration of liver function was noticed in the DC-81-treated mice. In summary, potent apoptosis could be elicited by the PBD indole conjugate IN6CPBD, accompanied with a better efficacy and less liver function impairment than the mother compound DC-81 in treating established melanoma metastasis in vivo.
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PMID:Pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugate (IN6CPBD) has better efficacy and superior safety than the mother compound DC-81 in suppressing the growth of established melanoma in vivo. 1943 78

Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fourier-transform IR, (1)H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel > docetaxel, whereas deslorelin alone had no effect, with deslorelin-docetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G(2)-M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel > docetaxel >> deslorelin > PBS, with deslorelin-docetaxel exerting approximately 5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy.
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PMID:Luteinizing hormone-releasing hormone receptor-targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy. 1950 61

MnTE-2-PyP(5+) is a potent catalytic scavenger of reactive oxygen and nitrogen species, primarily superoxide and peroxynitrite. It therefore not only attenuates primary oxidative damage, but was found to modulate redox-based signaling pathways (HIF-1alpha, NF-kappaB, SP-1, and AP-1) and thus, in turn, secondary oxidative injury also. Cancer has been widely considered an oxidative stress condition. The goal of this study was to prove if and why a catalytic SOD mimic/peroxynitrite scavenger would exert anti-cancer effects, i.e., to evaluate whether the attenuation of the oxidative stress by MnTE-2-PyP(5+) could suppress tumor growth in a 4T1 mouse breast tumor model. Tumor cells were implanted into Balb/C mouse flanks. Three groups of mice (n=25) were studied: control (PBS) and 2 and 15 mg/kg/day of MnTE-2-PyP(5+) given subcutaneously twice daily starting when the tumors averaged 200 mm(3) (until they reached approximately 5-fold the initial volume). Intratumoral hypoxia (pimonidazole, carbonic anhydrase), HIF-1alpha, VEGF, proliferating capillary index (CD105), microvessel density (CD31), protein nitration, DNA oxidation (8-OHdG), NADPH oxidase (Nox-4), apoptosis (CD31), macrophage infiltration (CD68), and tumor drug levels were assessed. With 2 mg/kg/day a trend toward tumor growth delay was observed, and a significant trend was observed with 15 mg/kg/day. The 7.5-fold increase in drug dose was accompanied by a similar (6-fold) increase in tumor drug levels. Oxidative stress was largely attenuated as observed through the decreased levels of DNA damage, protein 3-nitrotyrosine, macrophage infiltration, and NADPH oxidase. Further, hypoxia was significantly decreased as were the levels of HIF-1alpha and VEGF. Consequently, suppression of angiogenesis was observed; both the microvessel density and the endothelial cell proliferation were markedly decreased. Our study indicates for the first time that MnTE-2-PyP(5+) has anti-cancer activity in its own right. The anti-cancer activity via HIF/VEGF pathways probably arises from the impact of the drug on the oxidative stress. Therefore, the catalytic scavenging of ROS/RNS by antioxidants, which in turn suppresses cellular transcriptional activity, could be an appropriate strategy for anti-cancer therapy. Enhancement of the anti-cancer effects may be achieved by optimizing the dosing regime, utilizing more bioavailable Mn porphyrins (MnP), and combining MnP treatment with irradiation, hyperthermia, and chemotherapy. Mn porphyrins may be advantageous compared to other anti-cancer drugs, owing to their radioprotection of normal tissue and the ability to afford pain management in cancer patients via prevention of chronic morphine tolerance.
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PMID:Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor. 1959 20

Cyclooxygenase (COX)-2 is known to correlate with poor cancer prognosis and to contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal prostaglandin E(2) (PGE(2))-prostaglandin E2 receptor (EP)3 signaling appears critical for tumor-associated angiogenesis and tumor growth. Here we tested whether the EP3 receptor has a critical role in tumor metastasis. Lewis lung carcinoma (LLC) cells were intravenously injected into WT mice and mice treated with the COX-2 inhibitor NS-398. The nonselective COX inhibitor aspirin reduced lung metastasis, but the COX-1 inhibitor SC560 did not. The expression of matrix metalloproteinases (MMP)-9 and vascular endothelial growth factor (VEGF)-A was suppressed in NS-398-treated mice compared with PBS-treated mice. Lungs containing LLC colonies were markedly reduced in EP3 receptor knockout (EP3(-/-)) mice compared with WT mice. The expression of MMP-9 and VEGF-A was downregulated in metastatic lungs of EP3(-/-) mice. An immunohistochemical study revealed that MMP-9-expressing endothelial cells were markedly reduced in EP3(-/-) mice compared with WT mice. When HUVEC were treated with agonists for EP1, EP2, EP3, or EP4, only the EP3 agonist enhanced MMP-9 expression. These results suggested that EP3 receptor signaling on endothelial cells is essential for the MMP-9 upregulation that enhances tumor metastasis and angiogenesis. An EP3 receptor antagonist may be useful to protect against tumor metastasis.
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PMID:Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. 1979 10

Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment. However, clinical studies have shown that cognitive impairment can also be noticed in some cancer patients before any systemic treatment is initiated. We aim in the present study to discern whether hippocampal cell proliferation is negatively affected by tumor growth and if the presence of a tumor amplifies the effects of methotrexate. Buffalo rats were subcutaneously injected with PBS or Morris Hepatoma 7777 cells to induce a tumor. Two weeks after this injection the animals received an intraperitoneal injection of methotrexate or saline. Three weeks later hippocampal cell proliferation was quantified using immunohistochemical staining. Treatment with Morris Hepatoma 7777 cells decreased the number of proliferating cells as compared to control animals. An overall tumor effect was absent mainly because methotrexate treatment significantly decreased cell proliferation with no differences between animals with or without a tumor. Neither methotrexate nor the tumor induced pica behavior. These findings indicate that although the presence of a tumor reduces hippocampal cell proliferation it does not affect the negative effect of methotrexate on this plasticity marker. Since sickness behavior is not induced by methotrexate or tumor presence it does not play a role in the development of cognitive deficits. This study further indicates that the effects of methotrexate on brain and behavior can be studied in healthy animals.
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PMID:Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor. 1982 28

The inhibitory effect of recombinant canstatin on tumor growth was investigated using an orthotopic oral squamous cell carcinoma (AT-84 cells) animal (C3H/HeN) model. Recombinant canstatin from stably transfected Drosophila S2 cells was purified to homogeneity using a simple one-step Ni NTA affinity fractionation. In our oral cancer model, the final volume and weight of tumors in groups treated with purified canstatin were both reduced to 44% of values for a control group treated with PBS. Blood or lymphatic vessel densities of tumors in the canstatin-treated group were reduced to 72% and 44% of control group values, respectively. Recombinant canstatin at 20 microg/ml effectively inhibited tube formation in HUVEC and lymphatic endothelial cells. Our results show that recombinant canstatin has anti-tumoral effects against primary oral squamous cell carcinoma.
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PMID:Recombinant canstatin inhibits tumor growth in an orthotopic AT-84 oral squamous cell carcinoma model. 1983 34

Interleukin-12 has been elucidated as a powerful anti-cancer factor in pre-clinical research. However, the obstacles of this modality that emerged from human clinical trails included the toxicity of repeated large dose administration and short effective duration. Therefore, a prolonged, constant therapeutic level of interleukin-12 is required to reduce the adverse effects and enhance the therapeutic efficacy. In this study, 54 nude mice were divided into three groups treated with rAAV2 encoding interleukin-12, rAAV2 vector, and PBS, respectively. All nude mice received human glioblastoma multiforme cell line DBTRG implantation. The biochemistry studies included serum levels of interleukin-12, isotypes of immunoglobulin, interferon-gamma, and TNF-alpha. The activated NK cells were sorted from the spleen by flow cytometry and the cytotoxicity of NK cells were evaluated by LDH assay. In the rAAV2 encoding interleukin-12 group, substantial expression of interleukin-12 was obtained with a serum level of 120-150 pg/ml through the experimental course and a significant increase of activated NK cells was achieved. The splenocytes extracted from the spleen in rAAV2 encoding IL-12 mice strongly exhibited cytotoxic activity compared to the control groups (p<0.001). The IgG1, IgG2a, and IgM also showed a significant increase in the rAAV2 encoding IL-12 group compared to the control groups (p<0.05). The tumor growth rate decreased obviously in the rAAV2 encoding IL-12 group with a significant difference from the control groups (p<0.001). This study demonstrated an encouraging result of immunomodulative therapy in malignant brain tumors by rAAV2 carrying IL-12 through activating NK cells.
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PMID:AAV2-mediated interleukin-12 in the treatment of malignant brain tumors through activation of NK cells. 1988 59

FVE is a documented immunomodulatory protein purified from Enoki mushroom (Flammulina velutipes) and known as an activator for human T lymphocytes. This present study was aimed to investigate the anti-tumor effect and the related mechanisms of oral administration of FVE using a murine hepatoma model. Oral administration of FVE (10mg/kg) significantly increased the life span and inhibited the tumor size of BNL 1MEA.7R.1 (BNL) hepatoma-bearing mice. Tumor-bearing mice receiving oral FVE treatment had the highest tumoricidal capacity of peritoneal macrophages and tumor-specific splenocytes against BNL hepatoma cells. In addition, in vivo neutralization of interferon-gamma (IFN-gamma) demonstrated a significant decrease of FVE-induced anti-tumor effect (P<0.05). The expression levels of major histocompatibility complex (MHC) class I and II molecules and costimulatory molecule CD80 on peripheral blood mononuclear cells obtained from the FVE-treated mice were upregulated as compared with those of the PBS-treated mice. Furthermore, immunohistochemical staining showed a strong inhibition of tumor growth and angiogenesis in hepatoma tissues after oral administration of FVE. Taken together, oral administration of FVE displayed anti-tumor activity through activating both innate and adaptive immunity of the host to prime a cytotoxic immune response and IFN-gamma played a key role in the anti-tumor efficacy of FVE.
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PMID:Oral administration of an Enoki mushroom protein FVE activates innate and adaptive immunity and induces anti-tumor activity against murine hepatocellular carcinoma. 1990 27

In order to research the survivin gene's action on an animal tumor, we used an adenovirus-mediated siRNA system to inhibit the expression of survivin in an animal model of hepatocarcinoma using nude mice. We constructed a hepatocarcinoma model with nude mice using the hepatocarcinoma cell line HepG2 and divided the mice into four groups depending on the injection dose of AdsiRNA-survivin. We injected the constructed survivin-siRNA adenovirus into tumor-bearing nude mice, observed tumor growth, and determined the tumor growth curve. We then detected tumor cell apoptosis using a TUNEL kit that can assay sliced DNA in tumor cells. The growth of tumors injected with a high or low dose of AdsiRNA-survivin was obviously inhibited, and this level of inhibition was positively correlated with the injected dose of adenovirus. Results of the TUNEL test showed that many of the apoptotic cells were brown in color with concentrated nuclei and an irregular cell shape for both the high and low injection doses. The number of apoptotic cells decreased by group in the order of the high dose group, the low dose group, the AdsiRNA-U6 group, and the PBS group. In conclusion, our results demonstrated that an adenovirus-mediated siRNA system can be used for animal experiments in vivo. AdsiRNA-survivin efficiently inhibited tumor growth and induced tumor cell apoptosis, and it did so in a dose-dependent manner.
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PMID:Adenovirus-mediated siRNA inhibited survivin gene expression induces tumor cell apoptosis in nude mice. 2010 33


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