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)

The HER-2/neu proto-oncogene is frequently amplified or overexpressed in human breast and ovarian cancers, and is significantly correlated with shorter survival. We have previously reported that the adenovirus type 5 early region 1A (E1A) gene product can repress HER-2/neu overexpression by repressing HER-2/neu promoter activity, and suppress the tumorigenic potential of HER-2/neu-overexpressing ovarian cancer cells. To examine E1A tumor suppressor function in breast cancer, we transduced E1A in vitro by adenovirus into both HER-2/neu-overexpressing and low expressing human breast cancer cell lines. In HER-2/neu-overexpressing cells, E1A greatly inhibited tumor cell growth in vitro. However, in HER-2/neu low expressing cancer cell lines, E1A had no significant effect on cell growth in culture medium. To test the therapeutic efficacy of E1A, we used both adenovirus-mediated and cationic liposome-mediated E1A gene delivery systems in an orthotopic breast cancer animal model. An advanced breast cancer model was established by inoculation of HER-2/neu-overexpressing human breast cancer cells in mammary fat pad and treated by local injections of either replication-deficient adenovirus expressing E1A, Ad.E1A(+) or a liposome-E1A DNA complex. As controls, mice bearing tumors were also treated with Ad.E1A(-) which is virtually the same adenovirus as Ad.E1A(+) except that E1A is deleted, a liposome-E1A frame-shift mutant DNA complex, or just PBS. In mice bearing a HER-2/neu-overexpressing breast cancer cell line, E1A delivered either by adenovirus or liposome significantly inhibited tumor growth and prolonged mouse survival compared with the controls. In fact, 60-80% of E1A-treated mice lived longer than 2 years versus only 0-20% of control mice (P<0.05). Western blot analysis showed that E1A protein was expressed in tumor tissue and immunohistochemical analysis showed that HER-2/neu p185 protein expression was suppressed. Taken together, our results indicated that both adenovirus and cationic liposome delivery systems were effective in transfering E1A gene for tumor suppression in a HER-2/neu-overexpressing breast cancer model.
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PMID:The tumor suppression activity of E1A in HER-2/neu-overexpressing breast cancer. 905 54

We have previously described potent growth-inhibitory effect of a recombinant adenovirus expressing wild type p53 (AdWTp53) in metastatic prostate cancer cells via activation of cellular p53 pathways. We have extended these observations to analyze the effects of AdWTp53 on primary cultures of radical prostatectomy specimens (RPS) and have also evaluated the gene therapeutic potential of the AdWTp53 in a nude mice model. Infection of primary cultures of prostate cancer specimens resulted in about 80% cell growth inhibition in comparison with cultures treated with control adenovirus dl312. Single injection of AdWTp53 into pre-established tumor nodules of DU145 prostate cancer cells suppressed tumor growth significantly (p = 0.0407) as determined by comparison of tumor volumes of the AdWTp53-treated vs. control vector (dl312) or PBS-treated groups. Moreover, there was no significant difference in tumor growth inhibition between single vs. multiple injections of AdWTp53. Our observations support the potential of AdWTp53 for gene therapy of prostate cancer.
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PMID:Inhibition of the growth of pre-established subcutaneous tumor nodules of human prostate cancer cells by single injection of the recombinant adenovirus p53 expression vector. 913 72

Replication-defective adenovirus vectors were generated in which the gene of interest (lacZ, luciferase or HSV-tk) is driven by the adenovirus major late promoter (MLP) or the human cytomegalovirus immediate-early gene promoter/enhancer (CMV). In vitro experiments with rat (II-45) and human (MERO 25) mesothelioma cell lines revealed that the CMV promoter was stronger than the MLP promoter regarding levels of expression of the luciferase reporter gene and ganciclovir (GCV) killing efficiency after tk gene transfer. Following administration of IG.Ad.CMV.lacZ recombinant adenovirus (Introgene, IG) into the pleural cavity of Fischer rats with established mesothelioma, a widespread distribution of infectious virus particles through the thorax contents was demonstrated. However, a relatively small proportion of tumor cells were transduced. Nevertheless, a strong tumor growth inhibition was observed following treatment with IG.Ad.CMV.TK recombinant adenovirus and GCV. Separate groups of rats inoculated on day 0 with 10(5) II-45 cells in the pleural cavity, received 7 x 10(9) infectious particles of IG.Ad. CMV.TK on day 1, day 2, day 4 or day 8. One day after virus administration, 25 mg/kg GCV or PBS (controls) was injected i.p. (intraperitoneally) twice daily. On day 15, all animals were killed. Significant tumor regression, equivalent to 5 log cell kill, occurred in the treated rats suggesting an impressive bystander effect. In a survival study, animals were treated 9 days after inoculation of 10(5) tumor cells with IG.Ad.CMV.TK and a 14 days course of GCV. This treatment prolonged symptom-free survival time from 19 days in the controls to 33 days in the treated group. These responses can be best explained by assuming continued tk expression in or around the tumor tissue during GCV treatment. Our results confirm and extend earlier findings with the same model and demonstrate the potential of the herpes simplex virus thymidine kinase suicide gene therapy as a local treatment for malignant mesothelioma.
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PMID:Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSVtk gene. 917 12

The effect of the antiviral agent (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (cidofovir) on the EBV-associated tumor nasopharyngeal carcinoma (NPC) was evaluated in NPC xenografts in athymic mice. Intratumoral injection arrested tumor growth within 1 week, and by 4 weeks, tumors regressed to 8-75% (39 +/- 33%) of the original size, whereas control tumors injected with PBS grew to 282 +/- 25% of the original size. Ganciclovir slowed but did not arrest or cause regression of tumor growth. A striking antitumor effect was also produced by systemic administration; at 4 weeks, tumors were 79 +/- 49% of the original size, compared with 635 +/- 91% for the controls. Widespread apoptosis was detected after treatment for 2-6 days in C15 as well as two other NPC xenografts, C17 and C18; the latter NPCs have mutations in the p53 gene. These data indicate that cidofovir induces rapid cell death through apoptosis in EBV-transformed epithelial cells.
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PMID:The antiviral agent cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine] has pronounced activity against nasopharyngeal carcinoma grown in nude mice. 945 76

Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits bone metastasis. We examined the effects of TNP-470 in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-MB-231 (MDA-231) produced osteolytic bone metastasis. After inoculation of MDA-231 cells into the left heart ventricle, TNP-470 (30 mg/kg, three times a week) or PBS was s.c. administrated for 4 weeks. After this period, the TNP-470 had reduced not only the number and area of osteolytic bone metastases (approximately 60 and 70%, respectively) but also their radiolucency. Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer. Numerous active osteoclasts were present along the trabecular bone surface surrounded by the metastatic MDA-231 cancer cells aggressively invading the bone marrow. In contrast, in the bone from TNP-470-treated mice, bone destruction was markedly inhibited, and there were much fewer osteoclasts. In a murine bone marrow culture under 1,25-dihydroxyvitamin D3 in which mature functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells. And also, TNP-470 suppressed the in vivo bone resorption in calvaria treated with interleukin-1beta, an osteoclast stimulator. These data suggested that TNP-470 inhibited bone metastasis through not only antitumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.
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PMID:Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption. 945 90

Growth factor-induced angiogenesis was studied using subcutaneously implanted gelatin sponges loaded with 10 mg ml-1 of acidic fibroblast growth factor (aFGF) in 20 micrograms ml-1 PBS heparin. The administration of 1,3,6-naphthalenetrisulfonate (NTS) directly into the sponge (20 mg ml-1) or intraperitoneally (200 mg kg-1) blocks invasion of the sponge by vasculature. Since angiogenesis is essential for tumor progression, the findings of the present study that NTS is an efficient inhibitor of neovascularization warrant further investigation of the potential clinical utility of this angiostatic agent for treating tumor growth and metastasis.
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PMID:Suppression of acidic fibroblast growth factor-dependent angiogenesis by the antigrowth activity of 1,3,6-naphthalenetrisulfonate. 1010 Feb 7

At present more than 70 human papillomaviruses (HPV) genotypes have been described and each shows a predilection for a cutaneous or mucosal surface. There is a strong association between infection with specific genital viruses (i.e., types 16 and 18) and the development of cervical cancer. Thus, intervention with the natural history of HPV infection in the genital tract may form the basis for an effective anticancer strategy. We have shown that treatment of cell lines derived from human cervical carcinomas [i.e., SiHa and CaSki (HPV-16-positive)] and HeLa (HPV-18-positive)] with HPMPC (cidofovir) results in a concentration- and time-dependent inhibition of cell proliferation. We report here the effects of HPMPC on the growth of cervical carcinoma (SiHa) xenografts in athymic nude mice. Athymic mice between the age of 6 and 8 weeks were injected SC with 5 to 10x10(6) cells. Once tumors were established, the mice were injected with PBS (placebo), HPMPC, or cytarabine (AraC) at the tumor site. Animals that were injected intratumorally with HPMPC at a dose of 5 mg/ml (0.25 mg/injection) or 10 mg/ml (0.5 mg/injection) three or five times per week, once daily, during 4 weeks showed a statistically significant reduction in tumor size compared to the placebo group or AraC group. However, when HMPC was administered topically (as a cream) or systemically (intraperitoneally), no reduction of tumor growth was observed at nontoxic concentrations, suggesting that a high local concentration of HPMPC is required to achieve a significant decrease of tumor growth.
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PMID:Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa) xenografts in athymic nude mice. 1033 56

The mode of peptide-based cancer vaccine administration critically affects the ability to achieve a clinically relevant tumor-specific response. We have previously shown (Cole et al., Clin. Cancer Res., 3: 867-873, 1997) that a specific formulation of the polysaccharide poly-N-acetyl glucosamine (p-GlcNAc, designated as F2 gel) is an effective vehicle for sustained cytokine and peptide delivery in vitro. The purpose of this study was to evaluate the efficacy of F2 gel/peptide vaccination in the murine EG.7-OVA tumor model and to elucidate potential mechanisms involved in the observed cell-mediated response. C57BL/6 mice were given injections of 200 microl in the base of tail/footpad using either F2 gel alone or 200 microg of: SIINFEKL minimal peptide (OVA) in PBS, OVA peptide/endoplasmic reticulum insertion signal sequence fusion (ESOVA) in PBS, OVA in F2 gel, or ESOVA in F2 gel. Splenocytes were tested 10 days later for a secondary response using a Cr51 assay as well as a primary CTL response using the lactate dehydrogenase cytotoxicity assay. Splenocytes from immunized mice were harvested at specific time points and assayed for cell surface and intracellular markers. On day 10 postvaccination, animals were challenged with EG.7-OVA murine thymoma cells. Tumor size and appearance were recorded. Vaccination with F2 gel/peptide (either OVA or ESOVA) resulted in a primary T-cell response (up to 25% tumor cell-specific lysis) and no tumor growth in 69% of the mice. By 48 h, the proportion of splenic T cells had increased 4-fold compared with B cells. Presence of an increased Th1 CD4 helper population was demonstrated by IFN-gamma production. CD4 cells were activated at 24 and 48 h as shown by IL-2 receptor alpha chain expression (from 2% basal expression to 15.4% at 48 h). Activated splenic macrophages increased from 3 to 8% within 10 h, and their level of B7-2 expression doubled. Depletion of macrophages before vaccine injection abolished any tumor-specific primary CTL response. F2 gel/peptide tumor vaccine can prime the immune system in an antigen-specific manner by generating a measurable primary T-cell response with minimal peptide; this process involves macrophage presence and activation as well as induction of Th1 CD4 cells. This is the first demonstration of a primary CTL response generated with minimal peptide vaccination using a noninfectious delivery system. These results justify additional studies to better define the mechanisms involved in F2 gel/peptide vaccination in preparation for clinical trials.
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PMID:Primary T-cell and activated macrophage response associated with tumor protection using peptide/poly-N-acetyl glucosamine vaccination. 1035 54

We studied the effects of fragile histidine triad (FHIT) gene overexpression mediated by an adenoviral vector, Ad-FHIT, on cell proliferation, apoptosis, and cell cycle kinetics in human cancer cells and on tumorigenicity and tumor growth in nude mice. Overexpression of the FHIT gene significantly inhibited cell growth in various Ad-FHIT-transduced human lung cancer cells and head and neck carcinoma cells with FHIT gene abnormalities, but not in normal human bronchial epithelial cells. Fewer than 20% of cells in all Ad-FHIT-transduced cells survived at 7 days after transduction. Overexpression of the FHIT gene induced cell apoptosis and altered cell cycle processes. The apoptotic cell population markedly increased, and cells accumulated in S phase after Ad-FHIT transduction. The tumorigenicity of human H1299 lung cancer cells transduced by Ad-FHIT, in comparison with that of the control transductants and untreated cells, was eliminated in vivo. Subcutaneous tumor growth in nude mice who received intratumoral injections of Ad-FHIT, at a total dose of 3 x 10(10) plaque-forming units/tumor for H1299 tumors and 4 x 10(10)/tumor for A549 tumors, were suppressed by more than 85% and 90%, respectively, compared with that in nude mice who received injections of empty vector at the same dose or with PBS alone. Together, our results suggest that the FHIT gene, when delivered at high efficiency by a recombinant adenoviral vector, functions as a tumor suppressor gene both in vitro and in vivo.
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PMID:Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. 1041 89

Ablation of host submaxillary glands modifies Ehrlich tumor growth and tumor-infiltrating leukocytes, possibly by modifications in the serum level of growth factors produced by this gland. To extend this research, 7-month-old male EPM-1 mice (N = 30) were divided into two groups: 1) inoculated with tumor cells previously incubated with submaxillary salivary gland extract (SGE) in PBS for 30 min at 37%; 2) inoculated with tumor cells previously incubated with PBS, under the same conditions. Animals were inoculated into the footpad with 40 microl of a suspension containing 4.5 x 10(7) tumor cells/ml, and footpad thickness was measured daily for 10 days. Sections and smears of tumor cells were prepared from the tumor mass to determine mitosis frequency, percent of tumor cells immunopositive to nerve (NGF) and epidermal (EGF) growth factors and percent of tumor-infiltrating leukocytes. The incubation of tumor cells with SGE produced a tumor reduction of about 30% in size (P<0.01). This effect was not related to loss of cell viability during incubation, but a 33% increase (P<0.05) in the percentage of dead or dying tumor cells and a 15% increase in the percent of NGF/EGF-positive tumor cells (P<0.01) were observed in vivo at the end of experiment. Tumor-infiltrating lymphocytes and mitosis frequency did not differ between groups. These data suggest a direct effect of factors present in SGE on tumor cells, which induce degeneration of tumor cells.
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PMID:Effect of a submaxillary gland extract on Ehrlich tumor growth in mice. 1051 Feb 56


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