Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that intratumoral injection of AdK3, a recombinant adenovirus encoding human angiostatin kringle (K) 1 to 3, inhibits tumor vascularization and tumor growth. To reduce the serum clearance of this factor, we constructed an adenovirus (AdK3-HSA) that carries a chimeric gene encoding a fusion protein between angiostatin K1-3 and human serum albumin (HSA). This conjugate inhibited endothelial cell proliferation as efficiently as K1-3. K3-HSA serum concentrations in immunodeficient mice systemically injected with AdK3-HSA were dramatically higher than in AdK3-injected mice. Furthermore, the growth of MDA-MB-231 tumors grafted into nude mice that had been injected intravenously with AdK3-HSA was inhibited by 79% (versus 17% with AdK3). In TRP-1/SV40 Tag transgenic mice, which spontaneously develop eye tumors with brain metastases, intravenous injections of AdK3-HSA in newborn mice blocked metastatic dissemination efficiently and significantly, and prolonged survival by 3 weeks. After 2 months, only 46% of AdK3-HSA-treated animals developed micrometastases, whereas 94% of the AdCO1-injected group displayed numerous macrometastases. Nevertheless, ocular tumor growth was not modified because of impaired diffusion of the conjugate in the eye compartment. Our results show that HSA genetic coupling is an efficient way to increase the pharmacokinetics of circulating angiogenic inhibitors and thus their antitumoral activity.
...
PMID:Systemic administration of a recombinant adenovirus encoding a HSA-Angiostatin kringle 1-3 conjugate inhibits MDA-MB-231 tumor growth and metastasis in a transgenic model of spontaneous eye cancer. 1259 5

Incorporation of an 11 amino acid region of the HIV TAT protein transduction domain (TAT PTD) into proteins facilitates rapid, efficient entry into cells. We previously showed that rTAT-PTD-OVA-transduced dendritic cells (DC) stimulated antigen (Ag)-specific CTL and Th cells, and vaccinated against OVA-expressing tumors. Here we studied B16 melanoma in C57BL/6 mice, using murine tyrosinase-related protein 2 (Trp2) as a candidate tumor Ag. We produced a 472-amino acid N-terminal fragment of Trp2 protein (rTrp2Delta) with or without PTD. Although PTD-deficient rTrp2Delta was ineffective, mice given rTAT-PTD-Trp2Delta-transduced DC were efficiently primed for Trp2(180-188) peptide-specific and B16-reactive CTL. In 58% of such mice, growth of melanomas was prevented. Trp2(180-188) peptide-pulsed DC protected 35% of recipients, and irradiated GM-CSF-producing B16 cells protected 75%. rTAT-PTD-Trp2Delta-transduced DC induced a more vigorous memory response to B16 rechallenge than the other regimens, and protected 30% of recipients from progressive tumor development in treatment studies. In this setting, Trp2 peptide-treated DC protected 20% and irradiated GM-CSF-producing cells protected 0%. Both tumor prevention and tumor treatment were CD8(+) T cell dependent. Vaccination with rTAT-PTD-Trp2Delta-transduced DC induced a robust CTL response and durable anti-melanoma immunity. This approach should be clinically applicable, and offers theoretical and practical advantages to those that are in current use.
...
PMID:Dendritic cells transduced with TAT protein transduction domain-containing tyrosinase-related protein 2 vaccinate against murine melanoma. 1267 50

This study tested the hypothesis that combination of antiangiogenic therapy and tumor immunotherapy of cancer is synergistic. To inhibit angiogenesis, mice were immunized with dendritic cells (DCs) transfected with mRNA that encode products that are preferentially expressed during neoangiogenesis: vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie2 expressed in proliferating endothelial cells, and vascular endothelial growth factor (VEGF) expressed in the angiogenic stroma as well as the tumor cells used in this study. Immunization of mice against VEGF or VEGFR-2 stimulated cytotoxic T lymphocyte (CTL) responses and led to partial inhibition of angiogenesis. Antiangiogenic immunity was not associated with morbidity or mortality except for a transient impact on fertility seen in mice immunized against VEGFR-2, but not VEGF. Tumor growth was significantly inhibited in mice immunized against VEGF, VEGFR-2, and Tie2, either before tumor challenge or in the setting of pre-existing disease in murine B16/F10.9 melanoma and MBT-2 bladder tumor models. Coimmunization of mice against VEGFR-2 or Tie2 and total tumor RNA exhibited a synergistic antitumor effect. Synergism was also observed when mice were coimmunized with various combinations of defined tumor-expressed antigens, telomerase reverse transcriptase (TERT) or TRP-2, and VEGF or VEGFR-2. This study shows that coimmunizing mice against angiogenesis-associated and tumor-expressed antigens can deliver 2 compatible and synergistic cancer treatment modalities via a common treatment, namely immunization.
...
PMID:Synergy between tumor immunotherapy and antiangiogenic therapy. 1268 40

To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.
...
PMID:Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. 1270 87

Hybrid cells generated by fusing dendritic cells with tumor cells (DC-TC) are currently being evaluated as cancer vaccines in preclinical models and human immunization trials. In this study, we evaluated the production of human DC-TC hybrids using an electrofusion protocol previously defined for murine cells. Human DCs were electrically fused with allogeneic melanoma cells (888mel) and were subsequently analyzed for coexpression of unique DC and TC markers using FACS and fluorescence microscopy. Dually fluorescent cells were clearly observed using both techniques after staining with Abs against distinct surface molecules suggesting that true cell fusion had occurred. We also evaluated the ability of human DC-TC hybrids to present tumor-associated epitopes in the context of both MHC class I and class II molecules. Allogeneic DCs expressing HLA-A*0201, HLA-DR beta 1*0401, and HLA-DR beta 1*0701 were fused with 888mel cells that do not express any of these MHC molecules, but do express multiple melanoma-associated Ags. DC-888mel hybrids efficiently presented HLA-A*0201-restricted epitopes from the melanoma Ags MART-1, gp100, tyrosinase, and tyrosinase-related protein 2 as evaluated by specific cytokine secretion from six distinct CTL lines. In contrast, DCs could not cross-present MHC class I-restricted epitopes after exogenously loading with gp100 protein. DC-888mel hybrids also presented HLA-DR beta 1*0401- and HLA-DR beta 1*0701-restricted peptides from gp100 to CD4(+) T cell populations. Therefore, fusions of DCs and tumor cells express both MHC class I- and class II-restricted tumor-associated epitopes and may be useful for the induction of tumor-reactive CD8(+) and CD4(+) T cells in vitro and in human vaccination trials.
...
PMID:Hybrids of dendritic cells and tumor cells generated by electrofusion simultaneously present immunodominant epitopes from multiple human tumor-associated antigens in the context of MHC class I and class II molecules. 1273 82

The use of reverse immunology may be necessary to identify new tumor-associated antigens, particularly for cancers, against which tumor-reactive T cell populations have been difficult to establish. One approach has been to screen peptides derived from a candidate antigen with high major histocompatibility complex (MHC) binding affinities for the induction of tumor-reactive T lymphocytes in vitro. However, many candidate antigens that are overexpressed in tumors are nonmutated self-proteins, and unlike foreign or mutated proteins, immunodominant epitopes may not be expressed at high density on the surface of tumor cells. Therefore, to identify tumor-associated epitopes, it may be necessary to screen large panels of peptides with wide ranges of MHC binding affinities. The current methodology of stimulating peripheral blood lymphocytes (PBL) from donors expressing the MHC molecule of interest with individual peptides is impractical for screening such large panels. Therefore, we evaluated the use of mixtures of peptides with variable MHC binding affinities for the induction of tumor-reactive T lymphocytes with the melanoma antigens gp100 and an alternate isoform of tyrosinase-related protein 2 (TRP2-6b) as models. A mixture of 10 known human leukocyte antigen (HLA)-A*0201-restricted peptides from gp100 induced melanoma-reactive cytotoxic T lymphoycte (CTL) from multiple patients with metastatic melanoma. The majority of these T cell populations recognized the known immunodominant epitopes gp100:209-217 and gp100:280-288, even though the HLA-A*0201 binding affinities of these peptides were much lower than other peptides in the mixture. Similarly, melanoma-reactive CTL were generated with a mixture of HLA-A*0201-restricted peptides from TRP2-6b, and these responses were directed against the previously identified tumor-associated epitopes TRP2-6b:180-188, TRP2-6b:288-296 and TRP2-6b:403-411. These results suggest that the use of peptide mixtures may facilitate the identification of new tumor-associated antigens through the application of reverse immunology.
...
PMID:Stimulation of tumor-reactive T lymphocytes using mixtures of synthetic peptides derived from tumor-associated antigens with diverse MHC binding affinities. 1273 63

DNA vaccination against tissue-restricted antigens is a strategy for cancer therapy. Immune tolerance and ignorance of self antigens has been a hurdle for this approach. We have shown that immunization with xenogeneic DNA orthologues elicits tumor immunity. One model that we have developed entails immunization of mice against tyrosinase-related protein-2 (Tyrp2) using cDNA encoding homologous human Tyrp2. A subset of mice immunized with human Tyrp2 developed antibody responses to Tyrp1. Unexpectedly, this was not simply due to cross-reactivity, as mice with anti-Tyrp1 antibodies were not usually the same animals with anti-Tyrp2 antibodies. Although autoimmune vitiligo was frequently observed in mice that had been immunized with Tyrp2, its occurrence was not correlated with the development of antibodies to Tyrp1. This implies that the appearance of anti-Tyrp1 antibodies was not simply a consequence of the destruction of melanocytes by T-cells recognizing Tyrp2. This represents an example of intermolecular determinant recognition, but is not simply due to epitope spreading since antibodies against the antigen targeted by DNA vaccination are not typically detected.
...
PMID:Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: unexpected reactivity to a protein paralogue. 1274 53

Tyrosinase-related proteins-1 and -2 (gp75/TRP-1 and TRP-2) are melanosomal membrane glycoproteins recognized by antibodies and T-cells from patients with melanoma. Xenogeneic DNA immunization against gp75/TRP-1 generates antibody-dependent tumor immunity and autoimmune depigmentation. In contrast xenogeneic TRP-2 DNA immunization induces immunity mediated by CD8+ T-cells. The role of IFN-gamma in the generation of tumor immunity and autoimmune depigmentation in these two models was investigated. No tumor protection and minimal depigmentation was observed after immunization with human TRP-2 DNA in mice deficient in IFN-gamma ligand. Repletion with recombinant murine IFN-gamma restored tumor immunity. Experiments using IL4 deficient mice demonstrated that tumor immunity was unaffected but that autoimmune depigmentation was potentially accelerated, consistent with down-modulation of autoimmunity against TRP-2 by IL4. In contrast, IFN-gamma was not required for the generation of immunity to gp75/TRP-1. In fact, exogenous IFN-gamma ablated autoantibody responses against gp75/TRP-1 after xenogeneic DNA immunization, consistent with a down-regulatory effect of IFN-gamma. These results show that immunity to TRP-2 following DNA immunization uses an IFN-gamma-dependent Th1 pathway, but immunity to gp75/TRP-1 is down-regulated by IFN-gamma.
...
PMID:Alternative roles for interferon-gamma in the immune response to DNA vaccines encoding related melanosomal antigens. 1274 70

Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic oligodeoxynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses. The results show that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinase-related protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. Interestingly, whereas this combination therapy was effective when administered to tumor-bearing mice (therapeutic protocol), it had no significant effect when applied in the prophylactic mode (i.e., before the tumor challenge). Moreover, the antitumor effect of the combination immunotherapy required the participation of CD4+ and CD8+ T lymphocytes and was accompanied by the induction of antitumor CD4+ T-cell responses. The overall results suggest that peptide vaccination of tumor-bearing mice, applied in combination with a strong adjuvant and CTLA-4 blockade, is capable of eliciting durable antitumor T cell responses that provide survival benefit. These findings bear clinical significance for the design of peptide-based therapeutic vaccines for human cancer patients.
...
PMID:Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. 1281 Jun 60

Dendritic cells (DCs) need activation for the priming of antigen-specific immune responses. Recently activated DCs were described to prime in vitro strong T helper cell type 1 (Th(1)) responses, whereas at later time points, the same cells preferentially prime Th(2) cells [Langenkemp, A. et al., Nat. Immunol. 1: 311-316, 2000]. Because the immune response against cancer strongly depends on CTLs of Th(1)-like phenotype (Tc(1)), we verified here whether the kinetics of DCs activation also impacted on in vivo priming of tumor-specific CTLs. After pulsing with the CTL epitope TRP-2(180-188), bone-marrow-derived DCs, exposed to lipopolysaccharide (LPS) for 8 h (8hDC), elicited a more powerful Tc(1) response in C57BL/6 mice than did untreated DCs, or DCs exposed to LPS for 48 h (48hDC). Indeed, 8hDCs were the most potent protective and therapeutic vaccine against B16 melanoma. Despite a higher expression of MHC and costimulatory molecules by 48hDCs, 8hDCs and 48hDCs showed comparable allostimulatory and migration potential, and susceptibility to CTL-mediated apoptosis. However, 8hDCs exhibited a significantly higher interleukin (IL)-12 production potential. Release of IL-12 was necessary to induce potent Tc(1) cells, because DCs from IL-12p40(-/-) mice, irrespective of their maturation level, generated low CTL responses, comparable with 48hDCs and 0hDCs from wild-type animals. Our data are relevant for the design of DC-based vaccines.
...
PMID:Critical impact of the kinetics of dendritic cells activation on the in vivo induction of tumor-specific T lymphocytes. 1283 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---