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1.
Immunogenic HER-2/neu peptides as tumor vaccines 总被引:6,自引:0,他引:6
Baxevanis CN Sotiriadou NN Gritzapis AD Sotiropoulou PA Perez SA Cacoullos NT Papamichail M 《Cancer immunology, immunotherapy : CII》2006,55(1):85-95
During the last decade, a large number of tumor-associated antigens (TAA) have been identified, which can be recognized by
T cells. This has led to renewed interest in the use of active immunization as a modality for the treatment of cancer. HER-2/neu
is a 185-KDa receptor-like glycoprotein that is overexpressed by a variety of tumors including breast, ovarian, lung, prostate
and colorectal carcinomata. Several immunogenic HER-2/neu peptides recognized by cytotoxic T lymphocytes (CTL) or helper T
lymphocytes (TH) have been identified thus far. Patients with HER-2/neu over-expressing cancers exhibit increased frequencies
of peripheral blood T cells recognizing immunogenic HER-2/neu peptides. Various protocols for generating T cell-mediated immune
responses specific for HER-2/neu peptides have been examined in pre-clinical models or in clinical trials. Vaccination studies
in animals utilizing HER-2/neu peptides have been successful in eliminating tumor growth. In humans, however, although immunological
responses have been detected against the peptides used for vaccination, no clinical responses have been described. Because
HER-2/neu is a self-antigen, functional immune responses against it may be limited through tolerance mechanisms. Therefore,
it would be interesting to determine whether abrogation of tolerance to HER-2/neu using appropriate adjuvants and/or peptide
analogs may lead to the development of immune responses to HER-2/neu epitopes that can be of relevance to cancer immunotherapy.
Vaccine preparations containing mixtures of HER-2/neu peptides and peptide from other tumor-related antigens might also enhance
efficacy of therapeutic vaccination.
This article is a symposium paper from the conference “Progress in Vaccination against Cancer 2004 (PIVAC 4)”, held in Freudenstadt-Lauterbad,
Black Forest, Germany, on 22–25 September 2004 相似文献
2.
Mathupala SP Colen CB Parajuli P Sloan AE 《Journal of bioenergetics and biomembranes》2007,39(1):73-77
Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors.
Primarily the result of altered isozyme expression, these adaptations enhance the survival and proliferation of the tumor
at the expense of surrounding normal tissue. Consequently, they also expose a unique set of targets for tumor destruction
while sparing healthy tissues. Despite this fact, development of drugs to directly target such altered metabolic pathways
of malignant tumors has been under-investigated until recently. One such target is the ultimate step of glycolysis, which,
as expected, presents itself as a metabolic aberration in most malignant tumors. Termed “aerobic glycolysis” due to abnormal
conversion of pyruvic acid to lactic acid even under normoxia, the altered metabolism requires these tumors to rapidly efflux
lactic acid to the microenvironment in order to prevent poisoning themselves. Thus, exposed is a prime “choke-point” to target
these highly malignant, frequently chemo- and radio- resistant tumors. This review will focus on current outcomes in targeting
lactate efflux in such tumors using glioma as a model, an ongoing project in our laboratory for the past half-decade, as well
as supporting evidence from recent studies by others on targeting this “tail-end” of glycolysis in other tumor models. 相似文献
3.
4.
Brian M. Olson Thomas P. Frye Laura E. Johnson Lawrence Fong Keith L. Knutson Mary L. Disis Douglas G. McNeel 《Cancer immunology, immunotherapy : CII》2010,59(6):943-953
Prostatic acid phosphatase (PAP) has been investigated as the target of several antigen-specific anti-prostate tumor vaccines.
The goal of antigen-specific active immunotherapies targeting PAP would ideally be to elicit PAP-specific CD8+ effector T
cells. The identification of PAP-specific CD8+ T-cell epitopes should provide a means of monitoring the immunological efficacy
of vaccines targeting PAP, and these epitopes might themselves be developed as vaccine antigens. In the current report, we
hypothesized that PAP-specific epitopes might be identified by direct identification of pre-existing CD8+ T cells specific
for HLA-A2-restricted peptides derived from PAP in the blood of HLA-A2-expressing individuals. 11 nonamer peptides derived
from the amino acid sequence of PAP were used as stimulator antigens in functional ELISPOT assays with peripheral blood mononuclear
cells from 20 HLA-A2+ patients with prostate cancer or ten healthy blood donors. Peptide-specific T cells were frequently
identified in both groups for three of the peptides, p18–26, p112–120, and p135–143. CD8+ T-cell clones specific for three
peptides, p18–26, p112–120, and p299–307, confirmed that these are HLA-A2-restricted T-cell epitopes. Moreover, HLA-A2 transgenic
mice immunized with a DNA vaccine encoding PAP developed epitope-specific responses for one or more of these three peptide
epitopes. We propose that this method to first identify epitopes for which there are pre-existing epitope-specific T cells
could be used to prioritize MHC class I-specific epitopes for other antigens. In addition, we propose that the epitopes identified
here could be used to monitor immune responses in HLA-A2+ patients receiving vaccines targeting PAP to identify potentially
therapeutic immune responses. 相似文献
5.
Chang-Gi Kim Dae In Kim Hyo-Jeong Kim Ji Eun Park Bumkyu Lee Kee Woong Park Soon-Chun Jeong Kyung Hwa Choi Joo Hee An Kang-Hyun Cho Young Soon Kim Hwan Mook Kim 《Journal of Plant Biology》2009,52(3):251-258
We conducted a 2-year field assessment of the gene flow from genetically modified (GM) chili pepper (Capsicum annuum L.), containing the PepEST (pepper esterase) gene, to a non-GM control line “WT512” and two commercial hybrid cultivars, “Manidda” and “Cheongpung Myeongwol
(CM).” After seeds were collected from the pollen-recipient non-GM plants, hybrids between them and the GM peppers were screened
by a hygromycin assay. PCR with the targeting hpt gene was performed to confirm the presence of transgenes in hygromycin-resistant seedlings. Out of 7,071 “WT512” seeds and
6,854 “Manidda” seeds collected in 2006, eight and 12 hybrids, respectively, were detected. In 2007, 33 hybrids from 3,456
“WT512” seeds and 50 hybrids from 3,457 “CM” seeds were found. The highest frequency of gene flow, 6.19%, was observed in
that 2007 trial. These results suggest that a limited isolation distance would be sufficient to prevent gene flow from GM
to conventionally bred chili peppers. 相似文献
6.
Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β) co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET) (TS plasmid), in comparison to the plasmid with constitutive promoter (CON plasmid), in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET) of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined. 相似文献
7.
The effects (and interaction) of two solution concentrations of Mg (50, 500, μM) and two of K (250, 4250 μM) on the growth of micropropagated plants of “F. 12/1” and “Colt” were investigated using a flowing solution culture system.
Magnesium inflow and growth of “Colt” and “F. 12/1” were inhibited to a similar extent by an increased concentration of K
in the nutrient solution. However, the consequences of this inhibition were different. Reduced inflow of Mg in “F. 12/1” caused
Mg deficiency symptoms at high and low concentrations of K, whereas this only occurred with a combination of high K concentration
and low Mg concentration in “Colt”. The distribution of dry matter within the plant was significant in determining susceptibility
to Mg deficiency. Since “F. 12/1” has a smaller root:shoot ratio than Colt it is unable to sustain the same concentration
of Mg in leaves as “Colt” irrespective of external K concentration. The molar ratio of K:Mg in soil solutions should remain
<8.5:1 in order to ensure maximum growth of “F. 12/1” and “Colt”.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
8.
Pedersen PL 《Journal of bioenergetics and biomembranes》2007,39(1):1-12
This introductory article to the review series entitled “The Cancer Cell’s Power Plants as Promising Therapeutic Targets”
is written while more than 20 million people suffer from cancer. It summarizes strategies to destroy or prevent cancers by
targeting their energy production factories, i.e., “power plants.” All nucleated animal/human cells have two types of power
plants, i.e., systems that make the “high energy” compound ATP from ADP and P
i
. One type is “glycolysis,” the other the “mitochondria.” In contrast to most normal cells where the mitochondria are the
major ATP producers (>90%) in fueling growth, human cancers detected via Positron Emission Tomography (PET) rely on both types
of power plants. In such cancers, glycolysis may contribute nearly half the ATP even in the presence of oxygen (“Warburg effect”).
Based solely on cell energetics, this presents a challenge to identify curative agents that destroy only cancer cells as they
must destroy both of their power plants causing “necrotic cell death” and leave normal cells alone. One such agent, 3-bromopyruvate
(3-BrPA), a lactic acid analog, has been shown to inhibit both glycolytic and mitochondrial ATP production in rapidly growing
cancers (Ko et al., Cancer Letts., 173, 83–91, 2001), leave normal cells alone, and eradicate advanced cancers (19 of 19)
in a rodent model (Ko et al., Biochem. Biophys. Res. Commun., 324, 269–275, 2004). A second approach is to induce only cancer
cells to undergo “apoptotic cell death.” Here, mitochondria release cell death inducing factors (e.g., cytochrome c). In a
third approach, cancer cells are induced to die by both apoptotic and necrotic events. In summary, much effort is being focused
on identifying agents that induce “necrotic,” “apoptotic” or apoptotic plus necrotic cell death only in cancer cells. Regardless
how death is inflicted, every cancer cell must die, be it fast or slow. 相似文献
9.
A reevaluation of floral and vegetative morphology together with data from analysis of floral fragrance and flavonoid co-pigment
chemistry suggest that specific status is warranted for the two kinds ofPhalaenopsis violacea Witte known informally as the “Bornean type” and the “Malayan type.”Phalaenopsis violacea var.bellina Rchb.f. is elevated to specific rank, providing a name for the “Bornean type” plants. 相似文献
10.
Molecular addresses in blood vessels as targets for therapy 总被引:9,自引:0,他引:9
We have isolated several organ- and tumor-homing peptides by using in vivo phage display. This technology involves the screening of peptide libraries in a living animal. The peptides that result from such a selection home to specific organs or tissues because they recognize molecular 'addresses', receptors that are differentially expressed in vascular beds. Targeted delivery of chemotherapeutics, pro-apoptotic peptides and cytokines to tumors using these peptides improved therapeutic efficacy in animal models. Translation of this technology into clinical applications will form the basis for targeting therapeutic and imaging agents in the context of cancer and other diseases. 相似文献
11.
Driessens G Nuttin L Gras A Maetens J Mievis S Schoore M Velu T Tenenbaum L Préat V Bruyns C 《Cancer immunology, immunotherapy : CII》2011,60(2):273-281
Vaccination of dendritic cells (DC) combined with GM-CSF secreting tumor cells has shown good therapeutic efficacy in several
tumor models. Nevertheless, the engineering of GM-CSF secreting tumor cell line could represent a tedious step limiting its
application for treatment in patients. We therefore developed in rats, an “all in vivo” strategy of combined vaccination using
an in vivo local irradiation of the tumor as a source of tumor antigens for DC vaccines and an exogenous source of GM-CSF.
We report here that supplying recombinant mGM-CSF by local injections or surgical implantation of osmotic pumps did not allow
reproducing the therapeutic efficacy observed with in vitro prepared combined vaccines. To bypass this limitation possibly
due to the short half-life of recombinant GM-CSF, we have generated adeno-associated virus coding for mGM-CSF and tested their
efficacy to transduce tumor cells in vitro and in vivo. The in vivo vaccines combining local irradiation and AAV2/1-mGM-CSF
vectors showed high therapeutic efficacy allowing to cure 60% of the rats with pre-implanted tumors, as previously observed
with in vitro prepared vaccines. Same efficacy has been observed with a second generation of vaccines combining DC, local
tumor irradiation, and the controlled supply of recombinant mGM-CSF in poloxamer 407, a biocompatible thermoreversible hydrogel.
By generating a successful “all in vivo” vaccination protocol combining tumor radiotherapy with DC vaccines and a straightforward
supply of GM-CSF, we have developed a therapeutic strategy easily translatable to clinic that could become accessible to a
much bigger number of cancer patients. 相似文献
12.
Chang-Gi Kim Bumkyu Lee Dae In Kim Ji Eun Park Hyo-Jeong Kim Kee Woong Park Hoonbok Yi Soon-Chun Jeong Won Kee Yoon Chee Hark Harn Hwan Mook Kim 《Journal of Plant Biology》2008,51(1):74-77
Gene flow from genetically modified (GM) crops to conventional non-GM crops is a serious concern for protection of conventional
and organic farming. Gene flow from GM watermelon developed for rootstock use, containing cucumber green mottle mosaic virus
(CGMMV)-coat protein (CP) gene, to a non-GM isogenic control variety “Clhalteok” and grafted watermelon “Keumcheon” was investigated
in a small scale field trial as a pilot study. Hybrids between GM and non-GM watermelons were screened from 1304 “Chalteok”
seeds and 856 “Keumcheon” seeds using the duplex PCR method targeting theCGMMV- CP gene as a marker. Hybrids were found in all pollen recipient plots. The gene flow frequencies were greater for “Chaiteok”
than for “KeumcheonD; with 75% outcrossing in the “Chaiteok” plot at the closest distance (0.8 m) to the GM plot. A much larger
scale field trial is necessary to identify the isolation distance between GM and non-GM watermelon, as the behaviors of insect
pollinators needs to be clarified in Korea. 相似文献
13.
Jing Zhang Yan Liu Dan Yu Hongze Song Jingjin Cui Tao Liu 《Journal of applied phycology》2011,23(2):165-171
Hybridization of gametophytes, continuous self-crossing and targeted selection were utilized to breed a new Laminaria variety. After five-generation selection breeding, the new variety “Rongfu” was obtained. Its male parent “Yuanza No.10”
was the high-yield cultivation variety, and its female parent was variety “Fujian” which could tolerate relatively high seawater
temperature. “Yuanza No.10” and “Fujian” were different but complement in their morphological characteristics and biological
habits. Variety “Rongfu” was bred through their hybridization which exhibited high-yield potential and high seawater temperature
tolerance. The results of traits evaluation in consecutive years showed that “Rongfu” attained higher yields by 24–27% compared
to the control (widely used commercial variety) and also contained considerable amounts of iodine, mannitol, and algin. When
seawater temperature was 18–21°C, the blade growth of “Rongfu” was maintained and tissue loss by abrasion was significantly
lower than the control. Since the adoption of variety “Rongfu” in 2001, its cultivation areas have been extended to Shandong,
Fujian and Guangdong province and have reached 14,133 ha currently, i.e., almost one-tenth of the total cultivation areas
of Laminaria in China. The results of Random Amplified Polymorphic DNA analysis showed that the relationship between “Rongfu” and other
cultivation varieties in China was very close. 相似文献
14.
15.
Over two consecutive years in the North Bank Plain Zone of Assam, India, during the spring growing season (February–June)
of- 2006 and 2007 we examined effects of morpho-physiological characteristics of rice (Oryza sativa L.) plants in relation to methane (CH4) emission from paddy fields. Traditional cultivar “Agni” and modern improved cultivar “Ranjit” were grown in light textured
loamy soil under irrigation. A higher seasonal integrated methane flux (E
sif) was recorded from “Agni” compared to “Ranjit”. Both cultivars exhibited an emission peak during active vegetative growth
and a second peak at panicle initiation. Leaf and tiller number, leaf area, length, and volume of root were greater in “Agni”,
but grain yield and yield-related parameters such as increased photosynthate partitioning to panicles at the expense of roots
were greater in “Ranjit”. “Ranjit” also photosynthesed faster than “Agni” during panicle development but slower than “Agni”
at tillering. In both the years, a higher soil organic carbon content was recorded in plots of “Agni”. Our results suggest
that in “Agni” enhanced diversion of photosynthate to roots resulted in more substrate being available to methanogenic bacteria
in the rhizosphere. Additionally, the more extensive vegetative growth of this cultivar may enhance methane transport from
the soil to the above-ground atmosphere. 相似文献
16.
Peptides derived from extracellular matrix proteins have the potential to function as potent therapeutic reagents to increase
neuronal regeneration following central nervous system (CNS) injury, yet their efficacy as pharmaceutical reagents is dependent
upon the expression of cognate receptors in the target tissue. This type of codependency is clearly observed in successful
models of axonal regeneration in the peripheral nervous system, but not in the normally nonregenerating adult CNS. Successful
regeneration is most closely correlated with the induction of integrins on the surface of peripheral neurons. This suggests
that in order to achieve optimal neurite regrowth in the injured adult CNS, therapeutic strategies must include approaches
that increase the number of integrins and other key receptors in damaged central neurons, as well as provide the appropriate
growth-promoting peptides in a “regeneration cocktail.” In this review, we describe the ability of peptides derived from tenascin-C,
fibronectin, and laminin-1 to influence neuronal growth. In addition, we also discuss the implications of peptide/receptor
interactions for strategies to improve neuronal regeneration. 相似文献
17.
Citrus is an important fruit crop as regards accumulation of carotenoids. In plant carotenoid biosynthesis, phytoene synthase gene
(Psy) plays a key role in catalyzing the head-to-head condensation of geranylgeranyl diphosphate molecules to produce colorless
phytoene. In the present paper, we reported the phytoene contents determination and characterization of Psy during fruit ripening of “Washington” navel orange and its red-fleshed mutant “Cara Cara”. Results showed that phytoene was
exclusively accumulated in peel and pulp of “Cara Cara”. Although phytoene was observed accumulating with fruit ripening of
“Cara Cara”, the contents in pulp were 10 times higher than those in peel. The isolated two Psy cDNAs were both 1520 bp in full length, containing 436 deduced amino acid residues, with a different amino acid at 412th.
Genomic hybridization results showed that one or two copies might be present in “Cara Cara” and “Washington” genomes. During
“Cara Cara” and “Washington” fruit coloration, expression of Psy was observed to be up-regulated, as revealed by tissue specific profiles in the flavedo, albedo, segment membrane and juice
sacs. However, Psy expression in albedo of “Cara Cara” was higher than that in “Washington”, as evidenced by phytoene accumulation in the peel. 相似文献
18.
Electrical stimulation of hypothalamic “feeding areas” (VMH & LHA) through stereotaxically implanted electrodes was carried
out in normal and streptozotocinized diabetic conscious male rhesus monkeys. In normal monkeys, the VMH stimulation resulted
in a significant decrease in serum insulin and blood glucose while opposite responses were observed following LHA stimulation.
Serum growth hormone, FFA and plasma cortisol levels increased significantly on stimulation of LHA and VMH in normal animals.
The pattern of blood glucose and serum growth hormone responses to stimulation of “feeding areas” was similar in normal and
diabetic animals. The serum insulin, FFA and plasma cortisol were largely unaffected while growth hormone increased significantly
by stimulation of these areas in diabetes. The present study indicates that the stimulation of “feeding areas” does not alter
the diabetic syndrome significantly nor does diabetes prevent the changes in metabolism seen after stimulation of “feeding
areas.” 相似文献
19.
Werner W. Franke Steffen Rickelt Mareike Barth Sebastian Pieperhoff 《Cell and tissue research》2009,338(1):1-17
Immunocytochemical, electron-, and immunoelectron-microscopical studies have revealed that, in addition to the four major
“textbook categories” of cell-cell junctions (gap junctions, tight junctions, adherens junctions, and desmosomes), a broad
range of other junctions exists, such as the tiny puncta adhaerentia minima, the taproot junctions (manubria adhaerentia), the plakophilin-2-containing adherens junctions of mesenchymal or mesenchymally derived cell types including malignantly
transformed cells, the composite junctions (areae compositae) of the mature mammalian myocardium, the cortex adhaerens of the eye lens, the interdesmosomal “sandwich” or “stud” junctions in the subapical layers of stratified epithelia and the
tumors derived therefrom, and the complexus adhaerentes of the endothelial and virgultar cells of the lymph node sinus. On the basis of their sizes and shapes, other morphological
criteria, and their specific molecular ensembles, these junctions and the genes that encode them cannot be subsumed under
one of the major categories mentioned above but represent special structures in their own right, appear to serve special functions,
and can give rise to specific pathological disorders. 相似文献
20.
Immunotherapeutic approaches to cancer should focus on novel undertakings that modulate immune responses by synergistic enhancement
of anti-tumor immunological parameters. Cancer vaccines should preferably be composed of multiple defined tumor antigen specific
B- and T-cell epitopes. The main focus of this article is to briefly review the present status of Her-2/neu vaccine strategies
and to describe the innovative strategies developed in my laboratory for a vaccine against HER-2/neu (ErbB-2) with emphasis
on the humoral arm of the immune response. Elucidating the underlining mechanisms of anti-tumor effects elicited by peptide
vaccines against a self-protein is a requirement for developing an immunotherapeutic strategy that might be effective in human
cancer vaccines. Our approach entails the identification of biologically relevant epitopes, establishing relevant in vitro assays for monitoring vaccine efficacy, devising strategies to engineer conformationally dependent sequences, developing
highly immunogenic vaccines for an outbred population and delivering the immunogen/vaccine in a safe and efficacious vehicle,
utilizing transgenic animal models for assessing tumor development, and developing challenge models using transplantable tumors
to study efficacy of vaccine constructs. We have developed a multi-HER-2/neu B-cell epitope approach and shown in preclinical
studies that immunization with a combination of two B-cell epitope was more effective in preventing mammary tumors than a
single epitope. We have translated that work to the clinic (OSU 0105) in an FDA approved, NCI sponsored “Phase 1 Active Immunotherapy trial with Chimeric and Multi-epitope based peptide vaccine targeting HER-2 oncoprotein and
nor-MDP adjuvant in patients with metastatic and/or recurrent solid tumors” at the James Cancer Hospital at the Ohio State University. The correlation between overexpression of HER-2/neu and up-regulation of VEGF has been demonstrated in breast cancer patients. Thus, blocking angiogenesis is an attractive strategy
to inhibit tumor growth, invasion, and metastasis. The hypothesis that combination of anti-angiogenic therapy and tumor immunotherapy
of cancer may be synergistic is an important future goal. In this review, I will discuss insights into our preclinical studies
that might aid in the design of the next generation of cancer vaccines and become an integrated component of prophylactic/preventive
and therapeutic approach. 相似文献