共查询到20条相似文献,搜索用时 15 毫秒
1.
Theoretical analysis of antibody targeting of tumor spheroids: importance of dosage for penetration,and affinity for retention 总被引:5,自引:0,他引:5
The interplay among antibody/antigen binding kinetics, antibody diffusion, and antigen metabolic turnover together determines the depth of penetration of antitumor antibodies into prevascular tumor spheroid cell clumps. A sharp boundary between an outer shell of bound high-affinity antibody and an inner antibody-free core has been previously observed and mathematically modeled and was termed the "binding site barrier." We show here that this process is well described by a simplified shrinking core model wherein binding equilibration is much more rapid than diffusion. This analysis provides the following experimentally testable predictions: (a) the binding site barrier is a moving boundary whose velocity is proportional to the time integral of antibody concentration at the spheroid surface (i.e. plasma antibody AUC); (b) the velocity of this moving boundary is independent of binding affinity, if the affinity is sufficiently high to strongly favor antibody/antigen complex formation at prevailing antibody concentrations; and (c) maximum tumor retention is achieved when the antibody/antigen dissociation rate approaches the rate of antigen metabolic turnover. The consistency of these predictions with published experimental results is demonstrated. The shrinking core model provides a simple analytic relationship predicting the effects of altered antibody pharmacokinetics, antibody molecular weight, antigen turnover rate, antigen expression level, and micrometastasis size on antibody penetration and retention. For example, a formula is provided for predicting the bolus dose necessary to accomplish tumor saturation as a function of antibody and tumor properties. Furthermore, this analysis indicates certain attributes necessary for an optimal tumor targeting agent. 相似文献
2.
E Cetínkaya B Alici Y G?k R Durmaz S Günal 《Journal of chemotherapy (Florence, Italy)》1999,11(2):83-89
Azolium salts and neutral 2-aryl derivatives of benzimidazole, benzothiazole and benzoxazole were synthesized and compounds were identified by 1H and 13C NMR spectroscopy and microanalytical methods. In this work the salts 1 and the neutral compounds 2 were evaluated for their in vitro antimicrobial activity against standard strains: Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Candida albicans and Candida tropicals. The compounds 1f, 1g, 1l, 1m, 1n, 2a, 2b, 2c, 2e, 2f showed antimicrobial activity against Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Candida albicans and Candida tropicals, with minimum inhibitory concentrations (MICs) ranging between 50 to 200 mg/mL. Compounds 1f, 1g, 1l, lm, 2b, 2c showed the highest activity. Benzothiazolium and benzoxazolium salts were more active than 1,3-disubstituted benzimidazolium salts and neutral 2-substituted benzimidazole, benzothiazole and benzoxazole derivatives. 相似文献
3.
恶性肿瘤是严重威胁人类生命的疾病之一,近年来免疫治疗已经成为肿瘤治疗的焦点,解决免疫治疗只对部分患者 有效的问题迫在眉睫。在肿瘤微环境(tumor microenvironment,TME)中趋化因子介导细胞的定向移动,同时具有多种调节功能, 既可以作用于免疫细胞,也可直接作用于肿瘤细胞,发挥了复杂的生物学作用。CXC趋化因子受体3(CXC chemokine receptor 3, CXCR3)通过与其同源CXC趋化因子配体9(CXC chemokine ligand 9,CXCL9)/10/11结合,不仅参与了肿瘤发生、侵袭并促进肿 瘤相关血管的形成,同时也介导了免疫细胞向肿瘤组织中浸润,为无免疫反应性或免疫反应性差的“冷肿瘤”转变为免疫反应性 的“热肿瘤”提供了新的思路,并且可能成为治疗的新靶点。这种抗肿瘤和促肿瘤的双重作用,似乎与CXCR3变体(CXCR3-A、 CXCR3-B)发挥相反的作用密切相关。本文就近年来CXCR3变体CXCR3-A、CXCR3-B及其配体CXCL9/10/11在TME中作用的 研究进展展开综述。 相似文献
4.
Adenoviral vectors: systemic delivery and tumor targeting 总被引:5,自引:0,他引:5
The development of a targeted adenoviral vector, which can be delivered systemically, is one of the major challenges facing cancer gene therapy. The virus is readily cleared from the bloodstream, can be neutralised by pre-existing antibodies, and has a permissive cellular tropism. Clinical studies using the ONYX virus have shown limited efficacy, but there are several hurdles to overcome to achieve an effective tumor-specific systemic therapy. In this review, we have summarized the various strategies used to overcome the limitations of adenoviral-mediated gene delivery. 相似文献
5.
6.
7.
8.
Turker Yilmaz Tilahun Jiffar Gabriel de la Garza Heather Lin Zvonimir Milas Yoko Takahashi Ehab Hanna Terry MacIntyre Jeffrey L Brown Jeffrey N Myers Michael E Kupferman 《Cancer biology & therapy》2010,10(6):644-653
Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease that has been modestly impacted by improvements in therapeutic strategies. Several lines of evidence support the role of TrkB for invasion and metastasis in various solid tumor models, and we have shown an important function of this receptor in HNSCC tumor biology. Therapeutic modulation of TrkB function has been supported in the literature by the development of small molecule inhibitors (SMI) with minimal success. To assess the validity of targeting TrkB in HNSCC, we tested a novel agent, AZ64 and show significant dose and time-dependent inhibition of cellular proliferation in cell lines. Genetic studies revealed the specificity of this compound for the TrkB receptor, as exposure of cells that had genetic suppression of TrkB did not demonstrate abrogated oncogenic signaling. We next assessed the impact of AZ64 as a chemotherapy-sensitizer and identified an enhancement of cisplatin-mediated anti-proliferation across all cell lines. We then demonstrated that AZ64 can overcome chemotherapy resistance in a novel model of cisplatin resistance in HNSCC. Modulation of the prooncogenic STAT3 and Src pathways was identified, suggesting molecular mechanisms of action for AZ64. In this study, we demonstrate the feasibility of targeting TrkB and suggest a novel approach for the treatment of some chemotherapyresistant HNSCC.Key words: TrkB, cisplatin resistance, squamous cell carcinoma, HNSCC, AZ64, small molecule inhibitor, therapeutic strategies 相似文献
9.
Twenty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose-dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines, and an alternative approach emerged to solve the problem of controlling tumor growth with minimal side effects: targeted therapy. The approach of using long-term antihormone therapy to control early-stage breast cancer growth would revolutionize cancer care by targeting the tumor estrogen receptor (ER). The success of the strategy would contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumor ER with a range of new antiestrogenic drugs would presage the current fashion of blocking survival pathways for the tumor by developing novel targeted treatments. But a surprise was in store when the pharmacology of "antiestrogens" was studied in detail: The nonsteroidal "antiestrogens" are selective ER modulators--ie, they are antiestrogens in the breast, estrogens in the bone--and they lower circulating cholesterol levels. This knowledge would establish a practical approach to breast cancer chemoprevention for women at high risk (tamoxifen) and low risk (raloxifene). 相似文献
10.
Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. 总被引:9,自引:0,他引:9
David C Blakey F Russell Westwood Mike Walker Gareth D Hughes Peter D Davis Sue E Ashton Anderson J Ryan 《Clinical cancer research》2002,8(6):1974-1983
PURPOSE: The purpose of this study was to examine the antitumor effects of the novel vascular targeting agent ZD6126 and to use histology, CD31 immunohistochemistry, and electron microscopy to gain an insight into the mechanism of action of this novel agent. EXPERIMENTAL DESIGN: The antitumor effects of ZD6126 were examined using a range of solid tumor models: (a) ras-transformed mouse 3T3 fibroblasts (Hras5); and (b) human lung (Calu-6), colorectal (LoVo and HT-29), prostate (PC-3), ovarian (SKOV-3), and breast (MDA-MB-231) tumors, grown as xenografts in nude mice. RESULTS: In vivo, a well-tolerated dose of ZD6126 was shown to cause rapid effects on tumor endothelium leading to exposure of the basal lamina after cell retraction and subsequent loss of endothelial cells. This led to thrombosis and vessel occlusion, resulting in extensive tumor necrosis 24 h after ZD6126 administration. Dose-response studies showed that these effects were seen at a dose 8- to 16-fold lower than the maximum tolerated dose, demonstrating that ZD6126 has a wide therapeutic margin in these mouse models. A single dose of ZD6126 (200 mg/kg) led to a significant growth delay in Calu-6 and LoVo tumors. Growth delay was increased when 100 mg/kg ZD6126 was given as a well-tolerated regime in five daily doses. Finally, combining ZD6126 with cisplatin resulted in greater than additive enhancement in growth delay in the Calu-6 model. CONCLUSIONS: These findings provide direct support that ZD6126 selectively disrupts tumor vasculature, demonstrate that it has activity in a range of tumor xenograft models, and show that it can significantly enhance the antitumor efficacy of cisplatin. 相似文献
11.
The role of adhesion molecules, alpha v beta 3, alpha v beta 5 and their ligands in the tumor cell and endothelial cell adhesion. 总被引:2,自引:0,他引:2
Ji Xiao Niu Wen Jian Zhang Li Ya Ye Lian Qiu Wu Guang Jin Zhu Zhi Hua Yang Georges E Grau Jin Ning Lou 《European journal of cancer prevention》2007,16(6):517-527
Tumor metastasis is a complex process involving the interaction between tumor cells and endothelial cells in which some adhesion molecules play an important role. It was our aim to investigate the role of the adhesion molecules, alpha v beta 3 and alpha v beta 5 and their ligands, developmental endothelial locus-1 (Del-1) and L1, in tumor cell adhesion to endothelial cells in vitro. In this study, the expression and regulation of alpha v beta 3, alpha v beta 5 and intercellular adhesion molecule -1 on liver sinusoidal endothelial cells and liver cancer endothelial cells (T3A) were analyzed by real-time PCR and fluorescent-activated cell sorter. The expression and regulation of the integrin ligands, Del-1 and L1, in six tumor cell lines were analyzed by real-time PCR and western blot. We found the expressions of alpha v beta 3 and alpha v beta 5 were higher on T3A than that on liver sinusoidal endothelial cells, whereas expression of intercellular adhesion molecule-1 was lower on T3A than that on liver sinusoidal endothelial cells. After 24 h hypoxia, the expressions of alpha v beta 3 and alpha v beta 5 were upregulated on T3A and liver sinusoidal endothelial cells; the expression of intercellular adhesion molecule-1 was increased on liver sinusoidal endothelial cells, but remained unchanged on T3A. Del-1 and L1 expression levels were obviously diverse in various tumor cell lines and differentially modulated after 12 h hypoxia. The adhesion of tumor cells with Del-1 and L1 expression was higher in T3A than that in liver sinusoidal endothelial cells, and was significantly increased under hypoxic conditions. Interestingly, the tumor cell adherence could be inhibited by antibodies against alpha v beta 5 and alpha v beta 5, but not by an antibody against intercellular adhesion molecule-1. The adhesion of tumor cells without Del-1 and L1 expression was also higher on T3A than that on liver sinusoidal endothelial cells, but the adhesion could not be inhibited by antibodies against alpha v beta 5, alpha v beta 5 or intercellular adhesion molecule-1, suggesting that other receptors are involved. In conclusion, alpha v beta 5, alpha v beta 5 and their ligands Del-1 and L1 play an important role in the process of tumor cells moving from the original place. 相似文献
12.
Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. 总被引:4,自引:0,他引:4
Angelina Sacchi Anna Gasparri Corrado Gallo-Stampino Salvatore Toma Flavio Curnis Angelo Corti 《Clinical cancer research》2006,12(1):175-182
PURPOSE: Subnanogram doses of NGR-tumor necrosis factor (TNF), a TNF-alpha derivative able to target tumor neovessels, can enhance the antitumor activity of doxorubicin and melphalan in murine models. We have examined the antitumor activity of NGR-TNF in combination with various chemotherapeutic drugs acting via different mechanisms, including, besides doxorubicin and melphalan, cisplatin, paclitaxel, and gemcitabine. EXPERIMENTAL DESIGN: Chemotherapeutic drugs were tested alone and in combination with NGR-TNF (0.1 ng) in murine lymphoma, fibrosarcoma, and mammary adenocarcinoma models. Different administration schedules have been tested and the effects on tumor growth, animal weight, tumor perfusion, and cell cytotoxicity have been investigated. RESULTS: Pretreatment with NGR-TNF enhanced the response to all these drugs although to a different extent. The increased efficacy was not accompanied by increased toxicity at least as judged from the loss of animal weight. The synergistic effect was transient, maximal synergism being observed with a 2-hour delay between NGR-TNF and drug administrations in all models and with all drugs tested. NGR-TNF did not increase the in vitro cytotoxicity of chemotherapeutic drugs against tumor cells, suggesting that the in vivo synergism depends on NGR-TNF effects on host cells rather than on tumor cells. CONCLUSIONS: Targeted delivery of low doses of NGR-TNF to the tumor vasculature can increase the efficacy of various drugs acting via different mechanisms. Optimal administration schedule requires 2 hours of pretreatment with NGR-TNF independently from the mechanism of drug cytotoxicity. This work could provide important information for designing clinical studies with NGR-TNF in combination with chemotherapeutic drugs. 相似文献
13.
Small unilamellar liposomes containing methotrexate or methotrexate-gamma-aspartate were conjugated to Staphylococcus aureus protein A and were thus able to bind cell-specific immunoglobulins for targeting to malignant human B- and T-cell lines. We were able to demonstrate enhanced protein A liposome uptake and growth inhibition by targeting with an anti-major histocompatibility complex class II antibody recognizing two different B-cell lines. The enhanced growth inhibition was specific for the targeting antibody and amounted to a 2- to 3-fold lowering of the concentration of drug required to inhibit cell growth by 50% as compared to nontargeted liposomes or liposomes targeted with an antibody not recognizing a cell surface antigen. A strong association between enhanced growth inhibition and liposome internalization as assessed by fluorescent-activated cell sorter analysis of carboxyfluorescein containing protein A liposomes was seen. By contrast, specific enhancement of growth inhibition was not seen with several anti-idiotype antibodies or antibodies to T-cell differentiation antigens. Liposome internalization did not occur with these antibodies. Failure of growth inhibition and PA liposome internalization could not be explained by differences in cell binding of the antibody PA liposomes or the degree of protein A binding of the targeting antibody. Although the ability of the targeting antibody to bind to the cell and to protein A are important, these factors alone are not sufficient to guarantee internalization and growth inhibition. Variations in rates of internalization of various cell surface antigen-antibody complexes may account for different protein A liposome mediated cytotoxicities. 相似文献
14.
Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15 总被引:5,自引:0,他引:5
Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors that share beta and gammac subunits of their receptors on T/NK-cells. Although these two cytokines share receptor components, the IL-15Ralpha molecule is expressed constitutively by various tissue cells, whereas the IL-2Ralpha expression is mostly restricted to activated mononuclear cells. Consequently, we postulated that the biodistribution of IL-15 might be different from that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL-15 in pharmacokinetics, biodistribution, and their tumor-targeting abilities. It found that only IL-2 showed specific binding to a protein, alpha2-macroglobulin, which may be the reason that IL-2 displays longer blood clearance than IL-15. Upon injection of these cytokines into mice, we observed that IL-15 accumulated significantly more than IL-2 in kidney, spleen, and bone. These are all tissues that express IL-15 receptor alpha but not IL-2 receptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells transfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting that the expression of the alpha chains is sufficient to define specific biodistribution of IL-2 and IL-15, although these cytokines share the beta and yc molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent. 相似文献
15.
16.
Dreischalück J Schwöppe C Spieker T Kessler T Tiemann K Liersch R Schliemann C Kreuter M Kolkmeyer A Hintelmann H Mesters RM Berdel WE 《International journal of oncology》2010,37(6):1389-1397
tTF-NGR consists of the extracellular domain of the (truncated) tissue factor (tTF), a central molecule for coagulation in vivo, and the peptide GNGRAHA (NGR), a ligand of the surface protein aminopeptidase N (CD13). After deamidation of the NGR-peptide moiety, the fusion protein is also a ligand for integrin αvβ3 (CD51/CD61). Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR showed binding to specific binding sites on endothelial cells in vitro as shown by flow cytometry. Subcutaneous injection of tTF-NGR into athymic mice bearing human HT1080 fibrosarcoma tumors induced tumor growth retardation and delay. Contrast enhanced ultrasound detected a decrease in tumor blood flow in vivo after application of tTF-NGR. Histological analysis of the tumors revealed vascular disruption due to blood pooling and thrombotic occlusion of tumor vessels. Furthermore, a lack of resistance was shown by re-exposure of tumor-bearing mice to tTF-NGR after regrowth following a first cycle of treatment. However, after subcutaneous (s.c.) push injection with therapeutic doses (1-5 mg/kg bw) side effects have been observed, such as skin bleeding and reduced performance. Since lethality started within the therapeutic dose range (LD10 approximately 2 mg/kg bw) no safe therapeutic window could be found. Limiting toxicity was represented by thrombo-embolic events in major organ systems as demonstrated by histology. Thus, subcutaneous injection of tTF-NGR represents an active, but toxic application procedure and compares unfavourably to intravenous infusion. 相似文献
17.
Marilena Greco Marianna De Mitri Fernanda Chiriac Giuseppe Leo Ettore Brienza Michele Maffia 《Cancer letters》2009,283(2):222-229
Currently clinical outcome in melanoma is not predictable by known serum biomarkers. The only reliable tool for the diagnosis of this tumor is the histopathological assay after surgical removing.We used a proteomic approach in order to identify novel non-invasive serum biomarkers of melanoma.Serum proteomic maps showed different patterns in relation to the presence and progression of the tumor in five regions of the map. Differently expressed spots were identified by MALDI-TOF mass spectrometry. Significant increases of expression were found for transthyretin (TTR) and angiotensinogen (AGT) while vitamin D binding protein (DBP) expression was decreased in presence of melanoma. Interestingly, protein expression came back to control values in stages I and II of the disease after 1 month since surgical removal of suspected melanoma. We related the decrease of DBP spot to the impaired immune response of cancer patients. In fact cancer cells release the alpha-N-acetylgalactosaminidase that can deglycosylate DBP thus interfering with the immune cascade response in which DBP is involved, leading to immunosuppression in melanoma patients. Specific enzymatic activity of serum alpha-N-acetylgalactosaminidase was significantly increased in stage III melanoma patients, but not in early stages. This enzymatic assay may provide a non-invasive way of evaluation of melanoma severity. 相似文献
18.
Alteration of glycine N-methyltransferase activity in fetal, adult, and tumor tissues. 总被引:2,自引:0,他引:2
Glycine N-methyltransferase activity has been examined in a number of fetal and adult organs, as well as in several rodent hepatomas, using both enzymatic and immunological techniques. In fetal rabbit liver, the activity first appears at a low level at about 20 days postfertilization and rises to high levels after birth, reaching maximum in the adult liver. In fast-growing hepatomas, the activity could not be detected by either enzymatic or immunological assay. It could be detected in the slower-growing hepatomas, but in considerably diminished levels compared with that of normal adult rat liver. Immunoassays gave no evidence for inactive forms of the enzyme in the tissues that had no enzymatic activity. Transfer RNA methyltransferase assays carried out simultaneously showed an inverse relationship to the glycine N-methyltransferase activity. The levels of transfer RNA methyltransferase activity were high in fetal and tumor tissues and lower in normal adult tissues. 相似文献
19.
R24 is an IgG3 mouse monoclonal antibody which recognizes the ganglioside GD3. Two variants of R24, in which one (V2-R24) or both (V1-R24) light chains were substituted by MOPC-21 light chains, were isolated and characterized. R24 had a 40-fold higher avidity for GD3 than either variant, suggesting that high avidity binding required the presence of two R24 light chains and, thus, divalency. R24 and both variants mediated antibody-dependent cellular cytotoxicity but antibody-dependent cellular cytotoxicity mediated by variants was weak compared to R24. The presence of at least one R24 light chain was required for complement-dependent cytotoxicity; complement-dependent cytotoxicity was mediated by R24 and weakly by V2-R24 but not by V1-R24. R24, but not V1-R24 or V2-R24, inhibited attachment of melanoma cells to plastic and activated T-lymphocytes, suggesting a threshold of avidity required for these biological effects. In a human melanoma xenograft model in nu/nu mice, radiolabeled R24, variants, and isotype-matched control monoclonal antibodies all appeared to localize in tumors (based on tumor:normal tissue ratios), but specific tumor targeting by R24 was generally 3- to 6-fold higher. R24 prevented melanoma outgrowth in nu/nu mice, while V2-R24 induced partial tumor protection. V1-R24 and the negative control monoclonal antibody did not inhibit tumor outgrowth. Antitumor activity of R24 corresponded to avidity and ability to mediate complement-dependent cytotoxicity in vitro. 相似文献
20.
Identification of novel human CTL epitopes and their agonist epitopes of mesothelin. 总被引:1,自引:0,他引:1
Junko Yokokawa Claudia Palena Philip Arlen Raffit Hassan Mitchell Ho Ira Pastan Jeffrey Schlom Kwong Y Tsang 《Clinical cancer research》2005,11(17):6342-6351
PURPOSE: Mesothelin is overexpressed in many pancreatic and ovarian cancers, mesotheliomas, and other tumor types. Clinical trials are ongoing using immunotoxins to target mesothelin, and patients immunized with allogeneic pancreatic tumor cell lines have shown immune responses to previously defined mesothelin epitopes. The purpose of this study was to define novel mesothelin CTL epitopes and, more importantly, agonist epitopes that would more efficiently activate human T cells to more efficiently lyse human tumors. EXPERIMENTAL DESIGN AND RESULTS: Two novel mesothelin HLA-A2 epitopes were defined. T-cell lines generated from one of these epitopes were shown to lyse pancreatic and ovarian tumor cells. Several agonist epitopes were defined and were shown to (a) have higher affinity and avidity for HLA-A2, (b) activate mesothelin-specific T cells from normal individuals or cancer patients to a greater degree than the native epitope in terms of induction of higher levels of IFN-gamma and the chemokine lymphotactin, and (c) lyse several mesothelin-expressing tumor types in a MHC-restricted manner more effectively than T cells generated using the native peptide. External beam radiation of tumor cells at nontoxic levels was shown to enhance the expression of mesothelin and other accessory molecules, resulting in a modest but statistically significant increase in tumor cell lysis by mesothelin-specific T cells. CONCLUSIONS: The identification of novel CTL agonist epitopes supports and extends observations that mesothelin is a potential target for immunotherapy of pancreatic and ovarian cancers, as well as mesotheliomas. 相似文献